IPCS INCHEM Home



    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 94



    PERMETHRIN








    This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1990


         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of
    chemicals.

    WHO Library Cataloguing in Publication Data

    Permethrin.

        (Environmental health criteria ; 94)

        1.Pyrethrins.  I.Series

        ISBN 92 4 154294 2        (NLM Classification: WA 240)
        ISSN 0250-863X

         The World Health Organization welcomes requests for permission
    to reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made
    to the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1990

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material
    in this publication do not imply the expression of any opinion
    whatsoever on the part of the Secretariat of the World Health
    Organization concerning the legal status of any country, territory,
    city or area or of its authorities, or concerning the delimitation
    of its frontiers or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar
    nature that are not mentioned. Errors and omissions excepted, the
    names of proprietary products are distinguished by initial capital
    letters.


CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR PERMETHRIN

INTRODUCTION

1. SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATION 

   1.1. Summary and evaluation  
        1.1.1. Identity, physical and chemical properties, analytical 
               methods 
        1.1.2. Production and use   
        1.1.3. Human exposure   
        1.1.4. Environmental fate   
        1.1.5. Kinetics and metabolism  
        1.1.6. Effects on organisms in the environment  
        1.1.7. Effects on experimental animals and  in vitro test systems  
        1.1.8. Effects on human beings  
   1.2. Conclusions      
        1.2.1. General population   
        1.2.2. Occupational exposure    
        1.2.3. Environment  
   1.3. Recommendations  

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS   

   2.1. Chemical identity   
   2.2. Physical and chemical properties    
   2.3. Analytical methods  

3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE; ENVIRONMENTAL LEVELS

   3.1. Industrial production   
   3.2. Use pattern      
   3.3. Residues in food and other products 
   3.4. Residues in the environment 

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION    

   4.1. Transport and distribution between media    
   4.2. Photodecomposition  
   4.3. Degradation in plants   
   4.4. Degradation in soils    

5. KINETICS AND METABOLISM  

   5.1. Metabolism in mammals   
        5.1.1. Mouse     
        5.1.2. Rat       
        5.1.3. Goat      
        5.1.4. Cow       
        5.1.5. Man       
   5.2. Metabolism in hens  
   5.3. Enzymatic systems for biotransformation 

6. EFFECTS ON THE ENVIRONMENT   

   6.1. Toxicity to aquatic organisms   
        6.1.1. Aquatic microorganisms   
        6.1.2. Aquatic invertebrates    
        6.1.3. Fish      
        6.1.4. Field studies and community effects  
   6.2. Toxicity to terrestrial organisms   
        6.2.1. Soil microorganisms  
        6.2.2. Terrestrial invertebrates    
        6.2.3. Birds     
        6.2.4. Mammals   
   6.3. Uptake, loss, bioaccumulation, and biomagnification 

7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS    

   7.1. Acute toxicity   
   7.2. Subacute and subchronic toxicity    
        7.2.1. Oral exposure    
               7.2.1.1 Mouse
               7.2.1.2 Rat  
               7.2.1.3 Dog  
               7.2.1.4 Rabbit   
               7.2.1.5 Cow  
        7.2.2. Dermal exposure  
        7.2.3. Inhalation exposure  
   7.3. Primary irritation  
        7.3.1. Skin irritation  
        7.3.2. Eye irritation   
   7.4. Sensitization    
   7.5. Long-term toxicity  
        7.5.1. Mouse     
        7.5.2. Rat       
   7.6. Carcinogenesis   
        7.6.1. Mouse     
               7.6.1.1 ICI study    
               7.6.1.2 FMC II study 
               7.6.1.3 BW study 
               7.6.1.4 Appraisal of mouse studies on carcinogenicity
        7.6.2. Rat       
               7.6.2.1 ICI study    
               7.6.2.2 BW study 
               7.6.2.3 Appraisal of rat studies on carcinogenicity  
   7.7. Mutagenicity     
        7.7.1. Microorganism and insects    
        7.7.2. Mammals   
   7.8. Teratogenicity and reproduction studies 
        7.8.1. Teratogenicity studies   
               7.8.1.1  Mouse   
               7.8.1.2  Rat 
               7.8.1.3  Rabbit  
        7.8.2. Reproduction studies 
               7.8.2.1  Rat 
   7.9. Neurotoxicity    
        7.9.1. Rat       
        7.9.2. Hen       

   7.10. Behavioural effects 
   7.11. Miscellaneous studies   
   7.12. Mechanism of toxicity (mode of action)  

8. EFFECTS ON HUMANS     

   8.1. Occupational exposure   
   8.2. Clinical studies 

9. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES 

REFERENCES          

APPENDIX I          

FRENCH TRANSLATION OF SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR PERMETHRIN

 Members

Dr V. Benes,  Department of Toxicology and Reference Laboratory, Insti-
   tute of Hygiene and Epidemiology, Prague, Czechoslovakia

Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood Experimental
   Station, Huntingdon, United Kingdom

Dr Y. Hayashi,  Division of Pathology,  National Institute of  Hygienic
   Sciences, Tokyo, Japan

Dr S. Johnson,  Hazard  Evaluation  Division, Office  of Pesticide Pro-
   gramme,  US  Environmental  Protection Agency,  Washington  DC,  USA
    (Chairman)

Dr S.K. Kashyap,  National  Institute  of  Occupational  Health  (ICMR)
   Ahmedabad, India  (Vice-Chairman)

Dr Yu. I. Kundiev,  Research  Institute  of Labour,  Hygiene, and Occu-
   pational Diseases, Kiev, USSR

Dr J.P. Leahey,  ICI  Agrochemicals,  Jealotts Hill  Research  Station,
   Bracknell, United Kingdom  (Rapporteur)

Dr J. Miyamoto,  Takarazuka Research Centre, Sumitomo Chemical Company,
   Takarazuka, Hyogo, Japan

Dr Y. Takenaka,  Division of Information  on Chemical Safety,  National
   Institute of Hygienic Sciences, Tokyo, Japan

 Representatives of Other Organizations

Dr M. Ikeda,  International Commission on Occupational  Health. Depart-
   ment of Environmental Health, Tohoku University, School of Medicine,
   Sendai, Japan

Dr H. Naito,  World Federation of  Poison Control Centres  and Clinical
   Toxicology.  Institute of Clinical Medicine,  University of Tsukuba,
   Tsukuba-Shi, Ibaraki, Japan

 Observers

Dr M. Matsuo,  Sumitomo  Chemical  Company, Biochemistry  &  Toxicology
   Laboratory, Osaka, Japan

Dr Y. Okuno,  Sumitomo  Chemical  Company,  Biochemistry  &  Toxicology
   Laboratory, Osaka, Japan

Dr N. Punja,  International Group of  National Association of  Manufac-
   turers  of  Agrochemical  Products  (GIFAP),  ICI  Plant  Protection
   Division, Fenhurst, Haslemere, United Kingdom

 Secretariat

Dr K.W. Jager, International Programme on Chemical Safety, World Health
   Organization, Geneva, Switzerland  (Secretary)

Dr R. Plestina,  Division of Vector Control, Delivery and Management of
   Vector Control, World Health Organization, Geneva, Switzerland

Dr J. Sekizawa,  Section of Information and  Investigation, Division of
   Information  on  Chemical  Safety, National  Institute  of  Hygienic
   Sciences, Tokyo, Japan  (Rapporteur)

NOTE TO READERS OF THE CRITERIA DOCUMENTS

    Every effort has been made to present information in  the  criteria
documents  as accurately as possible without unduly delaying their pub-
lication.   In the interest  of all users  of the environmental  health
criteria  documents, readers are  kindly requested to  communicate  any
errors  that may have occurred to the Manager of the International Pro-
gramme  on Chemical Safety, World Health Organization, Geneva, Switzer-
land,  in  order that  they may be  included in corrigenda,  which will
appear in subsequent volumes.


                              *   *   *


    A detailed data profile and a legal file can be obtained  from  the
International  Register  of  Potentially Toxic  Chemicals,  Palais  des
Nations,   1211  Geneva  10,  Switzerland  (Telephone  No.  7988400  or
7985850).


                             *   *   *


    The  proprietary  information  contained in  this  document  cannot
replace documentation for registration purposes, because the latter has
to  be closely linked  to the source,  the manufacturing route  and the
purity/impurities of the substance to be registered.  The  data  should
be  used  in  accordance  with  paragraphs  82-84  and  recommendations
paragraph 90 of the Second FAO Government Consultation (FAO, 1982).

ENVIRONMENTAL HEALTH CRITERIA FOR PERMETHRIN

    A  WHO Task Group on Environmental Health Criteria for Fenvalerate,
Permethrin,  and d-Phenothrin met in Tokyo from 4 to 8 July 1988.  This
meeting was convened with the financial assistance of the  Ministry  of
Health and Welfare, Tokyo, Japan, and was hosted by the National Insti-
tute of Hygienic Sciences (NIHS) in Tokyo.

    Dr  T.  Furukawa  and Dr K. Shirota opened the meeting on behalf of
the Ministry of Health and Welfare, and Dr A.  Tanimura,  Director-Gen-
eral  of the NIHS  welcomed the participants  to the Institute.   Dr M.
Mercier, Manager of the International Programme on Chemical Safety wel-
comed the participants on behalf of the three IPCS  cooperating  organ-
izations (UNEP/ILO/WHO). The group reviewed and revised the draft mono-
graph  and  made an  evaluation of the  risks for human  health and the
environment from exposure to permethrin.

    The first draft of this document was prepared by DR J. MIYAMOTO and
DR M. MATSUO  of Sumitomo Chemical Company  with the assistance of  the
staff  of the National  Institute of Hygienic  Sciences, Tokyo,  Japan.
Dr I. Yamamoto  of the Tokyo University of Agriculture and Dr M. Eto of
Kyushu  University, Japan, assisted with the finalization of the draft.
The  second draft was prepared  by DR J. SEKIZAWA, NIHS, Tokyo,  incor-
porating  comments received following circulation of the first draft to
the  IPCS contact points  for Environmental Health  Criteria documents.
Dr  K.W. Jager and Dr  P.G. Jenkins, both members  of the IPCS  Central
Unit,  were  responsible for  the  technical development  and  editing,
respectively, of this monograph.

    The  assistance of the  Sumitomo Chemical Company,  Japan, and  ICI
Agrochemicals,  United Kingdom, in making available to the IPCS and the
Task Group their toxicological proprietary information on permethrin is
gratefully  acknowledged.  This  allowed the  Task Group  to  make  its
evaluation on the basis of more complete data.

                              *   *   *

    The  United  Kingdom  Department  of  Health  and  Social  Security
generously supported the cost of printing.

ABBREVIATIONS

ai             active ingredient

Cl2CA          3-(2,2-dichlorovinyl)-2,2-dimethylcyclopro-
               panecarboxyclic acid

ECG            electrocardiogram

EEG            electroencephalogram

FID            flame ionization detector

GC             gas chromatography

GC-ECD         gas chromatography with electron capture
               detector

GC-SIM         gas chromatography with selected ion
               monitoring

GLC            gas-liquid chromatography

HPLC           high-performance liquid chromatography

JMPR           Joint FAO/WHO Meeting on Pesticide Residues

NOEL           no-observed-effect level

PBacid         3-phenoxybenzoic acid

PBalc          3-phenoxybenzyl alcohol

PBald          3-phenoxybenzaldehyde

TLC            thin-layer chromatography

INTRODUCTION

SYNTHETIC PYRETHROIDS - A PROFILE

1.  During  investigations to modify the chemical structures of natural
    pyrethrins, a certain number of synthetic pyrethroids were produced
    with improved physical and chemical properties and greater biologi-
    cal  activity.  Several of  the earlier synthetic  pyrethroids were
    successfully  commercialized, mainly for  the control of  household
    insects.   Other more recent  pyrethroids have been  introduced  as
    agricultural  insecticides  because  of  their  excellent  activity
    against a wide range of insect pests and their  non-persistence  in
    the environment.

2.  The  pyrethroids constitute another  group of insecticides  in  ad-
    dition  to  organochlorine, organophosphorus,  carbamate, and other
    compounds.   Pyrethroids  commercially  available to  date  include
    allethrin,  resmethrin, d-phenothrin, and tetramethrin (for insects
    of  public  health  importance),  and  cypermethrin,  deltamethrin,
    fenvalerate,  and  permethrin  (mainly for  agricultural  insects).
    Other pyrethroids are also available including furamethrin, kadeth-
    rin, and tellallethrin (usually for household insects), fenpropath-
    rin,  tralomethrin,  cyhalothrin,  lambda-cyhalothrin,  tefluthrin,
    cyfluthrin, flucythrinate, fluvalinate, and biphenate (for agricul-
    tural insects).

3.  Toxicological  evaluations  of  several synthetic  pyrethroids have
    been performed by the FAO/WHO Joint Meeting on  Pesticide  Residues
    (JMPR).   The acceptable daily intake  (ADI) has been estimated  by
    the  JMPR for cypermethrin, deltamethrin,  fenvalerate, permethrin,
    d-phenothrin, cyfluthrin, cyhalothrin, and flucythrinate.

4.  Chemically,  synthetic  pyrethroids  are esters  of  specific acids
    (e.g.,  chrysanthemic acid, halo-substituted chrysanthemic acid, 2-
    (4-chlorophenyl)-3-methylbutyric    acid)   and   alcohols   (e.g.,
    allethrolone,  3-phenoxybenzyl alcohol).  For  certain pyrethroids,
    asymmetric centre(s) exist in the acid and/or alcohol  moiety,  and
    the  commercial products  sometimes consist  of a  mixture of  both
    optical (1R/1S or d/1) and geometric (cis/trans) isomers.  However,
    most  of the insecticidal activity  of such products may  reside in
    only one or two isomers.  Some of the products (e.g., d-phenothrin,
    deltamethrin) consist only of such active isomer(s).

5.  Synthetic pyrethroids are neuropoisons acting on the axons  in  the
    peripheral and central nervous systems by interacting  with  sodium
    channels in mammals and/or insects.  A single dose  produces  toxic
    signs  in mammals, such as  tremors, hyperexcitability, salivation,
    choreoathetosis,  and paralysis.  The  signs disappear fairly  rap-
    idly, and the animals recover, generally within a week.   At  near-
    lethal  dose levels, synthetic pyrethroids  cause transient changes
    in  the nervous system, such  as axonal swelling and/or  breaks and
    myelin  degeneration in sciatic nerves.  They are not considered to
    cause  delayed neurotoxicity of  the kind induced  by some  organo-
    phosphorus  compounds.   The  mechanism of  toxicity  of  synthetic
    pyrethroids and their classification into two types  are  discussed
    in the Appendix.

6.  Some  pyrethroids  (e.g.,  deltamethrin, fenvalerate,  cyhalothrin,
    lambda-cyhalothrin,  flucythrinate,  and cypermethrin)  may cause a
    transient itching and/or burning sensation in exposed human skin.

7.  Synthetic  pyrethroids are generally metabolized in mammals through
    ester hydrolysis, oxidation, and conjugation, and there is no tend-
    ency to accumulate in tissues.  In the environment,  synthetic  py-
    rethroids are fairly rapidly degraded in soil and in plants.  Ester
    hydrolysis and oxidation at various sites on the molecule  are  the
    major degradation processes.  The pyrethroids are strongly adsorbed
    on  soil  and sediments,  and hardly eluted  with water.  There  is
    little tendency for bioaccumulation in organisms.

8.  Because  of low  application rates  and rapid  degradation  in  the
    environment, residues in food are generally low.

9.  Synthetic pyrethroids have been shown to be toxic for fish, aquatic
    arthropods,  and honey bees in laboratory tests.  But, in practical
    usage,  no serious adverse effects have been noticed because of the
    low  rates of application and  lack of persistence in  the environ-
    ment.   The toxicity of synthetic pyrethroids in birds and domestic
    animals is low.

10. In  addition to the evaluation documents of FAO/WHO, there are sev-
    eral good reviews and books on the chemistry, metabolism, mammalian
    toxicity,  environmental  effects,  etc. of  synthetic pyrethroids,
    including  those  by Elliott  (1977),  Miyamoto (1981),  Miyamoto &
    Kearney (1983), and Leahey (1985).

1.  SUMMARY AND EVALUATION, CONCLUSIONS, RECOMMENDATION

1.1  Summary and Evaluation

1.1.1  Identity, physical and chemical properties, analytical methods

    Permethrin  was first synthesized in 1973 and marketed in 1977 as a
photostable  pyrethroid.  It is  an ester of  the dichloro analogue  of
chrysanthemic acid, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-carb-
oxylic acid (Cl2CA),   and 3-phenoxybenzyl alcohol.  Technical products
are a mixture of four stereoisomers with the configurations [1R,trans],
[1R,cis], [1S,trans], and [1S,cis] in the approximate ratio of 3:2:3:2.
The ratio of cis:trans is around 2:3 and 1R:1S is 1:1  (racemic).   The
[1R,cis]  isomer is  the most  insecticidally active  of  the  isomers,
followed by the [1R,trans] isomer.

    Technical  grade permethrin is  a brown or  yellowish brown  liquid
which may crystallize partly at room temperature.  The melting point is
approximately  35°C and the boiling  point is 220°C at  0.05 mmHg.  The
specific gravity is 1.214 at 25°C and the  vapour pressure  is  1.3 µPa
at  20°C.  Permethrin  is almost  insoluble in  water (0.2 mg/litre  at
30°C),  but is soluble in organic solvents such as acetone, hexane, and
xylene.   It is  stable to  light and  heat, but  unstable in  alkaline
media.

    Residue  and  environmental  analyses  are  performed  using  a gas
chromatograph  equipped  with  an electron  capture  detector  (minimum
detectable  concentration of 0.005 mg/kg).  Technical products are ana-
lysed using a gas chromatograph with a flame ionization detector.

1.1.2   Production and use

    Approximately  600 tonnes per year of permethrin is at present used
world-wide, mostly for agricultural purposes. It has a potential appli-
cation in the protection of stored grain and it has been used in aerial
application for forest protection and vector control, for  the  control
of noxious insects in the household and on cattle, for the  control  of
body lice, and in mosquito nets.

    Permethrin  is  formulated as  emulsifiable concentrate, ultra-low-
volume concentrate, wettable powder, and dustable powder.

1.1.3  Human exposure

    The  rate of decline of  residue levels in various  crops is fairly
slow, half-lives ranging from about 1 to 3 weeks depending on the crop.
However, when permethrin is used as recommended, there is  no  signifi-
cant increase in residues following repeated application.

    Exposure  of the  general population  to permethrin  is mainly  via
dietary residues. Residue levels in crops grown according to good agri-
cultural  practice are generally  low.  The resulting  exposure of  the
general  population is expected to be low, but precise data in the form
of total-diet studies is lacking.

    Information  on occupational exposure  to permethrin is  very  lim-
ited.

1.1.4  Environmental fate

    In laboratory studies, permethrin has been shown to degrade in soil
with  a half-life of 28 days  or less.  The trans  isomer degraded more
rapidly  than the cis  isomer, ester cleavage  being the major  initial
degradative reaction.  The compounds generated by ester  cleavage  were
then  further oxidised, eventually yielding carbon dioxide as the major
terminal  product.  Studies to  investigate the leaching  potential  of
permethrin and its degradates showed that very little downward movement
occurs in soil.

    Permethrin  deposited  on  plants  degrades  with  a  half-life  of
approximately  10 days.  Ester cleavage and conjugation of the acid and
alcohol  released is the  major degradation pathway.   Hydroxylation at
various  positions of the  molecule and photo-induced  cis-trans inter-
conversion also occur.

    In water and on soil surfaces permethrin is photodegraded  by  sun-
light.   Ester  cleavage and  cis-trans  interconversion are,  as  with
plants, the major reactions.

    In general, the degradative processes which occur in  the  environ-
ment lead to less toxic products.

    Permethrin  disappears rapidly from the environment, in 6-24 h from
ponds  and streams, 7 days from pond sediment, and 58 days from foliage
and soil in a forest.  From cotton leaves in a field, 30% of  the  com-
pound was lost within 1 week.

    Under  aerobic conditions in soil, permethrin degrades with a half-
life of 28 days.

    There is very little movement of permethrin in the environment, and
it is unlikely that it will attain significant levels in  the  environ-
ment.

1.1.5   Kinetics and metabolism

    Permethrin  administered  to  mammals was  rapidly  metabolized and
almost  completely excreted in  urine and faeces  within 12 days.   The
trans isomer, being much more susceptible to esterase attack  than  the
cis isomer, was eliminated faster than the cis isomer.  The major meta-
bolic  reactions were ester cleavage and oxidation, particularly at the
terminal  aromatic ring  of the  phenoxybenzyl moiety  and the  geminal
dimethyl group of the cyclopropane ring, followed by conjugation.  Less
than  0.7% of the dose was detected in the milk of goats or cows admin-
istered permethrin orally.

1.1.6  Effects on organisms in the environment

    In laboratory tests, permethrin has been shown to be  highly  toxic
for  aquatic arthropods, LC50 values  ranging from 0.018 µg/litre   for
larval  stone crabs to  1.26 µg/litre   for a  cladoceran.  It is  also

highly toxic for fish, with 96-h LC50 values ranging from 0.62 µg/litre
for  larval rainbow trout  to 314 µg/litre   for  adult rainbow  trout.
The  no-observed-effect level for early  life stages of the  sheepshead
minnow  over 28 days is 10 µg/litre    and the chronic no-effect  level
for fathead minnow is 0.66-1.4 µg/litre.    Permethrin is less toxic to
aquatic molluscs and amphibia, 96-h LC50 values being >1000 µg/litre and
7000 µg/litre, respectively.

    In  field tests and in the use of the compound under practical con-
ditions,  this high potential toxicity is not manifested.  An extensive
literature  exists on the effects  of using permethrin in  agriculture,
forestry,  and in  vector control  in many  parts of  the world.   Some
aquatic  arthropods are killed, particularly when water is over-sprayed
but the effects on populations of organisms is temporary.   There  have
been  no reports of fish killed in the field.  This reduced toxicity in
the  field is related to the strong adsorption of the compound to sedi-
ments and its rapid degradation.  Sediment-bound permethrin is toxic to
burrowing organisms but this effect also is temporary.

    Permethrin is highly toxic for honey bees.  The topical  LD50    is
0.11 µg/bee,    but there is a strong repellent effect of permethrin to
bees  which reduced the toxic effect in practice.  There is no evidence
for  significant kills of honey  bees under normal use.   Permethrin is
more toxic to predator mites than to the target pest species.

    Permethrin  has very low toxicity to birds when given orally or fed
in  the diet.  The  LD50 is  >3000 mg/kg body  weight for acute  single
oral dosage and for dietary exposure it is >5000 mg/kg diet.  It has no
effect on reproduction in the hen at a dose of 40 mg/kg diet.

    Permethrin  is readily taken  up by aquatic  organisms,  bioconcen-
tration factors ranging from 43 to 750 for various organisms.   In  all
the aquatic organisms studied, absorbed permethrin is rapidly  lost  on
transfer  to clean water.  There  is no bioaccumulation in  birds.  The
compound  can,  therefore, be  regarded as having  no tendency to  bio-
accumulate in practice.

1.1.7   Effects on experimental animals and  in vitro test systems

    Permethrin  has a low  acute toxicity to  rats, mice, rabbits,  and
guinea-pigs,  though the LD50 value   varies considerably according  to
the  vehicle  used and  the cis:trans isomeric  ratio.  Signs of  acute
poisoning  become apparent within 2 h  of dosing and persist  for up to
3 days.   [1R, cis ]-  and [1R, trans ]-permethrin  belong  to the type I
group  of pyrethroids, which typically cause tremor (T-syndrome), inco-
ordination, hyperactivity, prostration, and paralysis. Core temperature
is markedly increased during poisoning.

    None of the metabolites of permethrin shows a higher acute (oral or
intraperitoneal) toxicity than permethrin itself.

    Permethrin  caused a  mild primary  irritation of  the  intact  and
abraded  skin of rabbits but  did not cause a  photochemical irritation
reaction after exposure of treated areas of rabbit skin to ultra-violet
light.   Permethrin did not cause  a sensitization reaction in  guinea-
pigs.

    Oral  subacute and subchronic  toxicity studies of  permethrin have
been  performed in rats and mice at dose levels up to 10 000 mg/kg diet
and  for 14 days  to 26 weeks  in duration.   Changes detected  at  the
higher level were an increase in liver/body weight  ratio,  hypertrophy
in  the liver, and clinical signs of poisoning such as tremor.  The no-
observed-effects  levels (NOEL) in rats  ranged from 20 mg/kg diet  (in
studies lasting 90 days or 6 months) to 1500 mg/kg diet (in  a  6-month
study).

    NOEL  values  in dogs  ranged from 5 mg/kg  body weight in  3-month
studies to 250 mg/kg body weight in 6-month studies.

    In  long-term studies in mice and rats, an increase in liver weight
was  found which was considered  to be associated with  an induction of
the liver microsomal enzyme system.

    The NOEL in a 2-year rat study was 100 mg/kg diet, corresponding to
5.0 mg/kg body weight.

    There  were  indications, from  three  long-term mouse  studies, of
oncogenicity  in the lungs of one strain of mouse (females only) at the
highest dose level (5 g/kg diet). Studies in rats revealed no oncogenic
potential in either sex.

    Permethrin was not mutagenic in  in vivo or  in vitro studies.

    Toxicological evidence from mutagenicity studies and from long-term
mouse and rat studies suggests that permethrin's oncogenic potential is
very low, is limited to female mice, and is probably epigenetic.

    Permethrin  is not teratogenic  to rats, mice,  or rabbits at  dose
levels up to 225, 150, and 1800 mg/kg body weight, respectively.

    In  a 3-generation reproduction  study, permethrin did  not  induce
adverse effects at levels up to 2500 mg/kg diet.

    Permethrin fed to rats at high dose levels  (6600-7000 mg/kg  diet)
for  14 days induced  sciatic nerve  damage in  one study  but did  not
produce  any ultrastructural changes  in the sciatic  nerve in  another
study.  Permethrin did not cause delayed neurotoxicity in hens.

1.1.8  Effects on human beings

    Permethrin can induce skin sensations and paraesthesia  in  exposed
workers, which develop after a latent period of  approximately  30 min,
peak by 8 h and disappear within 24 h. Numbness, itching, tingling, and
burning are symptoms frequently reported.

    No poisoning cases have been reported.

    The  likelihood of oncogenic effects  in human beings is  extremely
low or non-existent.

    There are no indications that permethrin has an adverse  effect  on
human beings when used as recommended.

1.2  Conclusions

1.2.1  General population

    The exposure of the general population to permethrin is expected to
be  low. It is not  likely to present a  hazard provided it is  used as
recommended.

1.2.2  Occupational exposure

    With reasonable work practices, hygiene measures, and  safety  pre-
cautions, permethrin is unlikely to present a hazard to  those  exposed
occupationally.

1.2.3  Environment

    It  is unlikely that  permethrin or its  degradation products  will
attain  levels of environmental significance  provided that recommended
application  rates are used.  Under laboratory conditions permethrin is
highly  toxic to fish,  aquatic anthropods, and  honey bees.   However,
lasting  adverse effects are not likely to occur under field conditions
provided it is used as recommended.

1.3  Recommendations

    Although  dietary levels arising  from recommended usage  are  con-
sidered to be low, confirmation of this through inclusion of permethrin
in monitoring studies should be considered.

    No adverse effects have been reported following human  exposure  to
permethrin during the many years of its use.  Nevertheless, it would be
wise to maintain observations of human exposure.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1   Chemical Identity

    Permethrin   was  synthesized  as   one  of  the   new  photostable
pyrethroids by Elliott et al. (1973). It is prepared by  the  esterifi-
cation of the dichloro analogue of chrysanthemic acid,   i.e.  (1R, cis;
1R, trans;  1S, cis; 1S, trans )-3-(2,2-dichlorovinyl)-2,2-dimethyl-cyclo-
propanecarboxyclic acid (Cl2CA), with 3-phenoxybenzyl  alcohol (PBalc).  
It contains four stereoisomers due to the chirality of the cyclopropane
ring (Fig. 1). The cis:trans isomer ratio is reported to be 2:3 and the
optical  ratio  of  1R:1S is  1:1  (racemic)  (FAO/WHO, 1980b).   Thus,
permethrin  contains the [1R,trans], [1R,cis], [1S,trans], and [1S,cis]
isomers  in the approximate  ratio of 3:2:3:2.   Table 1 gives  further
details of the chemical identity of permethrin.

    The  [1R,cis] isomer is  the most insecticidally  active among  the
isomers, followed by the [1R,trans] isomer.

Molecular formula:  C21H20Cl2O3

Chemical Structure

FIGURE 1


Table 1.  Chemical identity of permethrin and its various stereoisomeric compositions
------------------------------------------------------------------------------------------------------
Common name/           CAS Index name (9Cl)                     Stereoisomeric    Synonyms and
CAS Registry No./                                               compositionc      trade names
NIOSH Accession No.a   Stereospecific nameb
------------------------------------------------------------------------------------------------------
Permethrin             Cyclopropanecarboxylic acid,             (1):(2):(3):(4)   Permethrina, Ambush,
52645-53-1             3-(2,2-dichloroethenyl)-2,2-dimethyl-,   =3:2:3:2          Pounce, Outflank,
GZ1255000              (3-phenoxyphenyl)methyl ester                              Extin, Ectiban,
                                                                                  Stockade, NRDC143,
                       3-Phenoxybenzyl (1RS, cis,trans )-3-                        FMC33297, S-3151,
                       (2,2-dichlorovinyl)-2,2-dimethyl-                          SBP-1513, PP557,
                       cyclopropanecarboxylate                                    A13-29158, BW-21-Z

(+)- cis -Permethrin    same as permethrin                       -                 -
54774-45-7
GZ1257000              3-Phenoxybenzyl (1R, cis )-                    
                       3-(2,2-dichlorovinyl)-2,2-dimethyl-
                       cyclopropanecarboxylate

Permethrin             same as permethrin                        cis:trans =2:3    -
(racemic mixture)
-                      3-Phenoxybenzyl (1R, cis,trans)-3-
GZ1261000              (2,2-dichlorovinyl)-2,2-dimethyl-
                       cyclopropanecarboxylate

(+)- trans -Permethrin  same as permethrin                       -                 -
51877-74-8
GZ1260000              3-Phenoxybenzyl (1R, trans )-3-
                       (2,2-dichlorovinyl)-2,2-dimethyl-
                       cyclopropanecarboxylate

 cis-Permethrin         same as permethrin
61949-76-6
GZ1251540              3-Phenoxybenzyl (1RS, cis )-3-            -                 -
                       (2,2-dichlorovinyl)-2,2-dimethyl-
                       cyclopropanecarboxylate
------------------------------------------------------------------------------------------------------
a   Registry of Toxic Effects of Chemical Substances (RTECS) (1981-1982 edition).
b   (1R), (+) or (1S), (-) in the acid part of permethrin signifies the same stereospecific 
    conformation, respectively.
c   Numbers in parentheses identify the structures shown in Fig. 1.
2.2   Physical and Chemical Properties

    The  physical  and  chemical  properties  of  technical  permethrin
(cis/trans  isomeric  ratio  = 40:60,  purity  not  less than  89%) are
summarized  in Table 2.  Permethrin is stable to heat and light.  It is
more resistant in acidic media than alkaline, with an optimum stability
at pH 4.

Table 2.  Physicochemical properties of technical permethrina
----------------------------------------------------------------------
Physical state               crystal or viscous liquid

Colour                       yellow brown to brown

Relative molecular mass      391.31

Melting point                34 - 39 °C
                             63 - 65 °C (cis); 44 - 47 °C (trans)

Boiling point                220 °C (6.67 Pa), 200 °C (1.33 Pa)

Water solubility (30 °C)     0.2 mg/litre

Solubility in organic        soluble or miscible with most organic
solvents (25 °C)             solvents: acetone (450 g/litre), hexane
                             (> 1 kg/kg), methanol (258 g/kg), xylene
                             (> 1 kg/kg)

Density (25 °C)              1.214

Vapor pressure (20 °C)       Technical grade : 1.3 µPa
                             Pure : 2.5 µPa (cis), 1.5 µPa (trans)

Octanol-water partition      6.5b
coefficient (log Pow)
----------------------------------------------------------------------
a   From: Meister et al. (1983); Worthing & Walker (1987); FAO/WHO 
    (1980b); Wells et al. (1986)
b   From: Schimmel et al. (1983)

2.3   Analytical Methods

    Methods for the analysis of permethrin are summarized  in  Table 3.
The  common procedure of residue and environmental analysis consists of
(a) extraction,  (b) partition,  (c) chromatographic separation  (clean
up), and (d) quantitative and qualitative analysis of  the  insecticide
by  analytical instruments.  Table 3 also  indicates minimum detectable
concentration (MDC) and percentage recovery.

    To  analyse technical grade permethrin, the product is dissolved in
chloroform,  together with dioctyl phthalate (as an internal standard),
and  the  solution is  injected into a  GLC system equipped  with flame
ionization detector (FID)  (Horiba et al., 1977).

    The Joint FAO/WHO Codex Alimentarius Committee has  published  rec-
ommendations for methods of analysis of permethrin  residues  (FAO/WHO,
1985c).

    In  the internationally accepted CIPAC (Collaborative International
Pesticide Analytical Council) method for permethrin analysis, the prod-
uct  is  dissolved in  4-methylpentan-2-one containing  n-octacosane  as
internal  standard.  Separation is  carried out by  GLC on a  column of
chromosorb W-HP coated with silicone OV 210 (Henriet et al., 1985).

    A  gas chromatographic method for determining permethrin in techni-
cal  and formulated products has been developed and subjected to a col-
laborative study involving 19 laboratories (Tyler, 1987).   The  column
used was a 1.0 m x 4 mm glass column packed with 3% OV-210  on  chromo-
sorb  W-HP.  When five samples of technical material (90-95%), eight of
emulsifiable  concentrates (10-50%), two of  wettable powders (20-30%),
one  of dustable powder (1-2%),  and one of water-dispersible  granules
(1-2%)  were analysed,  the coefficient  of variation  of  the  results
obtained  ranged from  0.79 to  4.24%.  The  method was  adopted as  an
official  first-action method by the Association of Official Analytical
Chemists.


Table 3.  Analytical methods for permethrin
-------------------------------------------------------------------------------------------------------------------------------------
Sample                    Sample preparation                    Determination                MDCc       % Recovery         Reference
                                                                GLC or HPLC; detector,b                 (fortification
            Extraction  Partition          Clean up             carrier, flow, column,                  level)
            solvent                 Column       Elution        temperature, retention                  (mg/litre)d
                                                                time
-------------------------------------------------------------------------------------------------------------------------------------
 Residue analysis        

apple        n-hexane/   ext.sol.a   Silica gel   CH2Cl2         ECD-GC,N2, 50 ml/min,        0.01       91 - 106           Baker & 
            acetone :   /H2O                                    1 m, 3% OV-7, 235 °C                    (0.1 - 1.0)        Bottomley      
            (1/1)                                                                                                          (1982)

pear         n-hexane/   ext.sol.a   Silica gel   CH2Cl2         HPLC UV-206 nm, 25 cm        0.05       81 - 95            Baker & 
            acetone :   /H2O                                    ODS, propan-2-ol,                       (0.1 - 1.0)        Bottomley
            (1/1)                                               1 ml/min                                                   (1982)

blueberry   acetone      n-hexane/   Florisil     benzene/       ECD-GC, N2, 60 ml/min,       0.01       cis:79.6 - 87.1    MacPhee 
                        sat.NaCl                  n-hexane       0.9 m, 3% OV-210, 200 °C,               (0.05 - 0.25)      et al.
                                                 (4/1)          7.0(cis), 8.3 (trans) min               trans:73.3 - 84.2  (1982)
                                                                                                        (0.05 - 0.25)

celery      CH3CN        n-hexane/   Florisil     CH3CN/         ECD-GC, N2, 100 ml/min       0.005      94.2 - 97.0        Braun & 
                        2% NaCl                  CH2Cl2/        1.8 m, Ultra-Bond 20M,                  (0.01 - 1.0)       Stanek
                                                  n-hexane       220 °C, 3.5, 4.1 min                                       (1982)
                                                 (0.35/50/50)

corn        pentane     CH3CN/      Alumina      pentane/       FID-GC, N2, 28 ml/min        0.2        87.5 - 105         Simonaitis 
                        pentane                  ethyl acetate  1.22 m, 5% OV-225, 250 °C,              (0.2 - 22)         & Cail
                                                 (97/3)         9.5(cis), 10.0 (trans) min                                 (1977)

beef        CH3CN/       n-hexane    Florisil     CH3CN/         ECD-GC, N2, 100 ml/min       0.005      82.9 - 89.9        Braun & 
muscle      H2O         2% NaCl                  CH2Cl2/        1.8 m, Ultra-Bond 20M,                  (0.01 - 1.0)       Stanek
            (85/15)                               n-hexane       220 °C, 3.5(cis),                                          (1982)
                                                 (0.35/50/50)   4.1 (trans) min
-------------------------------------------------------------------------------------------------------------------------------------

Table 3 (contd.)
-------------------------------------------------------------------------------------------------------------------------------------
Sample                    Sample preparation                    Determination                MDCc       % Recovery         Reference
                                                                GLC or HPLC; detector,b                 (fortification
            Extraction  Partition          Clean up             carrier, flow, column,                  level)
            solvent                 Column       Elution        temperature, retention                  (mg/litre)d
                                                                time
-------------------------------------------------------------------------------------------------------------------------------------
 Environmental analysis

waste       XAD-2                   Florisil      n-hexane       GC-SIM/MS, He, 25 ml/min,    50         95 (0.11)          Siegel 
water       resin,                               /ether         1.8 m, SP-2250, 230 °C,      ng/litre   95 (0.26)          et al.
            ether                                (9/1)          3.5(cis), 3.7 (trans) min                                  (1980)

runoff       n-hexane                                            ECD-GC, N2, 150 ml/min,      100        97                 Carroll 
(sediment                                                       0.91 m, 5% SP-2330, 215 °C,  ng/litre                      et al.
+ water)                                                        3(cis), 4 (trans) min                                      (1981)

 Product analysis

technical   CHCl3                                               FID-GC, N2, 40 ml/min,                                     Horiba 
grade                                                           2% LAC-2R-446, 200 °C                                      et al.
                                                                                                                           (1977)
-------------------------------------------------------------------------------------------------------------------------------------
a   ext. sol = extraction solvent.
b   detector (ECD-GC = Coulson electrolytic conductivity detector-GC; GC-SIM/MS = GC-selected ion monitoring with mass spectroscopy).
c   MDC = minimum detectable concentration (mg/kg, unless stated otherwise).
d   fortification level indicates the concentration of permethrin added to control samples for the measurement of recovery.
3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE; ENVIRONMENTAL LEVELS

3.1   Industrial Production

    Permethrin was first marketed in 1977.  Worldwide  production  fig-
ures (1979-1982) are shown in Table 4.

Table 4.  World-wide production of permethrin
---------------------------------------------------------
Year         Production      Reference
             (tonnes)
---------------------------------------------------------
1979         800             Wood Mackenzie (1980)
1980         860             Wood Mackenzie (1981)
1981         660 - 700       Wood Mackenzie (1982, 1983)
1982         650             Wood Mackenzie (1983)
1983         600             Wood Mackenzie (1984)
1984         335             Battelle (1986)
---------------------------------------------------------

3.2.  Use Pattern

    Permethrin is a photostable synthetic pyrethroid.  It  possesses  a
high  level of  activity against  Leptidoptera and  is  also  effective
against Hemiptera, Diptera, and Coleoptera. It is a stomach and contact
insectide, but it has very little fumigant activity.  Permethrin is not
plant  systemic.  It is  fast acting and  effective against all  growth
stages, particularly larvae.  Permethrin also has significant repellent
action.   It is effective against  insects at low rates  of application
and  is sufficiently photostable to be of wide-ranging practical use in
agriculture.

    Permethrin  is mostly used on  cotton plants (61% of  consumption).
The  major consumer countries in 1980 were the USA (263 tonnes), Brazil
(38 tonnes),   Mexico  (36 tonnes),  and  Central  America  (27 tonnes)
(Battelle, 1982).

    Other  crops to which permethrin is applied are corn, soybean, cof-
fee,  tobacco, oil seed rape,  wheat, barley, alfalfa, vegetables,  and
fruits. In addition to its pre-harvest usage, permethrin has  a  poten-
tial  application in the protection of stored grain.  For example, per-
methrin has been applied to sorghum or wheat in large scale  trials  in
Australia (FAO/WHO, 1981b, 1982b).

    Permethrin is also used for the control of insects in household and
animal  facilities (Battelle, 1982) or in forest pest control, as a fog
in mushroom houses, and as a wood preservative.  Other applications are
in public health, particularly for insect control in  aircraft,  treat-
ment of mosquito nets, and human lice control.

    It is formulated in emulsifiable concentrates (1.25-50%), ultra-low-
volume  formulations (5%), wettable  powders (25%), and  fogging formu-
lations (2-5%) (FAO/WHO, 1980b).  Permethrin is normally  effective  at
50 g ai/ha on leaf brassicae, whereas 100 g ai/ha is often needed under
more  severe conditions in the  Americas, Africa, and South-East  Asia.
The concentration in most working dilutions is 0.04-0.08% (w/v).

3.3   Residues in Food and Other Products

    As  might be expected for a compound which is non-systemic and also
fairly  stable on leaf surfaces, the amount of residue found on differ-
ent parts of crops depends largely on the direct exposure at  the  time
of application.  This is particularly marked with leafy vegetables such
as  lettuce and  cabbage where  residue levels  on wrapper  leaves  are
usually  many times (e.g., 10-100)  higher than those on  central heads
(as trimmed for commercial distribution).  Similarly, residues on fruit
such as lemons, citrus, and kiwi fruits are almost entirely confined to
the  peel or similar outer protective surfaces.  This is illustrated by
the  1979 Joint FAO/WHO Meeting on Pesticide Residue (JMPR) evaluation,
which  contains findings from the  examinations of samples of  cabbage,
lettuce, oranges, melons, and kiwi fruit (FAO/WHO, 1980b).

    Residue levels in cotton seeds are influenced by the degree of boll
ripening/opening at the time of last spraying. Levels in root and tuber
vegetables are usually less than 0.05 mg/kg (FAO/WHO, 1980b).

    Ground  and aerial applications  have been found  to yield  similar
residue  levels  in a  wide range of  vegetable and field  crops. Simi-
larly,  there were no major differences in residue levels in greenhouse
curcurbitae  and solanaceae following spray and fogging applications at
effective rates under similar conditions (FAO/WHO, 1980b).

    Supervised  trials and residue  analyses have been  performed on  a
variety  of crops  such as  field crops,  foliar and  root  vegetables,
trees, soft fruits, and fruiting vegetables. Comprehensive summaries of
reports  (more than 5000 individual residue results on approximately 60
crops  from 17 countries) were described  in the evaluation reports  of
the JMPR, (FAO/WHO 1980b, 1981b, 1982b, 1983b, 1984b, 1985b, 1986b).  A
comprehensive  list  of maximum  residue limits for  a large number  of
commodities resulted from these evaluations (FAO/WHO 1986c).

    The  rate of decline of  residue levels in various  crops is fairly
slow,  half-life periods ranging from  about 1 to 3 weeks  depending on
the  crop.  However, there is no obvious build-up of residues following
repeated application within the rates and frequencies that  are  needed
to obtain good insect control (FAO/WHO, 1980b).

    Residues  were measured in cotton seeds in supervised trials during
1975-1977  in the USA.  When emulsifiable concentrate formulations (25-
40%)  of permethrin were  applied to fields  at rates of  110 or 450  g
ai/ha (3 to 16 times, until 0 to 76 days before harvest),  the  average
residue level in cotton seeds was 0.03-0.08 mg/kg, the  highest  values
ranging from 0.03 to 0.27 mg/kg in 27 samples (FAO/WHO, 1980b).

    Similar  results were  obtained when  sweet corn  was treated  6-13
times with 25% emulsifiable concentrate at a rate  of  280-450 g ai/ha.
The residue levels at 0-4 days after the last application  were  <0.01-
0.12 mg/kg (Ussary, 1978, 1979).

    Wheat  grains treated with  permethrin at a  rate of  0.5-5.0 mg/kg
revealed  a residue level of  0.36-4.5 mg/kg after 9 months of  storage
(Halls, 1981).  When wheat containing a residue level of 1.09 mg/kg was

subjected  to milling and baking processes, the level of the permethrin
residue declined to 0.12 mg/kg in white bread (Halls & Periam, 1980).

    Groups of three cows were fed  cis/trans (40/60)-permethrin at rates
of  0.2, 1.0, 10, 50,  or 150 mg/kg diet for  28-31 days.  Mean plateau
levels in whole milk were <0.01 µg/g   and 0.3 µg/g   at dietary levels
of 0.2 mg/kg and 150 mg/kg, respectively.  These levels,  however,  de-
clined  rapidly to <0.01 µg/g   within 5 days after permethrin adminis-
tration ceased. Residue levels of <0.01-0.04 µg/g fat and 2.8-6.2  µg/g 
fat were found in the perirenal fat of cows that were given  permethrin  
at dietary levels of 0.2 mg/kg and  150 mg/kg, respectively  (Edwards &
Iswaran, 1977; Swaine & Sapiets, 1981a, 1981b).

    In  studies  by Ussary  & Braithwaite (1980),  cows were given  six
whole-body  sprays of  permethrin at  a rate  of 1.0 g ai/cow  with  an
interval  of 14 days between each spray.  They were allowed free access
to a self-oiler containing a solution of 0.03 g ai/litre  (ensuring  at
least two applications per day for a period of 10 weeks). The cows were
housed in premises that were sprayed at a rate of  0.06 g ai/m2,    six
sprays taking place with a 14-day interval between sprays (the cows had
free  access to the premises during spraying).  This degree of exposure
is  at  the  highest end of the range that is likely to occur in normal
husbandry  practice.  When cows  were slaughtered five  days after  the
sixth application, the permethrin levels in muscle, liver,  and  kidney
were low (<0.01 mg/kg tissue). The highest residue levels detected were
0.10 mg/kg  and  0.04 mg/kg in  the  intestinal and  subcutaneous  fat,
respectively.

    Lactating  cows (three/group) fed permethrin  at dose levels of  0,
0.2,  1.0, 10, or  50 mg/kg diet for  28 days showed no  mortality, and
growth and milk production were normal.  Permethrin residues  were  ob-
served  in the milk  within 3 days at  the two highest  dietary levels;
levels  appeared to reach  a plateau rapidly  and not to  increase with
time.   Analysis of individual  cis and trans  isomers showed that  the
ratio  of permethrin  isomers in  milk appeared  to change  during  the
course of the study with the cis isomer predominating. Permethrin resi-
dues  were  not  found in the tissues of animals that received doses of
1 mg/kg or less.  At dose levels of 10 or 50 mg/kg, residues  were  de-
tected  in the tissues, predominantly in the fat.  Low levels were also
present in the muscle and kidney at the highest dose level.  Permethrin
did  not appear to accumulate in the fat but to reach a plateau rapidly
(Edwards & Iswaran, 1977).

3.4  Residues in the Environment

    Data on precise levels of permethrin residues in the air, water, or
soil  are not available.  However,  an assessment of the  environmental
residues  resulting from permethrin application  has been made in  some
studies.

    Permethrin  deposits and airborne concentrations have been measured
downwind from a single swath application using a back-pack mist blower.
Samples from Kromekote cards (to assess droplet density and  size  dis-
tribution),  glass plates, water surface, bronze rods, and air samplers
were  collected,  cleaned up,  and analysed by  HPLC (Sundaram et  al.,

1987).   Permethrin  deposits on  all  static collectors  were greatest
within  30 m of the spray  swath. Beyond 30 m downwind,  the amounts of
the  insecticide trapped by various  collectors were extremely low  and
were barely detectable.

    Lindquist  et  al.  (1987) measured  permethrin  concentrations  in
greenhouse  air and deposition on glass plates following application by
several different methods.   Highest airborne residues were found after
thermal  pulse-jet applications and  lowest after hydraulic  sprayings.
Most airborne residues were detected within 4 h of application. Surface
residues  were highest after  hydraulic and mechanical  aerosol  appli-
cations.   Thermal pulse-jet applications resulted in low surface resi-
dues.

    Agnihotri  et al. (1986) evaluated the persistence of permethrin in
water and sediment contained in open trenches (3 m x 1 m x 30 cm) lined
with  alkathene sheet.  Insecticide emulsion was sprayed on the surface
of water at the normal recommended dosage and at twice this value.  The
dissipation of the insecticide from the water was rapid,  about  87-90%
of the pesticide being lost within 24 h at both rates  of  application.
However, residues were found to be absorbed by the sediment  and  these
persisted  even  beyond 30 days.   In  soil, persistence  was moderate,
lasting for around 30 days.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    The  degradation pathways of  permethrin by ultraviolet  light,  in
soils, and in plants are summarized in Fig. 2.

FIGURE 2

4.1   Transport and Distribution between Media

    In  laboratory studies, permethrin  in water was  rapidly  adsorbed
onto  lake  sediments or  soil columns and  was not desorbed  or eluted
easily  from them.  However in forest spray trials, permethrin residues
were not only dissipated from water streams very rapidly but  also  did
not  accumulate much in the bottom sediment.  This was explained by the
fact that the low density of permethrin and its insolubility  in  water
prevented it from reaching bottom sediments.  Residues in forest litter
and exposed soils were more stable.  Low levels of degradation products
can be translocated from soils to plants.

    When a 640-ha forest block in northern Ontario, Canada, was sprayed
once with permethrin at 17.5 g ai/ha, residues in water  persisted  for
less  than 96 h and attained peak concentrations of 147.0 µg/litre   in
ponds and 2.5 µg/litre   in streams after one hour.   Accumulation  and
persistence  of the pesticide in bottom sediment were negligible. Resi-
due levels in the treated streams ranged from 0.05 to 0.89 µg/litre and
persisted for a maximum of 96 h, but in another case, residues  fell to
a non-detectable  level (less than 0.05 µg/l)  after 6-24 h. Permethrin
residues  appeared 2.1 km downstream from the treatment block 6 h after
spraying. The level reached a peak of 0.18 µg/litre   at 12 h  and  did
not persist beyond 96 h.  Accumulation of the insecticide in pond sedi-
ment  was minimal (5-8 µg/kg)   and persisted for less than 7 days.  No
permethrin  residue was found  in stream sediments.   The sprayed  per-
methrin formulation had a density (0.88 g/ml) less than that  of  water
and  was practically insoluble in water.  It therefore formed a surface
film  when brought into contact  with stagnant or slowly  moving water.

This significantly reduced the likelihood of the  insecticide  reaching
the  bottom sediment or exposing fish in the treated ponds and streams.
Insecticide residues in foliage, soil, and litter were more stable than
in  water and remained at  detectable concentrations to the  end of the
58-day  sampling  period.   Deciduous and  coniferous foliage contained
permethrin residues ranging from 0.02 to 0.78 mg/kg and  retained  con-
centrations  of 0.02-0.05 mg/kg for  at least 57 days.   Forest  litter
within the treatment block showed a residue level of 0.07 mg/kg 58 days
after  the pesticide application.  The permethrin residue levels in ex-
posed soil in the treatment block were fairly constant (0.04-0.07mg/kg)
for up to 58 days (Kingsbury & Kreutzweiser, 1980a).

    In another field test where permethrin was  sprayed  (17.5 g ai/ha)
twice  at  intervals of  9 or 10 days  in two forest  blocks in Quebec,
Canada, the stagnant water in the sprayed region  contained  permethrin
levels  of no more than  0.62 µg/litre   and 0.84 µg/litre   after  the
initial and second applications, respectively. Samples from the streams
showed residue levels ranging from 0.05 to 1.84 µg/litre.    Permethrin
concentrations in the water persisted at mean  levels of  0.15 µg/litre 
for 96 h and 0.03 µg/litre for 48 h after the  first and second  appli-
cations,  respectively  (detection  limit: 0.01 µg/litre).    Sediments
collected  from a pond and streams, contained 30-95 µg   permethrin/kg.
Accumulation  of residual permethrin  in stream sediment  4.5 km  down-
stream from the treatment block was minimal.  Permethrin residue levels
in  forest litter increased  substantially following the  second appli-
cation.   Mean concentrations ranged from 0.01 mg/kg to 0.053 mg/kg but
fell to non-detectable levels within 59 days (Kreutzweiser, 1982).

    In  a laboratory adsorption-desorption study, more than 95% of per-
methrin  in  aqueous  solutions (6-42 µg/litre)    was rapidly adsorbed
onto  lake sediment, and  the adsorbed insecticide  was not easily  de-
sorbed  from the sediment by several water rinses.  A high distribution
coefficient  (i.e., g adsorbed  per g sediment  divided by g per ml  of
solution)  of 389 ml/g was obtained from the adsorption isotherm.  Per-
methrin in aqueous solution applied to the surface of a sediment column
did  not  penetrate through  more than 2  cm of the  sediment (Sharom &
Solomon, 1981).

    In a laboratory  soil-leaching experiment, 14C-labelled (+)- cis or
(+)- trans- permethrin   was incubated with  two types of  soils  (light
clay soil of Kodaira and sandy clay loam soil of Azuchi) for  0 day  or
21 days, then these permethrin-soil mixtures were applied to the top of
a  soil column and  eluted with water.   When a mixture  with  no  pre-
incubation  was  applied  to the column, only 1.0 to 3.4% of the radio-
carbon was found in lower layer and no radiocarbon was eluted. However,
the  degradation products from  the pre-incubated samples  were  eluted
with water to a slight extent (see section 4.4) (Kaneko et al., 1978).

    Similar  results  were obtained  by Kaufman et  al. (1981) in  soil
mobility studies using soil TLC methods.

    The  uptake of permethrin  and its degradation  products by  plants
from soil was studied by Leahey & Carpenter (1980). Sandy loam soil was
treated separately with  [14C-cyclopropyl]- and [14C-phenyl]-permethrin 
at a  spray application  rate of  2 kg/ha.  The top 8 cm of the treated 
soil was  thoroughly  mixed, and sugar beet, wheat, lettuce, and cotton 

seeds were sown at intervals of  30, 60, and 120 days  after treatment.  
Low  radioactive  residues  (up to 0.86  mg/kg) were detected in mature 
plants, but the residues  were  higher in crops  grown in  soil treated 
with [14C-cyclopropyl]-permethrin. It appeared that  certain carboxylic
acid metabolites formed in the soil were subsequently taken up  by  the
plants.   However, under field conditions, no residues of permethrin or
its  metabolites were detected in crops sown 60 days or more after soil
treatment (Swaine et al., 1978).

4.2   Photodecomposition

 Appraisal

     Photochemical studies of permethrin in thin films and in solution
 have shown it to be much more stable to light (10-100 times) than
 synthetic pyrethroids developed earlier. In solution, photoisomeriz-
 ation at the 1,3-bond of the cyclopropane ring and ester cleavage were
 shown to be the major reactions.

    In  a  thin  film  on  plywood, permethrin  remained  insecticidally
active after 26 days, compared with 4-8 days and <2 days for phenothrin
and  resmethrin, respectively.  When exposed to daylight as a thin film
(0.2 mg/cm2)   indoors near a window, phenothrin photodecomposed with a
half-life of about 6 days, whereas 60% of applied  permethrin  remained
undecomposed  after 20 days.  Thus, replacement of the isobutenyl group
with  the dichlorovinyl substituent  significantly enhanced the  photo-
stability  of permethrin.  Permethrin was  reported to be 10-100  times
more photostable than other pyrethroids synthesized earlier (Elliott et
al., 1973).

    The photolysis  of [1RS, trans ]- or  [1RS, cis ]-permethrin (5)a has 
been  examined using  materials labelled with 14C at the carboxy (acid)   
or  benzyl (alcohol) group (Fig. 2).  On irradiation  with  ultraviolet 
light (peak wavelength: 290-320 nm), both permethrin isomers decomposed
slightly  faster in hexane than in methanol.  In both solvents, the cis
isomer photodecomposed about 1.6 times faster (T´ = 43-58 min) than the
trans  isomer.   The  photodecomposition  reaction  involved  extensive
isomerization  of the cyclopropane  ring, i.e. interconversion  of  the
trans  and cis isomers.   This probably occurred  via a triplet  energy
state  forming the diradical  intermediate through Cl-C3  bond fission,
since the reaction was efficiently quenched by 1,3-cyclohexadiene.  The
isomerization  reaction reached a state  of equilibrium after 1-4 h  of
irradiation   and  the  more  thermodynamically   stable  trans  isomer
constituted 65-70% of the isomer mixture.  Apart from the isomerization
reaction,  ester cleavage was  the major photolytic  reaction.  As  the
result  of  ester cleavage  and  other photolytic  reactions,  products
formed  from  permethrin  also included  smaller  or  trace amounts  of
monochloro-permethrin  (22) (from reductive dechlorination), 3-phenoxy-
benzaldehyde   (PBald)  (11),  3-phenoxybenzoic  acid   (PBacid)  (12),
3-phenoxybenzyl-3,3-dimethylacrylate  (23)  (from diradical  intermedi-
ate),  and benzyl alcohols (9,10), as well as their corresponding acids
(15,16). In addition, large amounts of unidentified polar products were
-----------------------------------------------------------------------
a   Numbers in parentheses refer to the corresponding numbers in Fig.2

detected,  especially  in water.   Permethrin and monochloro-permethrin
(0.1-0.5 g) did not undergo photo-oxidation or other reactions within 7
days in oxygenated methanol solution using Rose Bengal as a sensitizer.
Thus the chlorine atoms at the vinyl position had a  pronounced  effect
in   protecting this substituent from oxidation or epoxidation, as com-
pared with the isobutenyl in chrysanthemate (Holmstead et. al., 1978).

    Holmstead et al. (1978) also investigated the  photodegradation  of
permethrin on a soil surface.  The degradation on soil was  similar  to
the degradation pathways established in solution, but the rate  of  de-
gradation  was slower and photo-isomerisation less important.  Exposure
of the permethrin isomers on Dunkirk silt loam soil for  48 h  resulted
in about a 55% loss of permethrin under sunlight and about a  35%  loss
in the dark. The amount of unextractable material was about 6%  in  the
dark and about 18% in the light.  On soil, permethrin did  not  undergo
extensive isomerization of the cyclopropane ring as it did in solution.
There  was little difference in the amount of free acid detected in the
dark  or in light,  and 3-phenoxybenzyl alcohol  (PBalc) (6)  (approxi-
mately 5%) was the major cleavage product of the alcohol moiety.  Other
products  detected in trace amounts  were essentially similar to  those
present in solutions that had undergone photolysis.

4.3  Degradation in Plants

 Appraisal

     Thorough investigations of the fate of permethrin in plants have
 been performed using bean plants and cotton plants. No significant
 differences in the types of metabolic pathways were detected for the
 two plant species.  Very little translocation of permethrin or its
 metabolites was observed following either topical application or stem
 injection of permethrin to plants. Photochemical reactions played an
 important role in the fate of permethrin applied to the surface of
 plants.  A major degradation pathway in plants was ester cleavage,
 followed by rapid conjugation with sugars of the Cl2 CA and PBalc thus
 formed.

    The metabolism of the [1R,trans] and  [1R,cis] isomers of  14C-per-
methrin,  labelled separately in  the dichlorovinyl and  benzyl  carbon
atoms,  in snap  bean seedlings  has been  studied in  the  greenhouse.
Whole-body  autoradiography  of the  plants  showed that  little trans-
location of radiolabelled permethrin or its metabolites  had  occurred.
The amounts of radiocarbon remaining after 14 days were 13-17%  of  the
dose in the surface wash, 46-58% in the methanol extract, and 8-14% un-
extracted in the plant residues.  Some interconversion of the trans and
cis  isomers occurred and the  cis isomer was slightly  more persistent
than  the  trans isomer.  The initial half-lives  of the cis  and trans
isomers of permethrin in the seedlings were 9 and 7 days, respectively.
A  large number of metabolites were detected in the plant extracts, the
major  ones from the alcohol moiety being PBalc (6) and its correspond-
ing  2'- (8) or  4'-hydroxy (7) derivatives,  which occurred mainly  as
glucoside  conjugates (Fig. 1).  There  were seven or  eight additional
minor  unidentified products.   The cis  and trans  isomers of  3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropanecarboxyclic  acid (Cl2CA)   (17)
were  the major metabolites from the acid moiety and occurred mainly as

conjugated  forms.  In addition, trace  amounts of the 2'-  (24) or 4'-
hydroxy  (26) derivatives of  permethrin were also  detected. From  the
hydrolysis experiments using beta-glucosidase, it was inferred that the
sugar concerned was glucose, but no detailed evidence of  the  identity
was obtained (Ohkawa et al., 1977).

    In  a separate study, Gaughan  & Casida (1978) examined  the metab-
olism  of the [1RS,trans] and  [1RS,cis] isomers of permethrin  in snap
beans in the glasshouse and in cotton both in the glasshouse  and  out-
doors.   Individual leaves of snap beans and cotton plants were treated
with  1 µg   of  cis- or  trans-14C-permethrin    labelled either at the
carboxy  or methylene carbon.  Under field conditions, about 30% of the
radiolabel  was lost from  cotton plants within  one week after  appli-
cation and some trans/cis isomerization at the cyclopropane  ring  took
place  by  photodecomposition.   trans-Permethrin   was metabolized more
rapidly than the cis isomer.  The major degradation pathway  was  again
hydrolysis, followed by rapid conjugation of Cl2CA   (17) and PBalc (6)
with sugars. There were at least two types of conjugates; the minor one
was  a glycoside readily cleaved by beta-glucosidase and the  major one
was a conjugate which was resistant to beta-glucosidase but was readily
cleaved  by cellulase.  Other products identified included the hydroxy-
lated  compounds  reported by  Ohkawa et al.  (1977) in their  study of
beans treated with permethrin.  In addition, hydroxylation at either of
the  two methyl groups in  the acid moiety (27)  with subsequent conju-
gation  occurred to a greater  extent with the more  stable cis isomer.
Similar  metabolites  to  those  formed  under  field  conditions  were
detected in bean and cotton plants under glasshouse conditions.

    Roberts  & Wright (1981)  studied the conjugation  of 14C-PBalc  in
cotton plants using abscised leaves to obtain more information  on  the
nature of the conjugates produced.  The alcohol was  rapidly  converted
to glucosyl 3-phenoxybenzyl ether and subsequently to more  polar  sub-
stances such as disaccharide conjugates with glucose and pentose (prob-
ably xylose or arabinose) sugars.  The alcohol and  its  monosaccharide
and  disaccharide  conjugates  underwent interconversion  in the cotton
leaves.  The  evidence was obtained from experiments with  14C-glucose,
which  showed the ready exchange of the glucose units of the conjugates
with free glucose in the leaves.  No larger sugar conjugates  of  PBalc
were detected in plants.

    From the above studies, it can be concluded that the types of prod-
ucts  formed from permethrin in  plants are similar to  those formed in
mammals, except for the nature of the conjugates (see section 5.1).

4.4  Degradation in Soils

 Appraisal

     Several studies on the degradation of permethrin in a wide variety of
 soil types have been carried out. These studies used permethrin labelled
 with 14 C at different positions, so that the fate of virtually all of the
 significant sub-units of the molecule has been traced. In all soil types
 degradation is fairly rapid under aerobic conditions, conversion to 14CO2
 being the major ultimate fate of the 14 C. With all soils and all positions
 of radiolabelling, the formation of unextractable residues is a major occur-
 rence. Under anaerobic conditions, similar degradation processes seem to

 occur, but the rate of ultimate conversion to 14 CO2  is slower than under
 aerobic conditions.

    Kaufman et al. (1977) studied the degradation of cis and trans iso-
mers  of permethrin in five soils under aerobic, anaerobic, and steril-
ized conditions.  Soils were treated with 14C-permethrin  labelled sep-
arately  in the carboxy and methylene groups at a dose rate of 224 g/ha
and stored under aerobic conditions at 25°C.  Degradation of permethrin
was rapid in four of five soils, with the trans isomer decomposing more
rapidly  than the cis isomer.  The initial half-lives were less than 28
days in all but one soil. Rapid evolution of 14CO2    was observed.  In
Hagerstown  silty clay loam soil, 62% of methylene- and 52% of carboxy-
labelled  permethrin were converted to 14CO2     in 27 days.  Only  15%
(methylene-labelled)  to 19% (carboxy-labelled)  of the applied  radio-
label was extractable with methanol, 25-27% remaining  unextracted  and
associated with soil organic matter.  Microbial metabolism was involved
in  permethrin degradation and  the major route  was hydrolysis of  the
ester  linkage to  form PBalc  and Cl2CA,    the former  product  being
subsequently  oxidized  to  PBacid.  In  contrast,  less  than 0.3%  of
14CO2 was    evolved from soils treated with sodium azide (an inhibitor
of microbial growth) or when the soil was incubated  under  waterlogged
anaerobic conditions.

    Kaneko et al. (1978) reported the degradation in two Japanese soils
of 14C-permethrin   labelled separately in the dichlorovinyl and methy-
lene  groups.  The initial half-lives of the trans and cis isomers were
6-9 days and 12 days, respectively, in soils treated at a rate of 1 mg/
kg  and stored at 25°C  under aerobic upland conditions.  14CO2     was
evolved at rates similar to those observed by Kaufman et al. (1981). As
one  of the 14C-preparations  was  different in labelled  position from
those used in the earlier work, the evolution of 14CO2 was    the  evi-
dence  for extensive degradation  of the cyclopropyl  moiety after  hy-
drolysis in the soils.  In addition to the hydrolysis products, several
oxidation  products  were identified,  including 3-(2,2-dichlorovinyl)-
2-methyl-2-hydroxymethyl-cyclopropanecarboxylic  acid  (19)  and  3-(4-
hydroxyphenoxy)benzyl- 3-(2, 2-dichlorovinyl)-2,2-dimethylcyclopropane-
carboxylate (26).

    The degradation of permethrin was studied in a flooded Memphis silt
loam soil incubated at 25°C, [14C-carbonyl]- cis-, [14C-carbonyl]- trans-,
and [methylene-14C]- cis-permethrin     being added to the soil at rates
of 0.1 and 1.0 mg/kg.  The soils were analyzed after 0, 4, 8,  16,  32,
and  64 days to determine the  distribution of 14C  in CO2,    solvent-
extractable  compounds, water-soluble polar compounds,  and soil-bounds
residues.   Thin-layer chromatographic analysis of  the organic solvent
extracts  showed that  trans-permethrin  was more  rapidly degraded than
the cis isomer. After 64 days, the amounts of 14C-trans-permethrin remain-
ing were 34.2% (at 0.1 mg/kg) and 30.3% (at 1.0 mg/kg) of  the  applied
14C,   and those of 14C- cis-permethrin    were 73.4% (at 0.1 mg/kg) and
69.8%  (at  1.0 mg/kg).   Two metabolites,  3-(2,2-dichloro-vinyl)-2,2-
dimethylcyclopropanecarboxylic  acid (17) and PBalc (6), resulting from
permethrin  hydrolysis were identified.  Other  metabolites were PBacid
(12)  and PBald (11).  Fragmentation  of (17) and (12)  to CO2 was  not
extensive,  and cumulative 14CO2 recoveries   were  less than 3.5%  for
all  treatments during the  64-day incubation period.   The  metabolism
of  trans-permethrin  resulted in the accumulation of polar compounds in
the  water.   Soil-bound residues  gradually  increased with  time  and

accounted  for  3.3-11.4%  of the 14C   activity  after  64 days.   The
largest  percentage of soil-bound 14C  residue  was in the fulvic  acid
fraction (Jordan & Kaufman, 1986).

    When 14C-permethrin  preincubated with soil for 21 days was applied
on top of a soil column and eluted with water, 7.9-17.2% of the applied
radiocarbon  was recovered in the  lower layers of the  column and 0.3-
2.6%  was found in  effluents (Kaneko et  al., 1978). Only  degradation
products of permethrin, such as PBacid (12)  and  3-(4-hydroxyphenoxy)-
benzyl-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate   (26) 
were  identified  in  the effluent.  Permethrin was not present  in the 
effluent (see section 4.1).

    The persistence of permethrin in soil was studied in  aqueous  sus-
pensions of soil spiked with permethrin at a rate of 17.8 mg/kg under a
range  of redox potential (-150, +50, +250, and +450 mV) and at pH 5.5,
7.0, and 8.0.  The results of this study indicated that both the pH and
redox  potential significantly influence the degradation of permethrin.
After  25  days, permethrin  disappeared  almost completely  under well
oxidized  (+450 mV) conditions at  all three pH levels.   Under reduced
conditions  (-150  mV), only  about 40% of  the applied permethrin  was
degraded.  The rate of degradation of permethrin was moderate at weakly
oxidized  (+250 mV) and moderately reduced (+50 mV) conditions at pH 8.
Thus,  permethrin was lost more rapidly under oxidizing conditions, and
increasing  the pH  enhanced this  loss under  moderately  reduced  and
weakly oxidized conditions (Gambrell et al., 1981).

    Jordan  et al. (1982) investigated the effect of temperature on the
degradation  of  permethrin in  soil.  Dubbs fine  sandy loam soil  was
treated  with [14C-carbonyl]- cis,     trans-permethrin   at a rate  of 1
mg/kg and incubated at 10, 25, and 40°C for up to 64 days.   The  half-
lives of disappearance for  trans and  cis isomers were 14 and 55 days at
10°C, 5 and 12 days at 25°C, and 4 and 27 days at  40°C,  respectively.
The most rapid rate of degradation of permethrin occurred at 25°C, per-
methrin being converted to Cl2CA   (17) and ultimately to 14CO2.     At
40°C  rapid degradation  of permethrin  to Cl2CA    also occurred,  but
further degradation of Cl2CA   to 14CO2 was   reduced.  The  amount  of
14CO2 evolved     after 64 days was  56% at 25°C, compared  with 29% at
10°C and 24% at 40°C.

    Lord  et al. (1982) investigated the factors affecting the persist-
ence  of permethrin in  three loam soils  under laboratory  conditions.
The degradation of  trans-permethrin  (4 mg/kg) at 30°C was  similar  at
three  moisture  contents  ranging from  40  to  80%  of  water-holding
capacity, but more rapid degradation occurred in an aqueous  soil  sus-
pension  system probably due to better distribution of the insecticide.
Four repeated applications of permethrin (4 mg/kg) at 20-day intervals,
or addition of nutrients including sucrose (1 mg/kg),  powdered  cellu-
lose (100 mg/kg), and NH4Cl   (80 mg/kg) plus K2HPO4     (260 mg/kg) to
soils  caused  no drastic  changes in the  rate of degradation  of per-
methrin.

    The influence of organic materials on the degradation of permethrin
in soil was also studied by Doyle et al. (1981). [14C-carbonyl]- cis-per-
methrin  was added to  silty loam soil  which had been  pretreated with
sewage  sludge or dairy manure at rates of 0, 50, or 100 tonnes/ha, and

total CO2 and 14CO2     evolution were monitored regularly throughout a
60-day  incubation period at 25°C. The incorporation of sewage or dairy
manure  at the rate of 50 and 100 tonnes/ha increased permethrin break-
down by 87% and 149% (sewage), or 64% and 134% (dairy manure)  based on
the  values measured in  unamended soil, respectively.   In the  waste-
amended soils, a lag period of 28-38 days during which  time  virtually
no 14CO2 was evolved, was followed by a rapid evolution of 14CO2 before
the rate became stabilized. The highest rates (0.21-0.22% per day) were
observed  in soils amended with either dairy manure or sewage sludge at
100 tonnes/ha.  The rate of 14CO2 formation    correlated directly with
the total microbial activity, as measured by total CO2 production.

    In  studies  by Williams  & Brown (1979),  the persistence of  per-
methrin in six soils was compared with that of fenvalerate  under  lab-
oratory conditions. The soils were treated with one of the insecticides
at  1 mg/kg and incubated  under aerobic conditions  for 16 weeks at  a
temperature alternating between 20°C for 15 h and 10°C for 9 h to simu-
late the actual field conditions.  With the exception of  organic  soil
from Cloverdale, degradation of permethrin was rapid in all soils, with
half-lives  of 3 weeks or less.   Under identical conditions, the  half
life  for fenvalerate was about 7 weeks.  Again,  trans-permethrin   was
lost more rapidly than the cis isomer, and there was very  little  loss
of either insecticide in the sterilized soils.  With Cloverdale organic
soil,  a greater degree  of adsorption onto  the soil organic  fraction
might have contributed to the slower degradation rate.

    When  soil  was treated  with [14C-cyclopropyl]-permethrin,   sugar
beet  grown on  the treated  soil was  found to  contain  radiolabelled
conjugates  of Cl2CA   and  3-(2,2-dichlorovinyl)-2-methylcyclopropane-
1,2-dicarboxylic acid (21) (Leahey & Carpenter, 1980).  It was possible
that  both  carboxylic  acids were  formed  in  the soil  and were sub-
sequently taken up by the plants (see section 4.1).

5.  KINETICS AND METABOLISM

5.1   Metabolism in Mammals

 Appraisal

     The metabolic pathways of permethrin in mammals are summarized in
 Fig. 3.

     The metabolism of permethrin has been studied in great detail in
 various species of mammals, using a variety of radiolabelled isomers.
 Permethrin administered to mammals was rapidly metabolized and almost
 completely eliminated from the body within a short period of time. The
 trans isomer of permethrin was eliminated more rapidly that the cis
 isomer. Radiocarbon from  trans- permethrin was excreted mostly in
 urine, whereas that from the cis isomer was eliminated both in urine
 and faeces to a similar extent. Expiration as CO2  contributed little
 to its elimination in mammals. Major routes of metabolism for both
 trans and cis isomers were ester cleavage and oxidation of the 4'-
 position of the terminal aromatic ring. A less important reaction in
 mammals was hydroxylation of the geminal dimethyl group of the cyclo-
 propane ring. Major metabolites thus formed were Cl2 CA in free and
 glucuronide form, sulfate conjugate of 4'-hydroxy-3-phenoxybenzoic
 acid, PBacid in free and conjugate form, and hydroxymethyl-Cl2 CA as a
 glucuronide conjugate. This latter compound was also isolated as a
 lactone where the hydroxymethyl group and the carboxy group had a cis
 configuration.

FIGURE 3

5.1.1  Mouse

    In studies by Shah et al. (1981), 14C- cis-permethrin    was applied
to the clipped skin of mice at a level of 1 mg/kg body weight in 0.1 ml
of  acetone.  The mice were restrained until the solvent had evaporated
and  then placed in mouse metabolism cages.  They were sacrificed at 1,
5, 15, 50, 480, and 2880 min after treatment and examined  for  absorp-
tion, distribution, and excretion of the insecticide.  About 40% of the
applied  permethrin had moved from the site of application within 5 min
and appeared to move rapidly to other parts of the body.

5.1.2   Rat

    When a preparation of  [1RS, trans ]-  or  [1RS, cis]-permethrin (14C-
labelled in the alcohol or acid moiety) was administered orally to male
rats at levels of 1.6-4.8 mg/kg, the compounds were rapidly metabolized
and  labels in the  acid and alcohol  fragments were almost  completely
eliminated from the body within a few days.  The  radiocarbon  (alcohol
or  acid label) from the cis isomer was eliminated in the urine (52-54%
of the dose) and the faeces (45-47%), whereas 79-82% of the radiocarbon
from  the  trans  isomer appeared in the urine and 16-18% in the faeces
within 12 days after administration.  The 14CO2    contained in the ex-
pired  air corresponded  to less  than 0.5%  of the  dose.  The  tissue
residues  were very  low, although  the cis  isomer  showed  relatively
higher residue levels (0.46-0.62 mg/kg tissue) in the fat  (Gaughan  et
al., 1977). The major metabolite from the acid moiety was Cl2CA   (17),
which  was mostly  excreted in  the urine,  conjugated with  glucuronic
acid. This accounted for 50-63% of the dose from  trans-permethrin   and
15-22%  from  cis-permethrin.  Oxidation at  either of the  geminal  di-
methyl groups occurred to the extent of 4.3-10.4% (trans) or 12.2-14.9%
(cis),  and these oxidised  products were eliminated  in the urine  and
faeces  as such or as the lactone or glucuronide.  The major metabolite
from  the alcohol moiety was  3-(4'-hydroxyphenoxy)benzoic acid (4'-OH-
PBacid)  sulfate, accounting  for 30.7-42.8%  of the  dose (trans)  and
19.5-29.3% (cis). From  cis-permethrin,  2'-OH-PBacid sulfate (about 3%)
was identified.  Another significant metabolite was PBacid,  which  oc-
curred free and as glucuronide or glycine conjugates, and accounted for
25-31% (trans) and 5.7-10.1% (cis) of the dosed radiocarbon. Except for
a  trace of PBacid, all  the above metabolites from  the alcohol moiety
were excreted entirely in the urine.  However, the faeces of rats dosed
with  trans-permethrin  contained 1-2% of the radioactive dose as PBalc.
Thus  substantial  portions  of  the  radioactive  metabolites  in  the
recovered  excreta were identified. The proposed metabolic pathways for
 cis-    and  trans-permethrin   are shown in Fig. 2.  The five principle
sites  of  metabolic  attack in  both  permethrin  isomers  were  ester
cleavage,  oxidation  at  the  trans-  and  cis-methyl   of  the  geminal
dimethyl  group of the acid  moiety, and oxidation at  the 2'- and  4'-
positions  of the  phenoxy group.   Conjugation of  the resultant  car-
boxylic acids, alcohols, and phenols with glucuronic acid, glycine, and
sulfuric acid occurred to varying extent.  cis-Permethrin  (29) was more
stable  than  trans-permethrin   (30), and  the cis isomer yielded  four
faecally excreted ester metabolites that resulted from hydroxylation at
the  2'- or  4'-position of the  phenoxy  group or at the  trans- or  cis-
methyl group on the cyclopropane ring (e.g., (35'), (36')).  The ester-
cleaved  metabolites were extensively  excreted into the  urine whereas
the  metabolites retaining an ester bond were found only in the faeces.

The major metabolite from the acid moiety of both isomers  was  Cl2CA
(31,31') in free (1-8%) and glucuronide (14-42%)  forms. Other signifi-
cant  metabolites  were   trans-OH-Cl2CA  (32,32')  (1-5%)  and   cis-OH-
Cl2CA    (33,33')  in  the free  (3-5%),  lactone  (34,34') (0-4%)  and
glucuronide  (1-2%)  forms.   On the  other  hand,  the alcohol  moiety
released after cleavage of the ester bond of both isomers was converted
mainly  to  the  sulfate of  3-(4'-hydroxyphenoxy)benzoic  acid (4'-OH-
PBacid)  (13) (29-43% of the dose)  and PBacid (12) in the free (1-10%)
and  glucuronide (7-15%) forms.   Other significant metabolites  of the
alcohol moiety were PBalc (6), PBacid-glycine and the sulfate of 3-(2'-
hydroxyphenoxy)  benzoic acid (2'-OH-PBacid) (14).   [1RS, trans ]-   and
[1RS, cis ]-permethrin    showed no significant differences  in metabolic
fate  in the rat from [1R, trans ]-   and [1R, cis ]-permethrin,   respect-
ively (Elliott et al., 1976; Gaughan et al., 1977).

5.1.3   Goat

    When ten consecutive oral doses of 14C- trans-  or 14C- cis-permethrin
(labelled  in  the  acid or  alcohol  moieties)  at 0.2-0.3  mg/kg body
weight/day  were given to lactating goats, they excreted 72-79% and 25-
36% of the trans and cis isomer doses, respectively, in urine  and  12-
15%  and  52-68%,  respectively, in  the  faeces.   The amounts  of the
radiocarbon appearing in the milk were less than 0.7% with any  one  of
the four 14C-labelled  preparations. Concerning the tissue residues 24h
after  the last dose,  detectable levels of  radiocarbon were found  in
most  tissues, but none was higher than 0.04 mg/kg for the trans isomer
or 0.25 mg/kg for the cis isomer (Hunt & Gilbert, 1977).

    The permethrin metabolites in goats were formed through cleavage of
the ester linkage, hydroxylation at the  cis- or  trans-methyl   of  the
geminal  dimethyl group, and  hydroxylation at the  4'-position of  the
phenoxybenzyl  moiety.  Some of  these metabolic products  were further
oxidized and/or conjugated with glycine, glutamic acid  and  glucuronic
acid.  The major compounds found in faeces after  dosing  with   cis-per-
methrin  were  unmetabolized  parent compound,  4'-OH-permethrin (35'),
 trans-OH-permethrin (36'),  PBalc,   cis-OH- cis-Cl2CA-lactone  (34')  and
eight  unidentified ester metabolites  (Fig. 2).  The  faeces of  goats
treated  with the trans  isomer contained large  amounts of the  parent
compound (41-79% of the faecal 14C) and of PBalc (8-25%)  and   cis-OH-
 trans-Cl2CA-lactone      (34).  Also,  three unidentified  ester metab-
olites  were found (8-23%).   On the other  hand, major urinary  metab-
olites  from the alcohol moiety of both isomers were PBacid-glycine (7-
9%  of  the  urinary 14C)  and  4'-OH-PBacid-glycine  (4-12%).   PBalc,
PBacid,  4'-OH-PBalc (7), 4'-OH-PBacid, PBacid-glutamic acid and 4'-OH-
PBacid-glutamic  acid were also  identified as minor  metabolites.  The
urine  of goats treated  with both isomers  contained, as major  compo-
nents,  Cl2CA    in  the free form (2-47% of the urinary 14C)  and as a
glucuronide  (27-71%).   Cl2CA-glucuronide    was obtained  to a larger
extent  with the trans  isomer than with  the cis isomer.   Other major
metabolites  of the cis  isomer were  cis-OH-Cl2CA    (33')  (9-11%) and
 cis-OH- cis-Cl2CA-lactone (34') (11-16%).    trans-OH-Cl2CA  (32,32') was
detected as a minor metabolite of both isomers.  The milk of goats con-
tained  the parent compounds, PBacid-glycine, and 4 -OH-PBacid-glycine.
On  administration  of the  cis isomer, a  larger amount of  the parent
compound was excreted in the milk than in the case of the trans isomer.
Comparatively,  when the trans isomer  was administered, PBacid-glycine

was detected in the milk to a larger extent than with the  cis  isomer.
Most  of the radioactivity  in the fat  was attributable to  the parent
compound,  or  ester metabolites  such as  trans-OH-permethrin  (36,36')
and  trans-OH-permethrin conjugate (Ivie & Hunt, 1980).

5.1.4   Cow

    When four lactating Jersey cows were orally administered 14C- trans- or
 cis-permethrin   preparations (labelled either in the alcohol  or  acid
moiety; three doses of ca. 1 mg/kg  body weight at 24-h intervals), the
radiocarbon was almost completely eliminated in the faeces and urine 12
or 13 days after the initial dose. There was more faecal elimination of
the  radiocarbon and higher tissue  residue levels in the  fat with the
cis isomer than the trans isomer.  The 14C  blood level reached a tran-
sient  peak shortly after each  dose and decreased to  an insignificant
level within 2 to 4 days after the last dose.  Higher blood levels were
attained  with 14C- trans-permethrin    labelled in the acid moiety than
when  labelled in  the alcohol  moiety.  This  difference arising  from
labelling  positions was not evident  with  cis-permethrin.   The radio-
carbon  excreted in the milk was less than 0.5% of the dose. The lowest
14C    level  in  milk was  obtained from 14C- trans-permethrin    (acid
moiety labelling) and the highest with 14C-trans-permethrin    (alcohol
moiety  labelling). With all labelled preparations, however, the radio-
carbon levels in milk decreased to <100 µg/litre    within  2 to 4 days
after treatment ceased.  The only radiolabelled compound recovered from
milk,  in the case of  the trans isomer, was  unmetabolized permethrin,
whereas with the cis isomer 85% of the radiocarbon was as  parent  com-
pound and 15% as  trans-OH- cis-permethrin    (36 ).  The metabolic reac-
tions of permethrin in cows were similar to those in rats and hens.  In
cows, the permethrin isomers, their mono- and  dihydroxy   derivatives,
and  PBalc,  appeared only  in the  faeces,   while  the   cis-OH-Cl2CA-
lactones  (34,34')  appeared in both faeces and  urine.  The  remaining
metabolites  appeared only  in  the urine. Although  a slightly  larger
portion  of  cis-permethrin   than  trans-permethrin   was  excreted  un-
changed, there were similar amounts of ester metabolites with both iso-
mers. These ester metabolites were hydroxylated at the  trans-  or  cis-
methyl positions of the geminal dimethyl group, at the  4'-position  of
the  phenoxybenzyl group, or at  both the geminal dimethyl  and phenoxy
groups.   The preferred hydroxylation  site with both  isomers was  the
 trans-methyl    group.  The major metabolites from the acid moieties of
both  isomers  was  the corresponding  cis-OH-Cl2CA     (33,33') and its
lactone and Cl2CA-glucuronide, while   trans-OH- cis-Cl2CA (32') was also
a  major metabolite from  cis-permethrin.   On the other hand, the major
metabolites from the alcohol moiety of both isomers were PBacid-glycine
(3-11% of the dose), PBalc (8-10%), and PBacid-glutamic  acid  (12-28%)
(Gaughan et al., 1978a).

5.1.5   Man

    Two human volunteers, who consumed about 2 and 4 mg  of  permethrin
(25:75), respectively, excreted 18-37% and 32-39% of  the  administered
dose,  detected as  the metabolite  Cl2CA,   after  acid hydrolysis  of
their urine collected over 24 h (Cridland & Weatherley, 1977a,b).

5.2  Metabolism in Hens

    A mixture (cis:trans = 25:75) of permethrin labelled  with 14C   in
the  alcohol moiety was sprayed  on 28 hens at doses  of 3.77 or  11.94
mg/hen.  The hens treated with the low dose showed no detectable levels
of radiocarbon in the gizzard, heart, lung, muscle, or egg white  24  h
after spraying, but the radiocarbon in the egg yolk reached  a  maximum
level  of 0.049 mg/kg 5 days after treatment. The concentration of per-
methrin residues in the fat reached a peak 7 days after  treatment  and
no  significant radioactivity was detectable  after 4 weeks.  With  the
high dose, the radiocarbon in the skin had reached 6.69 mg/kg  after  3
days.   Small quantities of the radiocarbon were found in the egg yolks
(0.121 mg/kg) after 5 days and fat (0.110 mg/kg) after 1 day  (Hunt  et
al., 1979).

    When  White Leghorn hens were treated orally three consecutive days
with  one of four 14C- trans-   and  cis-permethrin  isomers labelled in
the  alcohol  or  acid moieties at 10 mg/kg body weight, they showed no
signs  of poisoning.  More  than 87% of  the radiocarbon from  the four
labelled preparations was found in the excreta 9 days after the initial
dose,  0.7-4.7% of the dose was exhaled as 14CO2,    and 0.12-0.47% and
0.06-0.66% of the radiocarbon was recovered in egg yolk and  fat  (sub-
cutaneous  and  visceral  fat),  respectively.   Both  the  cis isomers
labelled  in the alcohol and  acid moieties showed recoveries  3 to >10
times  higher in the fat  and egg yolk than  those shown by the  corre-
sponding  trans isomers.  The excreta (0-72 h) contained 1.7 times more
 cis-permethrin    than  trans-permethrin.    Hydroxylated  ester  metab-
olites of  trans-permethrin  were not excreted, but four monohydroxy and
dihydroxy  esters (i.e.,  trans-OH-permethrin,  4'-OH-permethrin, 4'-OH,
 trans-OH-permethrin (37) and   trans-OH-permethrin  sulfate) of  cis-per-
methrin  were found. Metabolites from the acid moieties of both isomers
were  the Cl2CA   isomers in  free, glucuronide, and taurine  conjugate
forms,  trans-OH-Cl2CA  (32,32'),   cis-OH-Cl2CA (33,33'),   cis-OH-Cl2CA
lactone  (34,34'),  and  cis-OH-Cl2CA  sulfate.    trans-OH-Cl2CA (32,32') 
was obtained from the cis isomer to larger extents than  from the trans 
isomer, whereas the amounts of  cis-OH-Cl2CA (33,33') were larger with
the  trans isomer than with  the cis isomer.  The  metabolites from the
alcohol moiety included PBalc, PBacid, their 4'-hydroxy-derivatives and
the corresponding sulfate, the glucuronide of PBalc, and a  variety  of
unidentified conjugates of 4'-OH-PBalc (7)  and 4'-OH-PBacid (13).  The
taurine conjugate of PBacid was not detected.  The metabolites produced
in  largest amounts were the unidentified conjugates of 4'-OH-PBalc (6-
13%  of the dose) and  4'-OH-PBacid (2-11%). The yolk  of eggs 5 and  6
days after initial dosing contained 4.4 times more  cis-permethrin  than
 trans-permethrin    in unchanged form and the same ester metabolites of
 cis-permethrin    as those found in  the excreta. Other metabolites  in
the  yolk  were generally  the same as  those in the  excreta. Overall,
 cis-permethrin    appeared at higher levels  than  trans-permethrin   in
the egg yolk, fatty tissues, and excreta. Radiocarbon from  cis-permethrin
preparations also persisted longer in the blood than that from  trans-per-
permethrin  preparations.  It probably  resulted from more  rapid ester
cleavage of the trans isomer than the cis isomer, based on the relative
amounts  of  hydrolysis products  from the two  isomers in hen  excreta
(Gaughan et al., 1978b).

5.3   Enzymatic Systems for Biotransformation

    In studies by Shono et al. (1979), 1 µg each of  [1RS, trans ]-permethrin
or  [1RS, cis ]-permethrin   was incubated at 37°C for 30 min with 2.2 ml
of ca. 10%    rat  and  mouse  liver  microsomes  under  the  following
conditions:

 *  microsomes  treated with tetraethyl pyrophosphate (TEPP) (no ester-
    ase and oxidase activity),

 *  normal microsomes (esterase activity),

 *  TEPP-treated microsomes plus NADPH (oxidase activity),

 *  normal microsomes plus NADPH (esterase plus oxidase activity).

Each   esterase  preparation  hydrolyzed  trans-permethrin   to  a  much
greater extent than the corresponding cis isomer.  In contrast, oxidat-
ive metabolism was greater for  cis-permethrin than for  trans-permethrin
except with the mouse microsomes, where the reactions of  both  isomers
proceeded  to a similar extent.  Aryl hydroxylation occurred at the 4'-
and 6-positions with the mouse enzymes but only at the 4'-position with
the  rat enzymes. Hydroxylation  at the 2'-position  was observed  only
with the  cis-permethrin and mouse oxidase system.   The amount of  trans-
hydroxymethyl  ester  metabolites  exceeded that  of  the corresponding
 cis-hydroxymethyl  compounds  except  with  rat enzymes acting on  trans-
permethrin.   In general, oxidative  activity with rat  microsomes  was
weaker than that with mouse microsomes.  The dihydroxy ester metabolite
was  evident  only with  cis-permethrin.    The  cis-hydroxymethyl  ester
derivatives  of  trans-permethrin  were further  oxidized to the  corre-
sponding aldehyde and carboxylic acid by the mouse enzymes.   The  pre-
ferred sites of hydroxylation, based on all identified  metabolites  in
the oxidase and esterase-plus-oxidase systems, were as  follows  (Shono
et al., 1979):

 trans-permethrin
     mouse:  cis-methyl  >  trans-methyl  > 4'-carbon = 6-carbon
     rat:   4'-carbon =  cis-methyl >  trans-methyl
 cis-permethrin
     mouse:  trans-methyl >  cis-methyl = 4'-carbon > 6-carbon
            > 2'-carbon
     rat:   4'-carbon =  trans-methyl >  cis-methyl

    When 100 nmol each of [1R, trans]-, [1S, trans]-, [1RS, trans]-, [1R, cis]-,
[1S, cis ]-,  or [1RS, cis ]-permethrin  were incubated individually with
2.5 ml of mouse liver microsome (1.5-2.0 mg of protein), the trans iso-
mers  were much more rapidly hydrolyzed than the corresponding cis iso-
mers.   Of  the trans  isomers, [1S,trans] isomer  was hydrolyzed to  a
greater extent than the other trans isomers.  On the other  hand,  when
esterase activity was suppressed, there were no distinct differences in
the  oxidative metabolic rates between trans and cis isomers (Soderlund
& Casida, 1977).

    The  persistence  of  isomers of  permethrin,  cypermethrin, delta-
methrin, and fenvalerate in the fat and brain after oral  or  intraper-
itoneal  administration of  these pesticides  to rats  was compared  by

Marei et al. (1982).  Residues in fat and brain were much higher and more
persistent  with   cis-permethrin  than with  trans-permethrin or the 
alpha-cyano phenoxybenzyl pyrethroids (cypermethrin, fenvalerate, delta-
methrin). Brain levels of  trans-permethrin  (but not of   cis-permethrin) 
were greatly elevated  after pretreatment with  pyrethroid esterase and  
oxidase inhibitors (i.e. tri- o-cresyl phosphate,  S,S,S-tributyl phosph-
orotrithioate, phenyl saligenin cyclic phosphanate as esterase inhibit-
ors  and  piperonyl butoxide as oxidase inhibitor).

    Pyrethroid  carboxyesterase(s)  that  hydrolyze esters  of chrysan-
themic  acid were purified by  Suzuki & Miyamoto (1978)  from rat liver
microsomes  by cholic acid  solubilization, ammonium sulfate  fraction-
ation,  heat treatment, and  DEAE-Sephadex A-50 column  chromatography.
The  45-fold purified enzyme  (38% yield) was  thought to consist  of a
single  protein with a relative molecular mass of approximate 74 000, a
Michaelis constant  (Km) of 0.21 mmol/litre for [1R, trans ]-phenothrin,  
and an optimum pH of 7-9.  It was susceptible  to inhibition by organo-
phosphate  and  carbamate  insecticides and insensitive to  p-chloromerc-
urybenzoic  acid  and  to mercuric  and cupric ions.  The enzyme seemed  
to require neither coenzymes nor cofactors and hydrolysed trans isomers 
of several  synthetic  pyrethroids (tetramethrin, resmethrin,  trans- or 
 cis-phenothrin and permethrin) well, at more or less similar rates.  On 
the other hand, the cis  isomers were hydrolysed at  rates one-fifth to 
one-tenth of those of the trans counterparts.  The purified  pyrethroid 
carboxyesterase was apparently identical in nature to malathion carbox-
yesterase  and   p-nitro  phenyl  acetate   carboxyesterase  (Suzuki & 
Miyamoto, 1978).

6.  EFFECTS ON THE ENVIRONMENT

    Acute toxicity data of permethrin on aquatic and  terrestrial  non-
target organisms are summarized in Tables 5 and 6, respectively.

6.1   Toxicity to Aquatic Organisms

6.1.1  Aquatic microorganisms

    Stratton & Corke (1982) investigated the toxicity of permethrin and
ten  of its  degradation products  on the  growth, photosynthesis,  and
acetylene-reducing  activity of two species of green  algae  ( Chlorella
 pyrenoidosa and  Scenedesmus quadricaudata ) and three species of cyano-
bacteria  ( Anabaena spp.).  Permethrin itself was  relatively non-toxic
to  photosynthesis (EC50 values  >100  mg/litre) and to  acetylene  re-
duction  (EC50 values  >100 mg/litre).   Its degradation products  were
similarly  non-toxic to green  algae.  However, the  cyanobacteria were
susceptible  to some of the  breakdown products of permethrin.   Growth
was the most sensitive parameter with growth yield  showing EC50 values 
of 2.5, 2.2, and 1.4 mg/litre for  the cyanobacteria and 2.8 and 4.3 mg/
litre  for  the  green algae with PBalc and similar values for three of
the five test species with PBald.  A complex test system found interac-
tions  between the various  metabolites and the  parent compound  which
were  sometimes additive and  sometimes synergistic.  The  authors con-
cluded that it is difficult to assess the true toxicity of compounds to
soil and water microorganisms without considering the  breakdown  prod-
ucts.   The cyanobacteria are significant  nitrogen-fixing organisms in
wet tropical soils.

6.1.2  Aquatic invertebrates

    Non-target  invertebrates, except molluscs,  are more sensitive  to
permethrin than fish, as shown in Table 5.

    During  exposure of  permethrin for  up to  28 days, the  caddisfly
 (Brachycentrus  americanus)  and  the  stonefly  (Pteronarcys  dorsata) 
showed behavioural changes or death at concentrations as  low  as 0.022 
µg/litre (Anderson, 1982).

    A  3-h exposure to  permethrin, at 50 mg/litre,  was not lethal  to
 Daphnia  pulex.  The no-effect levels were 1 µg/litre   for racemic, 1R
or  (+)-trans, and 1R or (+)-cis, and 50 µg/litre   for 1S or (-)-trans
and 1S or (-)-cis isomers (Miyamoto, 1976).

    Zitko  et al. (1979)  established lethal threshold  values for  the
lobster  Homarus  americanus of 7.00 µg/litre   for technical permethrin
and 0.40 µg/litre for [1R, cis ]-permethrin.

    Larval  oyster and bullfrog  (tadpole) are highly  tolerant to  the
insecticide,  with LC50 values  of >1000  and 7000 µg/litre,   respect-
ively.

    Stratton & Corke (1981) reported that the 48-h LC50   of permethrin
to juvenile  and adult waterfleas  Daphnia magna was 0.2-0.6 µg/litre.  A
further  series  of  experiments involved  the  addition  of  algae  or
bacteria  to the cultures of daphnids, since feeding of daphnids during

these  tests  had  been reported  to  reduce  the toxicity  of  several
chemicals  to the animals.  With permethrin, however, algae in the test
vessel  increased the  lethal effect of the  compound.  Algae, bacteria,
and  also inert silica powder  adhered to the swimming  antennae of the
daphnids,  causing the daphnids to  sink and die on  the bottom of  the
flasks.   The effect was  greatest with adults;  the shed carapaces  of
juvenile  showed the same  adhesion of particulates  but moulting  pro-
tected the juveniles to some degree.  This raised toxicity was due to a
direct effect of the permethrin on the daphnids and not to  a  tendency
for the compound to cause flocculation of the suspended material.

    Friesen  et  al.  (1983)  tested  the  toxicity  of  permethrin  to
sediment-living nymphs of the mayfly  Hexagenia rigida. In test vessels
containing water without sediment, the 6-h LC50 was  estimated  to  lie
between  0.58 and 2.06 µg/litre;   no nymphs survived exposure to water
concentrations  of  7.63 µg/litre.    In  the  presence  of   sediment,
lethality  was reduced; there  was 88% mortality of  nymphs exposed  to
permethrin  in water at 7.63 µg/litre   after 24-h exposure.  Mortality
reached  100% only after 7 days exposure with sediment. Maximum concen-
trations of permethrin in the sediment over the 7 days  were  estimated
to be 50 µg/kg   dry weight. The authors also exposed nymphs  to  sedi-
ment  previously exposed to permethrin. The initial water concentration
was again 7.63 µg/litre,   and the sediment was left for 8 days to take
up  the  insecticide before  the water was  decanted off.  Nymphs  were
introduced along with clean water over the contaminated sediment. There
was 100% mortality in the exposed nymphs.  Long-term exposure  to  both
water  and  sediment contaminated  with  permethrin led  to  increasing
mortality up to 4 weeks; there was little further mortality  between  4
and 10 weeks.  Lethality reached 100% after exposure to either water or
sediment at a simulated application rate of 7.3 g/ha over 10 weeks (95%
at 4 weeks), whereas a simulated exposure equivalent to 0.6 g/ha led to
74% mortality after a 10-week exposure of the nymphs in water  and  45%
after  exposure of the nymphs to sediment.  The authors comment that it
is  not yet possible to state a concentration of permethrin in sediment
which is sufficiently low to permit successful recolonization  of  con-
taminated sediment.

6.1.3  Fish

    Permethrin  is highly toxic  to fish, as  shown in Table 5.   Prep-
arations using an emulsifiable concentrate of permethrin  enhanced  its
toxicity twofold (Coats & O'Donnell-Jeffery, 1979).

    The  lethal  toxicity of  permethrin  varied inversely  with  water
temperature,  particularly between 10  and 20°C, and  with body  weight
between  1 and 50 g.  There  was a 10-fold difference  between the 96-h
LC50 values  at 10 and 20°C.  At 15°C, a large trout (200 g)  was  con-
siderably  more (about  100 times) tolerant  than a  small  fish  (1 g)
(Kumaraguru & Beamish, 1981).

    Toxicity to fish is linked more with the nature of the optical iso-
mers  than  with that  of the stereoisomers;  i.e. 1R isomers  are more
toxic  than 1S isomers. Trans  and cis isomers are  of similar toxicity
(Miyamoto, 1976).

    Zitko  et al. (1979)  established lethal threshold  values for  the
Atlantic  salmon  Salmo salar of 8.8 µg/litre   for technical permethrin
and 1.34 µg/litre for [1R, cis ]-permethrin.

    Hansen  et  al.  (1983) exposed  embryos  and  the hatched  fry  of
sheepshead minnow  (Cyprinodon  variegatus), continuously over 28 days,
to  concentrations  of permethrin  of 1.25, 2.5, 5.0, 10, 20, or 40 µg/
litre.  The  survival of  embryos was  unaffected by  any  of  the test  
concentrations.  Fry were affected by exposure to 20 µg/litre  or  more 
but unaffected by 10 µg/litre. The toxicity curve was steep; 99% of fry
survived  at 10 µg/litre   but only  1% at 20 µg/litre.    The  authors
estimated the ratio between the 96-h LC50 and the NOEL to be 0.8.

    Holdway  &  Dixon  (1988)  exposed  larval  fish   (white   sucker,
 Catastomus   commersoni,  and flagfish,  Jordanella  floridae ) to per-
methrin in a single 2-h pulse and examined lethality over the following
96-h. They examined the effect of age, and whether or not the fish were
fed, upon the toxic effect of the insecticide.  Feeding  decreased  the
toxicity  of permethrin to flagfish at 2 and 4 days of age but not at 8
days.   Age was the most important factor affecting toxicity.  The 96-h
LC50 (from   exposure  for  2 h) was  5.55 mg/litre, 7.91 mg/litre, and
0.57 mg/litre  for flagfish  of age  2, 4,  and  8 days,  respectively.
White  suckers were most susceptible  to permethrin at 20 days  of age,
with  a 2-h LC50 of  10.0 µg/litre.    Unfed white suckers at 13 and 20
days of age were highly susceptible to permethrin, with LC50 values  of
2.0 and 1.0 µg/litre,    respectively.  The  authors pointed  out  that
permethrin is  toxic  to cladocerans  (waterfleas) at levels of 0.5 µg/
litre and that  fish  could suffer both from the direct toxic effect of 
the insecticide and the added effect experienced during food deprivation.

    When used for mosquito control, the safety margins  (LC50 fish/LC50
mosquito larvae) for permethrin and  cis-permethrin  are 2-40 and 25-65,
respectively  (Mulla et al.,  1978a).  When intraperitoneally  injected
into  rainbow trout, the  trans- and  cis-permethrin  isomers  were about
110 and 5 times,  respectively,  more  toxic  to  trout  than  to mice,
(Glickman et al., 1981).

    Rainbow  trout exposed to sublethal concentrations of permethrin in
water  (0.09-0.35 µg/litre)   or in food  (85-350 µg/kg)   in 20-40-day
experiments  showed similar branchial changes,  i.e. epithelial separa-
tion or necrosis, mucus cell hyperplasia, clubbing of epithelial cells,
or hyperplasia and fusion of adjacent secondary lamellae (Kumaraguru et
al., 1982).

6.1.4  Field studies and community effects

    In  studies by Mulla et al. (1975), permethrin was applied to ponds
at  rates of  56 g/ha and  112 g/ha in  field trials.   The numbers  of
 Tanypodinae (mostly  Pentaneura and  Tanypus )  and  Chironominae (mostly
 Tanytarsus and  Chironomus )   midge  larvae were  slightly depressed by
the  56 g/ha treatment.  Mayfly  (mostly  Baetis sp.) naiads and  diving
beetle  ( Hydrophilidae and  Dytiscidae )    larvae  and adults  were also
affected.      However,  Copepoda (mostly  Cyclops and  Diaptomus )   and
 Ostracoda (mostly  Cypricercus and  Cyprinotus ) were not greatly affec-
ted.   The effect on these non-target organisms was much greater at the

higher  dose level of permethrin, except for the ostracods. It was con-
cluded  that  permethrin affected  mayfly  naiads severely  during  the
exposure  period.  Most populations recovered  within 2 weeks following
exposure.

    Mayfly naiads (mostly baetids) were also adversely affected by per-
methrin at 5.6-28 g/ha and by its cis isomer at 2.8-28 g/ha.  There was
a  slight recovery  within 1-3 weeks  after treatment  (Mulla  et  al.,
1978b).

    Permethrin  was applied weekly  for 6 or 8 successive weeks  at the
mosquito larvicidal rate of 28 g/ha (and at a rate 5 times  higher)  to
ponds  where 20 individuals  of mosquito  fish or  desert pupfish  were
maintained.   The insecticide produced  no adverse effects  on the  two
species  of fish, and the number of fish in the treated ponds increased
markedly during the experiment.  At the higher rate, mats of algae were
formed,  probably as the  result of elimination  by permethrin of  her-
bivorous arthropods that feed on the algae (Mulla et al., 1981).

    Kaushik  et al. (1985) investigated the effect of permethrin on the
pelagic zooplankton of a 10-ha lake in southern Ontario,  Canada.   The
insecticide  was applied to give  nominal water concentrations of  0.5,
5.0,  or  50 µg/litre    in  in situ aquatic  enclosures of 5 x 5 x 5 m.
Macrozooplankton (daphnids and copepods) were most susceptible  to  the
insecticide.   The numbers, which in untreated enclosures were 100-1000
organisms  per litre of water,  fell in the days  immediately following
treatment  to  1-10  at   0.5 µg/litre,   0.1-1.0 at  5.0 µg/litre, and 
0.01-0.1 organisms  per litre at 50 µg/litre   of permethrin (nominal). 
Microzooplankton (mainly rotifers) were unaffected  by all doses except  
the highest. At this dose, numbers fell transitorily to about one tenth 
of their  control levels (about 1000 organisms per litre). In all cases 
of treatment, rotifer numbers  increased  between 5- and 10-fold 20  to  
100 days after treatment. The authors  attributed this rise in  numbers 
to the resistance of the organisms to the insecticide coupled with a re-
duction in the predator organisms that normally feed on  the  rotifers.
Populations  of macrozooplankton had returned to normal within 250 days
of  treatment (after the winter  freeze) even with the  highest dose of
50 µg/litre.   Recovery was quicker with the lower doses (about 60 days
for  treatment at  5 µg/litre and  30 days for most species at 0.5  µg/
litre). Despite this recovery in overall  numbers of zooplankton, there  
was a decrease  in the species diversity of the larger, predator organ-
isms at  all  treatment levels.  The  enclosures, of  course, prevented 
immigration from the surrounding areas of water.

    Helson  et al. (1986) placed two species of aquatic arthropods (the
amphipod  Gammarus pseudolimnaeus and  the mosquito  Aedes aegypti )  in
open  containers of different  sizes downwind from  the application  of
permethrin to young spruce trees for control of defoliators. The insec-
ticide  was  applied  to trees 0.75-0.8 m tall in a single swath from a
mistblower backpack.  Nominal application rates of 36 g ai/ha were used
with  a swath width of  10 m, and standard and  ultra-low volume appli-
cations were made.  The mortality of  Gammarus after 48 h  averaged  95%
(range  76-100%) in the first trial and 85% (range 37-100%) in a dupli-
cate trial in containers 10 m downwind from the spraying.   The  effect
was  reduced to 12% and 18% at a distance of 30 m from the spraying and
further  reduced  to an  average of 5%  50 m from the  spray.  Mosquito

larvae  were examined only in the second trial and showed 76% (37-100%)
at  10 m falling to 6%  and 2% at 30  and 50 m, respectively, from  the
spray.  Mortality increased over the following 9 days. The authors also
determined  48-h LC50 values  for the two organisms in containers simi-
larly placed in the field. These were 0.37 µg/litre and  0.69 µg/litre for
 Gammarus and  mosquito  larvae,  respectively,  while  LC95 values were
0.61 µg/litre    for  Gammarus and 1.14 µg/litre   for  mosquito larvae.
The  authors regarded these data as a  "worst case" , since sediment in
natural  water and flowing water in streams could be expected to reduce
the  toxic effect of the permethrin.  They concluded that a 30-m safety
zone  needs to be left using this application method between a spraying
area and natural waters to avoid killing aquatic arthropods.

    When permethrin was applied by airplane to the surface of  a  creek
at  a nominal rate of 70 g ai/ha, the actual concentration that reached
the ground was 13.4 g ai/ha.  Dramatic, but short-lived,  increases  in
the  drift of aquatic insects (particularly large catches of springtail
 (Collembola),   mayfly  nymphs  (Ephemeroptera   heptageniidea), water
scavenger  beetle larvae  (Coleoptera  hydrophilidae), midge larvae and
pupae, water boatmen  (Hemiptera  corixidae), predaceous diving beetles
 (Coleoptera dytiscidae), and caddisfly larvae   (Trichoptera)) occurred 
after treatment. No effects on populations of organisms that  inhabited  
the bottom layer of  the creek were noticeable. The permethrin  sprayed  
had little effect on caged or native fish and no fish mortality was re-
corded due to the treatment. From these data, it could be inferred that
permethrin  had no significant impact on the aquatic system (Kingsbury,
1976).

    After an aerial application of permethrin at 17.5 g ai/ha, residues
attained  peak  concentrations of  147.0 µg/litre in ponds and  2.5 µg/litre
in  streams, but  accumulations and  persistence of  the  pesticide  in
bottom sediment were negligible.  Noticeable increases in the number of
drifting organisms occurred in the treatment block  ( Ephemeroptera  hepta-
 geniidae,   Baetidae, and  Plecoptera nymphs )  and  2.1 km   downstream
(mayfly and stonefly nymphs) over a 24-h period immediately  after  the
spray.    A   slight  reduction  in  the  bottom  fauna  also  occurred
downstream. When exposed in cages in the ponds, yellow perch  (Perca flu-
 vescens) did not exhibit any adverse effects; little or no accumulated
permethrin residues were detectable in the fish following exposure. Ob-
servations of the headwater ponds indicated that permethrin application
resulted  in noticeable levels of distress and mortality to surface and
littoral  invertebrates and produced a similar impact on benthic organ-
isms (Kingsbury & Kreutzweiser, 1980a).


Table 5.  Acute toxicity of permethrin to non-target aquatic organisms
--------------------------------------------------------------------------------------------------------------------------------------------
Species                          Size           Duration  Toxicitya   Formu-     Sys-  Tempera-  pH         Hardness   Reference
                                                of test   (µg/litre)  lationd    teme  ture (°C)
--------------------------------------------------------------------------------------------------------------------------------------------
A. Freshwater Organisms

 Arthropods
 Crayfish                        0.8 - 1.2 cm,  96 h      0.39        EC          S    24                   100        Jolly et al. (1978)
   (Procambarus clarkii)          (0.05 g)
                                 2 - 3 cm,      96 h      0.62        EC          S    24                   100        Jolly et al. (1978)
                                 (0.5 g)
 Water flea  (Daphnia pulex)                     3 h       > 50 000    T           S    25                              Miyamoto (1976)
                                                3 h       > 50 000    (+)-trans   S    25                              Miyamoto (1976)
                                                3 h       > 50 000    (+)-cis     S    25                              Miyamoto (1976)
                                                3 h       > 50 000    (-)-trans   S    25                              Miyamoto (1976)
                                                3 h       > 50 000    (-)-cis     S    25                              Miyamoto (1976)
 Water flea  (Daphnia magna)      1st instar     48 h      1.26        T           S    18        7.4        42         Mayer &
 Amphipod                        immature       96 h      0.17        T           S    17        7.4        42         Ellersieck (1986)
   (Gammarus pseudolimnaeus)                                                                                            Mayer &
 Midge  (Chironomus plumosus)     3rd instar     48 h      0.56        T           S    22        7.4        42         Ellersieck (1986)
 Caddisfly                                      21 days   0.17        T           F    15        7.6 - 7.8  46 - 48    Anderson (1982)
   (Brachycentrus americanus)

 Fish
 Salmon  (Salmo salar)            6.2 cm, 5.3 g  96 h      12          T           R    10                              McLeese et al.
                                                                                                                       (1980)
 Rainbow trout                   1 g            96 h      0.62        T           F    5         7.9 - 8.2  358 - 363  Kumaraguru &
   (Salmo gairdneri)              1 g            96 h      0.69        T           F    10        7.9 - 8.2  358 - 363  Beamish (1981)
                                 1 g            96 h      3.17        T           F    15        7.9 - 8.2  358 - 363  Kumaraguru &
                                 1 g            96 h      6.43        T           F    20        7.9 - 8.2  358 - 363  Beamish (1981)
                                 5 g            96 h      6.43        T           F    15        7.9 - 8.2  358 - 363  Kumaraguru &
                                 20 g           96 h      ca. 50      T           F    15        7.9 - 8.2  358 - 363  Beamish (1981)
                                 50 g           96 h      287         T           F    15        7.9 - 8.2  358 - 363  Kumaraguru &
                                 200 g          96 h      314         T           F    15        7.9 - 8.2  358 - 363  Beamish (1981)
                                 6 cm, 3 g      24 h      135         T                10        7.5        110        Coats & O'Donnell-
                                 6 cm, 3 g      24 h      61          EC               10        7.5        110        Jeffery (1979)
--------------------------------------------------------------------------------------------------------------------------------------------

Table 5.  (contd.)
--------------------------------------------------------------------------------------------------------------------------------------------
Species                          Size           Duration  Toxicitya   Formu-     Sys-  Tempera-  pH         Hardness   Reference
                                                of test   (µg/litre)  lationd    teme  ture (°C)
--------------------------------------------------------------------------------------------------------------------------------------------
 Rainbow trout (contd.)
   (Salmo gairdneri)              5 - 6 cm       48 h      6.0         EC               12-                             Mulla et al.
                                 5 - 6 cm       48 h      7.0         cis, EC          25.5                            (1978a)
                                 2 - 4 g        24 h      18          T           S    12                              Glickman
                                 2 - 4 g        24 h      25          cis         S    12                              et al.
                                 2 - 4 g        24 h      14          trans       S    12                              (1981)
 Killifish                       adult          48 h      41          T           S    25                              Miyamoto (1976)
   (Oryzias latipes)              adult          48 h      17          (+)-trans   S    25                              Miyamoto (1976)
                                 adult          48 h      13          (+)-cis     S    25                              Miyamoto (1976)
                                 adult          48 h      > 10 000    (-)-trans   S    25                              Miyamoto (1976)
                                 adult          48 h      > 10 000    (-)-cis     S    25                              Miyamoto (1976)
 Channel catfish                 1.4 - 1.7 cm,  96 h      1.1         EC          S    24                   100        Jolly et al. (1978)
   (Ictalurus punctatus)          (0.02 g)
 Largemouth Bass                 4.5 - 5.5 cm,  96 h      8.5         EC          S    24                   100        Jolly et al. (1978)
   (Micropterus salmoides)        (1.14 g)


 Mosquitofish                    1.5 - 2.5 cm,  96 h      15          EC          S    24                   100        Jolly et al. (1978)
   (Gambusia affinis)             (0.25 g)
                                 4 - 5 cm       48 h      97.0        EC               8.8 - 16                        Mulla et al.
                                 4 - 5 cm       48 h      13.0        cis, EC          8.8 - 16                        (1978a)
 Brook trout                     1.2 g          96 h      3.2         T           S    12        7.5        40         Mayer & Ellersieck
   (Salvelinus foutinalis)                                                                                              (1986)
 Fathead minnow                  0.6 g          96 h      5.7         T           S    22        7.3        38         Mayer & Ellersieck
   (Pimephales promelas)                                                                                                (1986)
 Bluegill sunfish                0.7 g          96 h      5.0         T           S    22        7.3        38         Mayer & Ellersieck
   (Lepomis macrochirus)                                                                                                (1986)
 Desert pupfish                  4 - 5 cm       48 h      5.0         EC          S    11 - 16.5                       Mulla et al.
   (Cyprinodon macularis)         4 - 5 cm       48 h      5.0         cis, EC     S    11 - 16.5                       (1978a)
  Tilapia mossambica              5 - 6 cm       48 h      44.0        EC          S    15 - 21.4                       Mulla et al.
                                 5 - 6 cm       48 h      5.6         cis, EC     S    15 - 21.4                       (1978a)
 Amphibian
 Bullfrog, tadpole               0.6 - 0.8 cm   96 h      7033        EC          S    24                   100        Jolly et al. (1978)
   (Rana catesbeiana)
--------------------------------------------------------------------------------------------------------------------------------------------

Table 5.  (contd.)
--------------------------------------------------------------------------------------------------------------------------------------------
Species                          Size           Duration  Toxicitya   Formu-     Sys-  Tempera-  pH       Salinity     Reference
                                                of test   (µg/litre)  lationd    teme  ture (°C)          (°/oo)
--------------------------------------------------------------------------------------------------------------------------------------------
B.  Estuarine and Marine Organisms

 Algae
   Skeletonema costatum                          96 h      92b         T                20                              Borthwich & Walsh
                                                                                                                       (1981)
 Molluscs
 Oyster  (Crassostrea virginica)  2-h larva      48 h      > 1000c     T           S    25                   20         Borthwich & Walsh
                                                                                                                       (1981)
 Arthropods
 Lobster  (Homarus americanus)    450 g          96 h      0.73        T           R    10                   30         McLeese et al.
 Shrimp  (Crangon Septemspinosa)  1.3 g          96 h      0.13        T           R    10                              (1980)
 Shrimp  (Mysidopsis bahia)       1-day,         96 h      0.046       T           S    25                   20         Borthwich        
                                 juvenile                                                                              & Walsh
 Stone crab  (Menippe mercenaria) Zoea larva     96 h      0.018       T           S    25                   20         (1981)
 Pink shrimp  (Penaeus duorarum)  adult          96 h      0.22        T           F    25                   25         Mayer (1987)

 Fish
 Harpacticoid  (Nitocra spinipes) 3-6 weeks old  96 h      0.6         EC          S    20 - 22   7.8        7          Linden et al.
 Bleak  (Alburnus alburnus)       8 cm           96 h      4 - 8       EC          S    10        7.8        7          (1979)
 Sheepshead minnow               28-day fry     96 h      88          T           S    25                   20         Borthwich & Walsh
   (Cyprinodon variegatus)                                                                                              (1981)
                                 adult          96 h      7.8         T           F    30                   22         Mayer (1987)
 Atlantic silverside             adult          96 h      2.2         T           F    26                   25         Mayer (1987)
   (Menidia menidia)
 Striped mullet  (Mugil cephalus) juvenile       96 h      5.5         T           F    24                   19         Mayer (1987)
--------------------------------------------------------------------------------------------------------------------------------------------
a   Values are LC50 unless stated otherwise.
b   EC50 (growth inhibition).
c   EC50 (abnormal development).
d   T = Technical, EC = Emulsifiable concentrate.
e   R = Renewal, S = Static, F = Flow-through.
f   expressed as mg CaCO3/litre.
    When  permethrin was sprayed at 8.8, 17.5, 35.0, or 70.0 g ai/ha by
aeroplane over small trout streams, the impact on aquatic invertebrates
and  effects on the general  fish population correlated with  the dose.
There was an increase in the number of organisms  drifting  downstream,
the major ones being mayflies, followed by caddisflies, stoneflies, and
chironomids.  The total number of drifting organisms was  greater  than
the pre-spray average by factors of 303, 699, 4960, and 6450 with spray
concentrations of 8.8, 17.5, 35.0, and 70.0 g ai/ha,  respectively.   A
return to pre-spray drift levels was evident within 36 h  after  appli-
cation  at 8.8 and 17.5 g ai/ha whereas drifting  of organism persisted
for  up  to  72 h at the higher application rates of 35 and 70 g ai/ha.
Following the spraying of permethrin at these higher doses,  there  was
no  evidence of fish mortality, but there appeared a dramatic change in
the diets of fish (such as the native brook trout and sculpins).  These
fish became virtually completely dependent on terrestrial invertebrates
rather than on the aquatic insects for food.  When the rate  of  appli-
cation  was low (8.8 g ai/ha) permethrin did not appear to affect these
fish,  either in mortality rate or in their diet composition (Kingsbury
& Kreutzweiser, 1980b).

    Serial applications of permethrin, once or twice  at  17.5 g ai/ha,
resulted in catastrophic drift of aquatic invertebrates and substantial
depletion of benthos in streams within the application blocks and up to
2 km  downstream. Despite massive disturbances of benthos, repopulation
of  bottom fauna was  evident within 2.5 months  and had virtually  re-
turned  to normal within 3.5 months.  Permethrin residues attained peak
levels  of  1.35 µg/litre   in  standing  water and  1.94 µg/litre   in
flowing  water in the  sprayed regions.  The  residue persisted at  low
concentrations for up to 96 h after spraying (Kreutzweiser, 1982).

    In  a study by Kingsbury & Kreutzweiser (1987), aerial applications
of  permethrin to forests over several seasons at 8.8, 17.5, 35, and 70
g ai/ha  did  not cause  mortality to native  and caged fish  (minnows,
mudminnows,  perch, and under-yearling  and yearling Atlantic  salmon).
The  composition of  the salmonid  diet was  subsequently altered  from
aquatic  insects (mayfly nymphs,  stonefly nymphs, and  various aquatic
fly  larvae) to terrestrial arthropods.  The duration of changes ranged
from  a few months after applications of 8.8 and 17.5 g ai/ha to a year
or longer after treatment with 35 and 70 g ai/ha.  There were temporary
reductions  in fish growth rate and fish densities in the treated area,
which  returned to normal within  four months after treatment.   In the
same  study, the  effect on  stream invertebrates  was also  evaluated.
Large  drifts of invertebrates  were observed immediately  after appli-
cations  and continued for 24 to 72 h.  Although the peak of permethrin
residues in stream water was higher after the second application (0.36-
1.80 µg/litre)    than the first (0.25-0.62 µg/litre),   drift response
to  the  second application  ranged from 6  to 62% of  the first drift,
indicating  that  first  application deleted  susceptible invertebrates
(e.g.,   Ephemeroptera  nymphs,   Plecoptera,  Trichoptera,   and   the
 Diptera   families) and that  a much smaller  residual population  re-
sponded  to the second treatment.  Recovery of benthic fauna was appar-
ent  between 1  and 18 months  after spraying.   The  double  treatment
reduced  benthos density to  a point at  which recovery of  numbers was
slower  than after the  single application (Kreutzweiser  &  Kingsbury,
1987).

6.2   Toxicity to Terrestrial Organisms

6.2.1   Soil microorganisms

    Mathur  et al. (1980) applied  permethrin (Ambush 5 G)  to Canadian
soils  with a high content of organic material at a rate of 2.24 kg/ha.
Lettuce or carrots were grown on the plots.  Soil cores were  taken  at
regular intervals and bacterial and fungal numbers were estimated, soil
nutrients  were measured, and acid phosphatase activity in the soil was
monitored.   Residues  of  permethrin persisted  throughout the growing
season  up to crop harvest,  when 65% of the  original concentration in
soil  was found (113 days after  application). This reflected the  poor
breakdown  of permethrin in  organic soils compared  to mineral  soils.
Permethrin suppressed bacterial and actinomycete populations in samples
taken  1, 9, and 27 days after application, but control levels were re-
gained  after 41 days (the next sampling time).  The available nitrogen
and  phosphorus  was lower  in treated soil  at some points  during the
study, but these changes were not consistent. Soil respiration and acid
phosphatase  activity were higher  in permethrin-treated plots,  though
not consistently so.  Permethrin had a greater effect when carrots were
grown  than when  lettuce was  grown.  The  yield of  neither crop  was
affected.  Most of the effects reported were transitory and  none  were
of overall significance for either the soil or the crop.

6.2.2  Terrestrial invertebrates

    Under  laboratory conditions, permethrin is highly toxic to certain
beneficial insects or natural enemies of pests, as shown in Table 6.

    Cox & Wilson (1984) treated honey bee workers topically with a sub-
lethal dose of permethrin (0.09 µg/bee   in 1.0 µl   of acetone applied
to  the thorax). This dose gave no higher mortality than treatment with
acetone alone. The bees, which were individually tagged, were housed in
an  observation hive and  trained before the  experiment to feed  at an
artificial  feeding station 5 m from the hive.  The experiment was con-
ducted  at  35°C because  at lower temperatures  this dose resulted  in
mortality. Treated bees made less foraging trips than controls and gave
food  less frequently to other bees in the hive.  Other behaviours were
increased  in treated bees,  i.e., self-cleaning, trembling  dance, ab-
domen tucking, and rotating and cleaning of abdomen while  rubbing  the
hind legs together. Gerig (1985) also reported minimal  lethal  effects
on  honey  bees of  permethrin used at  recommended rates and  that the
insecticide had a strong repellent effect.


Table 6.  Acute toxicity of permethrin to non-target terrestrial organisms
-----------------------------------------------------------------------------------------------------------------------------
Species                     Size           Application   Duration   Toxicitya            Temperature   Reference
                                                                                         (°C)
-----------------------------------------------------------------------------------------------------------------------------
 Bird
 Hen                                       oral                     > 1.5 g/kg b.w.b                   Millner & Butterworth
                                                                                                       (1977)
 Chicken                                   oral                     > 3 g/kg b.w.b                     Worthing & Walker
 Japanese quail                            oral          5 days     > 13.5 g/kg b.w.b                  (1983)
                                           diet          5 days     > 5 g/kg dietc                     Hill & Camardese
                                           diet          5 days     > 5 g/kg dietd                     (1986)
 Mallard duck                              diet          5 days     > 27.5 g/kg diet                   Ross et al. (1976b)
 Mallard duck                              oral                     > 13.5 g/kg b.w.b                  Ross et al. (1976a)
 Starling                                  diet          5 days     > 27.5 g/kg diet                   Ross et al. (1976d)
 Starling                                  oral                     > 38 g/kg b.w.b                    Ross et al. (1976c)
 Ring-necked pheasant                      diet          5 days     > 27.5 g/kg diet                   Ross et al. (1976e)
 Ring-necked pheasant                      oral                     > 13.5 g/kg b.w.b                  Ross et al. (1977a)

 Arthropods                                                                               
 Honeybee  (Apis mellifera)                 contact                  0.11 µg/beeb         26 - 27      Stevenson et al. (1978)
                                           oral                     0.28 µg/beeb         26 - 27      Stevenson et al. (1978)
 Insect parasite
 Ichneumoid  (Campoletis     adult male     film          24 h       0.31 µg/vial                      Plapp & Vinson (1977)
   sonorensis) 
 Insect predator
 Carabid  (Pterostichus      adult 0.16 g   topical                  > 2000 µg/insectb    21           Hagley et al. (1980)
   melanarius) 
 Carabid  (Harpalus affinis) adult 0.05 g   topical                  116 µg/insectb       21           Hagley et al. (1980)
 Carabid  (Amara sp.)        adult 0.03 g   topical                  25 µg/insectb        21           Hagley et al. (1980)
 Earwig  (Labidura raparia)  mature         soil 0.1 kg              6% mortality                      Workman (1977)
                                             ai/ha
                            mature         soil 0.2 kg              50% mortality                     Workman (1977)
                                             ai/ha
 Green lacewing             larvae
   (Chrysopa carnea)         5-6 days old   film                     9.87 µg/vial         25           Plapp & Bull (1978)
 Predaceous mite species
   Mataseiulus occidentalis  adult female   slide-dip                0.72, 1.32,          27.5         Roush & Hoy (1978)
  (3 strains)                              method                   14.8 mg ai/litre
                            young gravid   leaf-disc                2.8 mg ai/litre      27           Hoy et al. (1979)
                            female         method
   (Amblyseius fallacis)     adult female   slide-dip                14 mg ai/litre       27           Rock (1979)
                                           method
-----------------------------------------------------------------------------------------------------------------------------
a   LC50 values, unless stated otherwise.
b   LD50 values; b.w. = body weight.
c   Technical product.
d   Emulsifiable concentrate.
 
    Pike  et al. (1982) applied  permethrin by helicopter at  a rate of
0.22 kg ai/ha to fields of maize  (Zea  mays).  The  applications  were
made early in the morning before bees were actively foraging for pollen
and were repeated every 3 to 6 days (to a maximum of  six  applications
per season). The trial was repeated for 3 years. There was  no  differ-
ence  in  the  number of dead bees per hive between treated and control
areas, but a marked reduction in the number of bees foraging in treated
fields, indicating avoidance of permethrin.  The authors concluded that
treatment of corn fields with permethrin at the normal application rate
is  safe for bees as long as the application does not coincide with bee
activity in the area.

    The   acute  toxicity  values  of  permethrin  to  tobacco  budworm
 (Heliothis  virescens), to the green lacewing  (Chrysopa   carnea),  a
predator   of  tobacco  budworm,  and   to  Campoletis  sonorensis,  an
ichneumoid  parasite  of tobacco  budworm,  showed that  permethrin was
approximately  18 times less toxic  to the predators  than to the  pest
(Plapp & Bull, 1978; Plapp & Vinson, 1977).

    Larvae  of the green  lacewing exhibited marked  tolerance to  per-
methrin,  and to its  cis or trans  isomers, when dosed  topically with
250 µg per insect (about 25 000 µg/g).  This  value is ca. 10 000 times 
greater than the LD50 value for the tobacco budworm (Shour & Crowder, 
1980).

    Workman (1977) added permethrin to loamy sand soil into  which  the
striped  earwig  (Labidura  riparia),  an effective insect  predator of
the cabbage looper, was introduced. The insecticide was of low toxicity
to the earwig at dosage rates which gave good looper control.

    The  susceptibility of  carabids to  permethrin appears  to be  in-
versely related to beetle size, as shown in Table 6.   When  permethrin
was  applied  at  a concentration  of  0.21-0.85 kg ai/ha  to an  apple
orchard,  it did not  significantly affect the  numbers of  Pterostichus
 melanarius at any time during the season, but the  numbers  of  Harpalus
 affinis and  Amara sp.  were significantly reduced 3-5 days after appli-
cation. This result reflected the  toxicity  ratings  by  means of LD50
values obtained in laboratory studies.  The total seasonal  numbers  of
these  carabids were not significantly affected by permethrin, owing to
short residual effects (Hagley et al., 1980).

    In  laboratory tests, LC50 values  of permethrin for two strains of
spider  mites  (Tetranychus  urticae) were ca. 20-40 times   greater than
those for three strains of predator  mites   (Mataseiulus  occidentalis)
(Roush  & Hoy, 1978), and ca.15   times greater than those for  Amblyseius
 fallacis (Rock,  1979).  These studies  indicate that the  use of  per-
methrin  at the recommended rates of 60-120 mg ai/litre would be detri-
mental to orchard integrated mite control programs.

    In laboratory tests, the Pacific spider mite  (T.   pacificus)  has
been found to be 40 times more tolerant to permethrin than the predator
mite  (M.  occidentalis), (Hoy et al., 1979). The spraying of vineyards
with  15 or 30 mg ai/litre resulted in substantially higher populations
of  T.  pacificus and  E.   willamettei for about one month  due to  re-
duction  in predator species numbers.   Similarly, spraying with 60  or

120 mg ai/litre  produced  a  subsequent  increase   of    Eotetranychus
 willamettei  late in August and September for the above reason (Hoy et
al., 1979).

    When  permethrin was applied to  apple trees at a  concentration of
40 mg/litre, no predator mites  (Typhlodromus  pyri) were found for 4-6
weeks,  and only small numbers were found 10 weeks after the spray.  On
the  other hand, permethrin had  no appreciable toxicity to  the spider
mite  (Panonychus  ulmi). The virtual elimination of the predatory mite
by permethrin spraying led to  a marked population  increase of  P. ulmi
later in the same season (Aliniazee & Cranham, 1980).

    In  apple and pear  orchards, applications of  permethrin at  30 mg
ai/litre reduced the numbers of a predatory mite  (M.  occidentalis) to
almost  zero and dramatically increased the populations of spider mites
 (T. urticae,  Tetranychus mcdanieli, or  P. ulmi) (Hoyt et al., 1978).

    From the above findings it appeared that permethrin,  when  applied
according  to recommendations, is  relatively harmless to  insect pred-
ators,  with the exception of  predaceous mite species.  Everts  et al.
(1985) investigated the effects of permethrin on beneficial terrestrial
arthropods in the soil and vegetation in areas surrounding applications
of  the insecticide to  control tsetse flies  in the Ivory  Coast, West
Africa.  Permethrin was used as a 2.5% wettable powder at a rate of 121
g ai/ha during January (a minimum temperature of 20.0°C and  a  maximum
of  36.0°C).   The  permethrin application  significantly reduced popu-
lations  of Coleoptera, Lepidoptera, Ephydridae, Chloropidae, Muscidae,
Ichneumonidea,  Chalcidoidea  and Proctotrupoidea.   The populations of
almost all these groups were found to recover to normal levels within 2
months, i.e., before the likely time of respraying for the  control  of
the tsetse flies.  However, one Proctotrupoid genus, Cremastobaeus, was
eliminated by permethrin treatment.

6.2.3  Birds

    Neither  an acute oral nor a dietary LD50 or  LC50 has  been estab-
lished  accurately because of  the very low  toxicity of permethrin  to
birds  (Table 6).  The acute LD50 is   >3000 mg/kg body weight  and the
dietary  toxicity >5000 mg/kg diet.  (Worthing & Walker,  1983; Hill  &
Camardese, 1986).

    The inclusion of permethrin at up to 40 mg/kg in the diet of laying
hens for 28 days had no adverse effects on the health of  parent  birds
or  on egg production  quality, hatchability, or  the viability of  the
chicks produced (Ross et al. 1977b).

6.2.4  Mammals

    Racey  & Swift (1986) treated  roosting boxes for pipistrelle  bats
with  various wood preservatives and  allowed the bats to  roost in the
boxes for up to 154 days.  There were no toxic effects of  mixtures  of
synthetic pyrethroids including permethrin.  The authors concluded that
the insecticide component of wood preservatives should  be  pyrethroids
when bats are present in the area.

6.3   Uptake, Loss, Bioaccumulation and Biomagnification

    Proposed metabolic pathways of permethrin in fish are summarized in
Fig. 4.

FIGURE 4

    When  rainbow trout  (Salmo  gairdneri)  were held in static  water
containing 5 µg/litre   of 14C-permethrin  for 24 h, both cis and trans
isomers  were similarly taken  up into the  fish.  The  bioaccumulation
ratios  for total radiocarbon in  the blood, muscle, liver,  and fat of
the fish were 30, 30, 300, and 400, respectively.  When the  fish  were
transferred  to fresh running water, radioactivity was eliminated, with
initial  half-lives of 9-35 h, from  all the tissues except  fat, where
little  decay in 14C-permethrin  concentrations occurred.  When rainbow
trout were injected intraperitoneally with 14C-permethrin  at a rate of
0.5 mg/kg,  32-43% of the dose was recovered after 48 h in the bile, 3-
7% in the urine, and 31-42% in the carcass. However, the urine and bile
of  the trout injected with the trans isomer contained higher levels of
radioactivity.  In the bile, the major metabolite was  the  glucuronide
conjugate   of   3-(4-hydroxyphenoxy)-benzyl-3-(2,2-dichlorovinyl)-2,2-
dimethyl-cyclopropanecarboxylate  (26)  and there  were few metabolites
formed  by  hydrolysis (Fig. 4).  The  urine contained  principally the
sulfate  conjugates of polar products.  The ability of rainbow trout to
hydrolyze permethrin  in vivo appeared minimal (Glickman et al., 1981).

    The  rates of  trans-permethrin  hydrolysis in  trout liver, kidney,
and  plasma incubated at 12°C were approximately 166, 38, and 59 times,
respectively,  lower  than those  in  the corresponding  mouse  tissues
incubated  at 37°C.  Although an increase in the incubation temperature
from  12°C to 37°C caused  an  increase in the rate of  trans-permethrin
hydrolysis  by trout liver microsomes,  trans-permethrin  was hydrolyzed
about  45 times  slower than  by mouse liver  microsomes at 37°C.   The
hydrolysis of permethrin in trout plasma, however, was higher than that
in trout liver microsomes (Glickman & Lech, 1981).

    When  the microsomal preparations  of both carp  and rainbow  trout
were fortified with NADPH, the carp microsomes oxidized permethrin iso-
mers  more actively than the trout microsomes.  Also, larger amounts of

hydroxy  ester metabolites were recovered with the cis isomer than with
the trans isomer.  The preferred site of oxidation of both  isomers  by
the  carp and trout microsomes was the 4'-position (26) of the phenoxy-
benzyl moiety. The geminal dimethyl group was attacked in preference to
the methyl group situated  trans to the carboxy group.  trans-Permethrin
primarily  underwent hydrolysis by both carp and trout liver microsomes
in the presence or absence of NADPH to yield PBalc (6) and Cl2CA   (17)
(Glickman et al., 1979).  In  this  respect,  the  results of  in vitro 
studies were different from those obtained  in vivo.

    Juvenile  Atlantic salmon (lipid content 4.2%), exposed for 96 h to
static  water containing 22 µg/litre   permethrin, took up the insecti-
cide  with a bioaccumulation ratio of 55.  Dead juvenile salmon exposed
for 12.5 h to 0.098-0.994 mg/litre contained 2.21-3.69 µg/g   (Zitko et
al., 1977).

    Residues  of  approximately  0.5-1.2 mg/kg were  detected  in  dead
juvenile Atlantic salmon exposed for 10-89 h to static water containing
permethrin at 6.9-85 µg/litre,   the bioaccumulation ratio ranging from
14 to 73.  The insecticide was not detected (detection limit 5 ng/g) in
dead lobster hepatopancreas or in dead shrimp (McLeese et al., 1980).

    When stoneflies  (Pteronarcys  dorsata) were exposed for 28 days to
running  water containing permethrin at 0.029-0.21 mg/litre, the bioac-
cumulation ratios of the survivors ranged from 43 to 570 (average, 183;
standard deviation, 171) (Anderson, 1982).

    When  carp were exposed to a 14C-permethrin  isomer (phenoxyphenyl-
labelled  [1R,trans], [1R,cis], [1S,trans],  or [1S,cis] isomers)  in a
flow-through  system at 25°C, the concentrations of 14C  and permethrin
isomers  in  the fish  body reached an  equilibrium on days  7-9 of ex-
posure. The bioaccumulation ratios of the permethrin isomers  at  equi-
librium were 330-750.  When the fish were transferred to  fresh  water,
the  permethrin isomers,  as well  as their  metabolites, were  rapidly
excreted.   The biological half-lives  for the permethrin  isomers were
2.0-2.8 days.  The major metabolic reactions involved were oxidation at
the 4 -position of the alcohol moiety or the methyl group of  the  acid
moiety, cleavage of the ester linkage, and conjugation of the resultant
alcohols  and phenols with glucuronic acid or sulfuric acid (Ohshima et
al., 1988).

    Bioconcentration factors for sheepshead  minnows  ( Cyprinodon vari-
 egatus exposed  to  permethrin  at  concentrations  between  1.25   and
10 µg/litre    for 28 days from  hatching varied between  290 and  620.
Maximum bioconcentration occurred after exposure at 2.5 µg/litre,   and
a  maximum  residue of 5.7 mg/kg occurred after exposure at 10 µg/litre
(the concentrations were for whole fish) (Hansen et al., 1983).

    Permethrin and its metabolites are not accumulated in birds. During
repeated dosing to quails and to mallard ducks, very  similar  patterns
and  levels of both the appearance and depletion of radioactive residue
in  tissues  were  found.  The level in fat, which was small, reached a
plateau  during a  28-day period.   In all  tissues, residues  declined
extensively during a 14-day period after the final dose (Leahey et al.,
1977).

7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    Toxicological  profiles of permethrins with different isomeric com-
positions (cis:trans ratios of 40:60 or 25:75) were compared in a range
of  toxicological  studies.   The toxicological  profile  of permethrin
(25:75)  resembles that of  permethrin (40:60) except  that it is  less
acutely toxic than permethrin (40:60).

7.1   Acute Toxicity

    Table 7  shows the results  of acute toxicity  tests of  permethrin
with  various animal species.  Aqueous suspensions usually produced the
least toxic results, LD50 values  ranging from 3000 to >4000 mg/kg body
weight.  However, corn oil is the more standard vehicle for pyrethroids
and yielded LD50 values  of about 500 mg/kg (in all studies except one)
for oral administration in rats and mice.

    Following  oral  administration of  permethrin  to rats,  signs  of
poisoning  became apparent within 2 h after dosing and persisted for up
to 3 days. At lethal levels, these signs included whole body tremors of
varying  degree from slight to convulsive, which in some cases were ac-
companied by salivation. Associated signs were hyperactivity and hyper-
excitability to external stimuli, urination and defecation, ataxia, and
lacrimation (Parkinson, 1978; Litchfield, 1983).

    Table 8 gives the acute oral toxicity of three lots  of  permethrin
to rats. The observed ten-fold decrease in LD50 when  corn oil or olive
oil  were used could be  due to enhanced absorption  of the insecticide
(Metker et al, 1977).

    The  acute  oral toxicity  of permethrin (25:75)  to groups of  six
female  C.S.E. Wistar rats  was determined in  five different  vehicles
(Table 9).  Most symptoms of acute poisoning developed within  12 h  of
dosing  and consisted of muscular tremors, hypersensitivity to stimuli,
and staining of abdominal fur.  The majority of deaths occurred between
1 and 3 days (Wallwork & Malone, 1974).

    Groups  of  female  Sprague-Dawley rats,  either  fed  ad libitum or
starved  for  24 h  beforehand,  were  given  a  single  oral  dose  of
permethrin  (25:75) (94.1% purity) in  corn oil solution  (40% w/v)  at
750, 1500, 3000, or 6000 mg/kg.  Permethrin was more toxic  in  starved
animals  (LD50 = 3000 mg/kg) than in animals that had been fed  (LD50 =
4251 mg/kg) (Piercy et al., 1976).

    The acutetoxicity  of  permethrin  with various  cis- and  trans-per-
methrin ratios is indicated in Table 10. These data clearly demonstrate
that   cis-permethrin   is more toxic than  trans-permethrin  to rats and
mice.


Table 7.  Acute toxicity of permethrin administered to various
animal species
-------------------------------------------------------------------------
Species Sex   Routea   Vehicleb    LD50         Reference
                                   (mg/kg body 
                                   weight)
-------------------------------------------------------------------------
Rat     M     oral     waterc      2949        Parkinson 1978
        F     oral     water       > 4000      Parkinson et al. 1976
        M     oral     DMSO        1500        Clark 1978
        F     oral     DMSO        1000        Clark 1978
        M     oral     corn oil    500         Jaggers & Parkinson 1979
        M     oral     corn oil    430         Kohda et al. 1979a
        F     oral     corn oil    470         Kohda et al. 1979a
        M&F   oral     corn oil    1200        Braun & Killeen 1975
        M&F   oral     water       1725        Sasinovich & Panshina 1987
        M     dermal   water       > 5176      Parkinson 1978
        F     dermal   noned       > 4000      Parkinson et al. 1976
        M     dermal   noned       > 2500      Kohda et al. 1979a
        F     dermal   noned       > 2500      Kohda et al. 1979a
        M&F   dermal   xylene      > 750       Clark 1978
        M&F   dermal   none        2000        Sasinovich & Panshina 1987
        M     sc       corn oil    7800        Kohda et al. 1979a
        F     sc       corn oil    6600        Kohda et al. 1979a
        M     ip       water       > 3200      Parkinson et al. 1976
        F     ip       water       > 3200      Parkinson et al. 1976
              ip                   463 - 1725  Sasinovich & Panshina 1987

Mouse   F     oral     water       > 4000      Parkinson et al. 1976
        M&F   oral     DMSO        250 - 500   Clark 1978
        M     oral     corn oil    650         Kohda et al. 1979a
        F     oral     corn oil    540         Kohda et al. 1979a
        M     dermal   noned       > 2500      Kohda et al. 1979a
        F     dermal   noned       > 2500      Kohda et al. 1979a
        M     sc       corn oil    > 10 000    Kohda et al. 1979a
        F     sc       corn oil    10 000      Kohda et al. 1979a

Rabbit  F     oral     waterc      > 4000      Parkinson et al. 1976
        F     dermal   noned       > 2000      Parkinson et al. 1976

Guinea- M     oral     water       > 4000      Parkinson et al. 1976
pig

Hen           oral                 > 1500      Milner & Butterworth 1977
-------------------------------------------------------------------------
a   sc = subcutaneous; ip = intraperitoneal.
b   DMSO = dimethyl sulfoxide.
c   as an aqueous suspension.
d   technical material applied without vehicle.
Table 8.  Acute oral toxicity of three lots of permethrin to rats
------------------------------------------------------------------
Lot No.c        Strain                Sex      Solvent     LD50 
                                                           (mg/kg)
------------------------------------------------------------------
827-RSP-1422    Sprague-Dawley        Male     None        5010
                                      Female   None        3801

827-RTP-1450    Sprague-Dawley-1a     Male     Corn oil    563

                Sprague-Dawley-2b     Male     Corn oil    383

827-RTP-1450    Long-Evans            Male     None        4892
                                      Female   None        2712

8719-RTP-1450   Sprague-Dawley        Male     Olive oil   584
                                      Female   Corn oil    413
------------------------------------------------------------------
a   Average body weight was 220 g.
b   Average body weight was 321 g.
c   Isomeric composition and the purity of the compound in each lot 
    were as follows:

--------------------------------------------
Lot No.           Isomeric Ratio    Stated
                  cis      trans    Purity
--------------------------------------------
827-RSP-1422      44%      56%      93.6%
827-RTP-1450      45%      55%      95.0%
8719-RTP-1450     46.5%    53.5%    92.4%
--------------------------------------------

Table 9.  Acute toxicity of permethrin (25:75) to rats
------------------------------------------------------
Vehicle                                LD50 (mg/kg)
------------------------------------------------------
Neat undiluted permethrin (control)    > 20 000
40% w/v in corn oil                    4672
40% w/v in petroleum distillate        > 8000
40% w/v in dimethylsulfoxide           > 8000
20% w/v in glycerol                    > 5048
------------------------------------------------------


Table 10.  Acute toxicity of permethrins with various cis:trans
isomeric ratios
---------------------------------------------------------------------------
Permethrin                       LD50
(cis:trans) Animal  Sex  Routea  (mg/kg body   Reference
                                  weight)
---------------------------------------------------------------------------
80:20       Rat     F    oral    396           Jaggers & Parkinson (1979)
57:43               F    oral    333
50:50               F    oral    748
40:60               F    oral    630
20:80               F    oral    2800
99:1        Mouse        ip      108           Glickman et al. (1982)
40:60                    ip      514
1:99                     ip      > 800

99:1        Mouse        iv      17            Glickman et al. (1982)
40:60                    iv      31
1:99                     iv      > 135
---------------------------------------------------------------------------
a   ip = intraperitoneal; iv = intravenous.
    Table  11  shows the  results of acute  oral toxicity tests  of the
metabolites of permethrin on rats (FAO/WHO, 1980b).

Table 11.  Acute oral toxicity to rats of several metabolites 
of permethrin
---------------------------------------------------------------
Chemical                                  No.a    LD50 (mg/kg
                                                  body weight)
---------------------------------------------------------------
3-phenoxybenzyl alcohol                   6       1330
3-(2,2-dichlorovinyl)-2,2-dimethylcyclo-  17      980
 propanecarboxylic acid
3-phenoxybenzaldehyde                     11      600
---------------------------------------------------------------
a   Chemical identification no. used in Fig. 3.

    Table 12 shows the results of the acute intraperitoneal toxicity to
mice of permethrin metabolites (Kohda et al., 1979b).

Table 12.  Acute intraperitoneal toxicity to mice of several
permethrin metabolites
---------------------------------------------------------------------
Chemicala                             No.b   LD50 (mg/kg body weight)
                                             Male         Female
---------------------------------------------------------------------
3-phenoxybenzyl alcohol               6      71           424
3-(4 -hydroxyphenoxy)benzyl alcohol   7      750 - 1000   750 - 1000
3-(2 -hydroxyphenoxy)benzyl alcohol   8      876          778
3-phenoxybenzoic acid                 12     154          169
3-(4 -hydroxyphenoxy)benzoic acid     13     783          745
3-(2 -hydroxyphenoxy)benzoic acid     14     859          912
3-phenoxybenzaldehyde                 11     415          416
---------------------------------------------------------------------
a   All compounds were dissolved in corn oil, except 3-phenoxybenzoic 
    acid, which was dissolved in DMSO.
b   Chemical identification no. used in Fig. 3.

7.2   Subacute and Subchronic Toxicity

7.2.1   Oral exposure

7.2.1.1   Mouse

    When male and female Alderly Park mice (20 of each sex  per  group)
were  fed permethrin in  the diet at  levels of 0,  200, 400, 2000,  or
4000 mg/kg  diet for 28 days,  mortality, growth, and  food utilization
were normal for all animals.  One additional group (permethrin level of
80 mg/kg  for 2 weeks and 10 000 mg/kg  for the final 2 weeks)   showed
weight  loss and poor food  utilization when feeding with  10 000 mg/kg
began.  Animals fed permethrin at 2000 mg/kg or more  showed  increased
liver  weight and liver-to-body weight ratio.  Higher weight and organ-
to-body  weight  ratios were  also observed in  the kidney, heart,  and
spleen of males receiving a dose of 10 000 mg/kg.  Gross tissue changes
were observed in females at 2000 and 10 000 mg/kg. On histopathological
examination, regenerating tubules in the renal cortex  and  hypertrophy
of  centrilobular hepatocytes with cytoplasmic eosinophilia, which were
not  dose related, were observed  in all the treated  animals (Clapp et
al., 1977b).

    In  a study by Wallwork et al. (1974a), groups of six mature female
mice  received daily oral doses of permethrin (25:75) in corn oil at 0,
200,  400, 800,  or 1600 mg/kg  body weight  for  10 consecutive  days.
Signs of acute toxicity, such as spasm and convulsion, were  seen  only
in the highest dose group, half of which died after the  initial  dose.
No  significant  changes in  haematology,  clinical chemistry,  or body
weights on the 11th day of dosing were recorded.  The mice  treated  at
800 and 1600 mg/kg body weight exhibited increased liver weights.

7.2.1.2   Rat

    Sprague-Dawley rats (six of each sex per group) were fed permethrin
in  the  diet  for 14 days at dose levels of 54, 108, 216, 432, 864, or
1728 mg/kg body weight per day.  All rats surviving to term were sacri-
ficed and various organs and tissues were examined histopathologically.
At  the two highest dose levels, all animals died except one female fed
864 mg/kg.   Muscle tremors were noted in all animals at 432 mg/kg, but
doses  of 216 mg/kg or less  caused no toxic signs  in either males  or
females.  There  was a  statistically  significant increase  in average
liver-to-body  weight ratios at 432 mg/kg,  but compound-related histo-
logical changes were not observed in any of the tissues or organs.  The
maximum NOEL in this study was 216 mg/kg (Metker et al., 1977).

    In  studies by Metker et  al. (1977), Long-Evans rats  (six of each
sex  per  group) were  fed permethrin in  the diet for  14 days at dose
levels of 0, 27, 54, 108, 216, or 432 mg/kg body weight per  day.   All
rats surviving to term were sacrificed and various organs  and  tissues
were examined histopathologically. At a dose of 432 mg/kg, three out of
six females died within the first five days.  Muscle tremors were noted
in all surviving animals at 216 and 432 mg/kg.  There was  a  statisti-
cally significant increase among female animals in the  average  liver-
to-body  weight ratio.  Compound-related histological  changes were not
observed in any of the tissues or organs examined.  The maximum dietary
NOEL was 108 mg/kg body weight per day.

    When  young  male  and female Wistar rats (8 of each sex per group)
were  fed  permethrin  in the diet at dose levels of 0, 200, 500, 1000,
2500,  5000, or 10 000 mg/kg diet  for 4 weeks, all rats  that received
the  highest  dose died  within 3 days. Mortality  was evident at  5000
mg/kg,  and  hyperexcitability was  observed  in animals  that received
2500 mg/kg.   Other non-specific signs  of poisoning were  observed  at
1000 mg/kg  on the first day  of the study only.   Food consumption and
growth were reduced in the animals dosed at 5000 mg/kg.  There  was  no
effect  on haematological parameters, clinical chemistry, or urinalysis
except  for a reduction in  urinary protein excretion in  males at 5000
mg/kg.   Liver weight and liver-to-body weight ratios were increased in
males at 2500 mg/kg or more and in females at 1000 mg/kg or more.  This
study had been designed as a preliminary range-finding test  for  long-
term dietary administration (Clapp et al., 1977a).

    In  a study of the reversibility of hepatic changes in rats follow-
ing short-term dietary administration of permethrin, female Wistar rats
(48 rats  per group) were fed  permethrin at levels of  0 or 2500 mg/kg
diet  for  28 days.   At the end of the feeding trial, rats were either
sacrificed  or maintained on control  diets and sacrificed at  1, 4, or
8 weeks after the termination of dosing.  There was no  mortality,  but
food consumption, food utilization, and body weight were reduced in the
permethrin-treated rats during the administration period.  However, the
animals  gained weight rapidly after the dosing period and there was no
difference in body weight between control and test animals at  the  end
of the study period. After the 4 weeks of permethrin  dosing,  signifi-
cantly higher absolute and relative liver weights were observed. During
the  8-week recovery period, the  relative liver weight of  permethrin-
treated animals was significantly higher than the control  values,  but
the  absolute  weights of  the liver of  control and test  animals were
similar. There were no effects of permethrin on plasma alanine transam-
inase over the course of the study.  Oxidative enzyme activity in liver
microsomes was significantly higher in test animals than in controls at
the end of dosing and 1 week later.  The activity of  liver  microsomal
enzymes  in  the permethrin-treated  animals  was normal  4 weeks after
dosing  but was elevated  8 weeks after dosing.   The amount of  smooth
endoplasmic reticulum in rat liver cells was significantly increased as
a result of permethrin dosing, but within 4 weeks after  dosing,  there
were  no  significant histological  differences  in the  liver  between
treated and control animals (Bradbrook et al., 1977).

    When male and female Charles River (CD) rats (six of each  sex  per
group)  were fed permethrin at levels of 0, 30, 100, 300, 1000, or 3000
mg/kg diet for five weeks, persistent tremors were evident  in  animals
fed  at 3000 mg/kg  although no  mortality was  observed.   Growth  was
inhibited in both males and females at this dose level.  Relative liver
weight was increased in both the males (1000 mg/kg or more) and females
(3000 mg/kg).  Slight effects on certain clinical chemistry parameters,
such  as increased prothrombin times  in males, were noted  at the 3000
mg/kg level. Examination of tissues and organs of the animals receiving
the two highest doses did not show any unusual effects as a  result  of
permethrin in the diet (Butterworth & Hend, 1976).

    Male  and  female Long-Evans  rats (10 of  each sex per  group) fed
permethrin  in the diet at dose levels of 0, 20, 100, or 500 mg/kg diet

for 90 days showed no mortality, and the growth and food consumption of
all animals were normal. The results of haematology,  clinical  chemis-
try,  urinalysis, and ophthalmological  examinations were also  normal.
Tremors  were noted in some  animals at the highest  dose level, mainly
during the first week of treatment.  There were  significant  increases
in  absolute and relative liver weights at the two highest dose levels.
These  increases were consistent with data from microscopic examination
of  the liver showing compound-related  centrilobular hepatocyte hyper-
trophy in both males and females.  There were no significant effects at
the  20-mg/kg level, although slight hepatic effects were reported in a
few of the male rats (Killeen & Rapp., 1976b).

    In studies by Metker et al. (1977), Sprague-Dawley rats (10 of each
sex  per  group) were  fed permethrin in  the diet for  90 days at dose
levels  of 0, 9, 27,  85, 270, or 850 mg/kg  body weight per day.   All
rats  surviving to term were killed and various tissues and organs from
each  animal were examined histopathologically.  At 850 mg/kg, all male
and  female rats died.  An increase in the average liver-to-body weight
ratio  was noted in both male and female rats fed 270 mg/kg.  Compound-
related  histological changes were not  observed in any of  the tissues
and organs examined.  The minimum effect level was 270 mg/kg  per  day.
At 85 mg/kg no effects were observed.

    When male and female Sprague-Dawley rats (16 of each sex per group)
were fed permethrin in the diet at dose levels of 0, 375, 750, 1500, or
3000 mg/kg  diet for 6 months, there  was no mortality and  all animals
exhibited  normal growth and normal food and water consumption. Urinal-
ysis,  haematological  values,  and  clinical  biochemistry  parameters
showed  no changes related to  permethrin dosing. Signs of  hyperexcit-
ability  and tremors were observed during the study in animals dosed at
3000 mg/kg and the liver weight and liver-to-body weight ratio of these
animals were slightly increased.  There were no significant histopatho-
logical  findings attributable to the presence of the permethrin in the
diet.  The NOEL was 1500 mg/kg (Kadota et al., 1975).

    In  a study designed to evaluate liver hypertrophy, male and female
Wistar  rats were fed permethrin at levels of 0, 20, 100, or 1000 mg/kg
diet for 26 weeks. There was no mortality, and the growth and food con-
sumption of the animals were normal. Although the mean liver weight was
increased  at all dose levels, a significant increase was noted only at
the highest dose level. The increase in liver weight at this dose level
was  accompanied by an increase in the smooth endoplasmic reticulum and
in  biochemical parameters associated with microsomal oxidative mechan-
isms.  At a dose level of 100 mg/kg, there were slight, non-significant
increases  in  biochemical activities.  No effects on  any of the  par-
ameters  measured were observed in  animals dosed at 20 mg/kg  (Hart et
al., 1977c).

    In a study by Wallwork et al. (1974b), groups of five to six female
Charles  River CDI rats received  permethrin (25:75) in corn  oil at 0,
200,  400, or 800 mg/kg body  weight by daily gavage  for 10 days.  The
animals  were sacrificed on the eleventh day so that haematological and
clinical chemical parameters and organ weights could  be  investigated.
Permethrin  (25:75)  gave  a  toxicity  profile  similar  to  that   of
permethrin (40:60).

7.2.1.3   Dog

    Beagle  dogs (four of each sex per group) fed permethrin in gelatin
capsules  daily  for  3 months at dose levels of 0, 5, 50, or 500 mg/kg
body weight showed no mortality, but clinical signs of  poisoning  were
noted  at  various  times in both males and females at the highest dose
level.   Growth and  food consumption,  as well  as clinical  chemical,
haematological,  and  urinalysis  parameters, were  normal.   The liver
weights and liver-to-body weight ratios of animals that  received  per-
methrin at 50 mg/kg or more were significantly  increased.  Histopatho-
logical  examination did not  reveal any changes  attributable to  per-
methrin (Killeen & Rapp, 1976a).

    Beagle dogs (four of each sex per group) administered permethrin in
gelatin capsules daily for 13 weeks at dose levels of 0, 10,  100,  and
2000 mg/kg body weight likewise showed no mortality, but clinical signs
of  poisoning  were  evident at  2000 mg/kg.   Haematological, clinical
chemical, and urinalysis values were normal in all animals. There was a
slight increase in the liver weight of animals dosed at 2000 mg/kg/day,
but  no accompanying histopathological changes in the liver (Edwards et
al., 1976).

    When  two  beagle dogs  were given daily  oral doses of  permethrin
(25:75)  at 500 mg/kg body weight  for 14 days, there were  no clinical
signs  of toxicity  or significant  effects of  the treatment  on  body
weight or on clinical chemistry or haematological  parameters  (Chesher
et al., 1975a).

    Groups of four male and four female beagle dogs, given encapsulated
permethrin  [(25:75) 4.5% w/v] at 0,  10, 50, or 250 mg/kg  body weight
for  6 months, revealed  no signs  of toxicity  and no  effect on  body
weight. Ophthalmoscopy and electrocardiography showed no abnormalities.
At  necropsy, there were  no gross pathological  or significant  histo-
pathological  findings.   Haematological  and clinical  chemistry para-
meters,  including plasma antipyrine elimination  rate, were unaffected
by treatment.  The results of this study indicate that daily oral doses
up  to  250 mg/kg  body weight  do  not  adversely affect  beagle  dogs
(Reynolds et al., 1978).

7.2.1.4  Rabbits

    In a study by Chesher & Malone (1974a), groups of five female Dutch
rabbits received permethrin (25:75) in 10 daily doses by gavage in corn
oil  at 0, 200, 400, or 800 mg/kg body weight.  The animals were killed
on  the eleventh day  so that clinical  chemical, haematological  para-
meters,  and organ weights could be investigated.  One rabbit, dosed at
400 mg/kg, exhibited mild hyperactivity and muscular fasciculation, but
only  at days 6 and 7.  Although  all animals, including  the controls,
exhibited some degree of weight loss, it was most marked in  the  high-
dose group.  There were no significant haematological or clinical chem-
istry  findings, but there was some decrease in liver and kidney weight
and  also some  enlargement of  adrenal gland  weights in  all  treated
groups.

7.2.1.5  Cow

    Lactating cows (three per group) fed permethrin in the diet at dose
levels  of 0, 0.2, 1.0, 10, or 50 mg/kg diet for 28 days showed no mor-
tality.  Growth and milk production were normal, and no histopathologi-
cal changes in the tissues were observed (Edwards & Iswaran, 1977).

7.2.2  Dermal Exposure

    Technical grade permethrin was applied daily to the clipped skin of
New  Zealand White rabbits (eight males per group) at dose levels of 0,
0.10,  0.32, or 1.0 g/kg body weight, each day for 21 consecutive days.
The application site was abraded on the first test day in half  of  the
animals in each group. Blood samples were drawn weekly from the animals
for clinical chemistry studies.  All animals were killed on  the  tenth
day  after exposure ceased.  Various tissues and organs were taken from
each animal and examined for microscopic lesions.  A  moderate  primary
irritation  of the  skin was  produced by  permethrin.  No  significant
changes in body weight, organ weight, or clinical chemistry values were
evident, neither were there any compound-related lesions in the skin or
other tissues (Metker et al., 1977).

    In further studies by Metker et al. (1977),  permethrin  (dissolved
in  acetone)  or  acetone (as a control) was placed on the skin twice a
week for 3 weeks to 6 groups of 10 shaved male New Zealand  White  rab-
bits. Cotton cloth treated with permethrin (1.25 or 0.125 mg/cm2)   was
applied to the skin over 1 ml of artificial sweat (salt  solution  imi-
tating  sweat).  In the case  of other rabbits, similarly  treated, the
sweat was omitted.  In the control groups, acetone-treated cotton cloth
with or without 1 ml of sweat was used.  Blood samples  were  collected
once  a week for clinical  chemistry determinations.  All animals  sur-
viving  to term were  killed and various  tissues and organs  from each
animal were examined for microscopic lesions.  No  significant  changes
were  noted in rabbit body weight or organ-to-body weight at the end of
the  21-day test, and no  skin irritation was observed.   There were no
significant  changes in clinical chemistry values in the treated groups
and no compound-related lesions in the skin or other tissues and organs
examined (Metker et al., 1977).

7.2.3   Inhalation exposure

    The  inhalation toxicity of  technical grade permethrin  was deter-
mined in three species of laboratory animals. Male Hartley guinea-pigs,
male  and female Sprague-Dawley rats,  and male and female  beagle dogs
were exposed to an aerosol of permethrin at concentrations of 125, 250,
or  500 mg/m3,   6 h per day,  5 days per week for  13 weeks.  The mass
median  diameter of the aerosol  droplets was 5.1 µm,   and  85% of the
total droplets had a diameter of 1.0 µm or less. At  500 mg/m3, tremors 
and convulsions  occurred in the rats during the first week of exposure 
but disappeared in the second week.  There was no difference in  oxygen
consumption between control and treated rats.  Urine metabolite studies
indicated  that permethrin was rapidly metabolized and excreted.  Post-
exposure  experiments in male rats showed that the hexobarbital-induced
sleeping  time  was  significantly  shortened  after  exposures  at 500
mg/m3 but   not at lower  doses.  No clinical  signs of poisoning  were

observed in the guinea-pigs and dogs when exposed to aerosols  of  per-
methrin  under similar conditions. Pulmonary function, clinical chemis-
try  parameters, and blood  cell counts were  unaffected in the  beagle
dogs  following  exposure.   No compound-related  gross  or microscopic
pathological  changes or other permanent  changes were observed in  the
dogs,  rats,  or  guinea-pigs as  a  result  of  permethrin  inhalation
(Metker, 1978).

7.3   Primary Irritation

7.3.1  Skin irritation

    When  undiluted  technical  permethrin (91.3%  purity,  0.5 ml) was
applied  to the clipped dorsal surface of Japanese White rabbits, there
was no irritation (Okuno et al., 1976).

    Single  applications of  0.05 ml of  25% (w/v)  permethrin (in  95%
ethanol)  or 10% (w/v) oil of bergamot solution (in 95% ethanol) (posi-
tive  control) were applied  to the intact  skin of six  rabbits.  Five
minutes later, some of the rabbits were exposed to UV light (365 nm) at
a  distance  of  10-15 cm for 30 min (the intensity of UV light was not
mentioned).   Skin  treated  with  the  positive  control  solution and
irradiated  exhibited  a  greater  irritation  reaction  than  did non-
irradiated  skin.   Permethrin did  not  cause any  irritation reaction
under the test conditions with or without irradiation (Metker  et  al.,
1977).

    When  a permethrin formulation  was applied to  the clipped  dorsal
surface (0.13 mg/cm2)   of six New Zealand White rabbits (three of each
sex) once a day for 16 days, a slight erythema appeared,  which  corre-
lated  with increased cutaneous  blood flow measured  by laser  Doppler
velocimetry.   No  significant histopathological  changes were detected
(Flannigan et al., 1985a).

7.3.2   Eye irritation

    In  a study by Okuno  et al. (1976), 0.1 ml  of undiluted technical
permethrin  (91.3% purity) was applied  to the eyes  of Japanese  White
rabbits.  The eyes were washed with distilled water 5 min or 24 h after
the application of permethrin.  No eye irritation was observed.

    Undiluted permethrin applied to the eyes of female  rabbits  caused
minimal pain, redness, chemosis of the conjunctiva, and a  slight  dis-
charge (Parkinson et al., 1976).

    Permethrin  (25:75) (40% in  corn oil) did  not produce any  ocular
effects  when 0.1 ml was instilled  into the ocular sac  of New Zealand
rabbits (Chesher & Malone, 1974c).

7.4   Sensitization

    In  a study by Parkinson  et al. (1976), guinea-pigs  were dermally
administered  permethrin  as a  10%  solution in  dimethylformamide for
3 consecutive  days.  This was followed 4 days later by challenge doses
of 0.1%, 1%, and 10% solutions of permethrin in dimethylformamide. Only

very slight erythema was observed.  Permethrin was therefore considered
to be either non-sensitizing or only mildly so.

    Guinea-pigs  (10 per  group) were  initially injected intradermally
with  0.1 ml permethrin solution and 14 days later were challenged with
an intradermal injection (0.1 ml) of either a 0.1% solution of permeth-
rin  or  dinitrochlorobenzene (DNCB).   Five  other animals  per  group
received  intradermally a  challenge dose  of 0.1%  permethrin or  DNCB
without a prior sensitizing dose. The positive control substance (DNCB)
elicited  sensitization reactions in  all guinea-pigs when  examined 24
and 48 h after the challenge dose, whereas permethrin did not cause any
sensitization reactions (Metker et al., 1977; Metker, 1978).

    Permethrin  (25:75)  in  corn  oil  (1% w/v)  or  Freund's complete
adjuvant (1% w/v) did not produce dermal irritation or sensitization in
groups  of 10 male  guinea-pigs when  applied as  a 25%  dispersion  in
petrolatum. The positive control, DNCB, (5% w/v) in petrolatum produced
marked sensitization (Chesher & Malone, 1974b).

7.5  Long-term Toxicity

7.5.1  Mouse

    SPF  Alderly Park strain mice  (70 males and 70 females per  group)
were  fed permethrin (cis 35-45%;  trans 65-55%) at dose  levels of  0,
250, 1000, or 2500 mg/kg diet for 2 years.  Ten males and  ten  females
were  designated for interim  kills at 26 and 52 weeks.   The mortality
rate  was unaffected by the  administration of permethrin.  Growth  was
slightly  decreased at the two  highest dose levels at  various periods
during  the study.  At the interim sacrifice of 52 weeks and at the end
of study, a significant dose-dependent increase in liver-to-body weight
ratio was observed at the two highest dose levels in females (with 2500
mg/kg  only  at  the end of the study) and at the highest dose level in
males.   Hepatic aminopyrine  N-demethylase  activity was  also substan-
tially  increased, although not consistently,  in both male and  female
mice  given the  highest dose.   Gross and  microscopic examination  of
tissues and organs (and specific examination for hepatic neoplasia) did
not  reveal any significant  carcinogenic effects as  a result of  per-
methrin  administration.  Many of the non-tumour abnormalities observed
were  considered to be those associated with aging of the mice, charac-
terized  by  increased  eosinophilia of  the centrilobular hepatocytes.
Also, a decrease in vacuolation of the proximal tubular  epithelium  of
the  kidney was noted at all dietary levels in males.  A high incidence
of  lung adenomas was observed with all animals in the study, but stat-
istical  analysis suggested  that this  was not  related to  permethrin
feeding.   Electron-microscopic  examination of  subcellular liver com-
ponents showed a proliferation of the smooth endoplasmic  reticulum  at
dose  levels of 1000 and 2500 mg/kg.  No notable effects on the sciatic
nerve  were found as the result of permethrin administration (Ishmael &
Litchfield, 1988).

    In  studies by Hogan & Rinehart (1977) and Rapp (1978), CD-1 strain
mice  (75 of each sex  per group) were fed  permethrin in the diet  for
104 weeks.  Alterations were made in the dietary dose levels during the
course of the study.  From weeks 1 to 19, the animals were  given  dose

levels of 0, 20, 100, and 500 mg/kg diet.  At week 19, the  dose  level
of  500 mg/kg was increased  to 5000 mg/kg and  maintained for  2 weeks
before  returning to  500 mg/kg.  At  week 21, the  100 mg/kg dose  was
increased  to 4000 mg/kg and maintained for the remainder of the dosing
period. Growth was inhibited in males at 4000 mg/kg. With the exception
of a reduced blood glucose level in the animals  receiving  4000 mg/kg,
dietary  administration of permethrin  had no other  effects on  haema-
tology or clinical chemistry parameters in the mouse.  The liver weight
was  higher than it  was in control  animals in both  male  and  female
animals at a dose level of 500 mg/kg or more.  In addition,  the  heart
weight  was higher at  4000 mg/kg.  Neoplastic changes,  not associated
with dietary levels of permethrin, were observed in some animals in all
groups.   While there was no direct effect with respect to hepatic neo-
plasms, it was noted that hepatocellular hypertrophy, pleomorphism, and
degeneration  occurred  in treated  mice  with increased  frequency and
appeared  to show a  dose-response relationship.  No  oncogenic effects
were observed in the test animals.

7.5.2  Rat

    Wistar rats (60 of each sex per group) were fed permethrin  in  the
diet  at  dose  levels of 0, 500, 1000, or 2500 mg/kg diet for 2 years,
and twelve rats of each sex per group were sacrificed at 1 year.  Signs
of  poisoning such as tremors  and hyperexcitability were noted  during
the  first 2 weeks of dosing  in the animals that  received the highest
dose. There was no mortality attributable to permethrin, and growth and
food  consumption were  unaffected.  There  were no  effects on  haema-
tological,  ophthalmological,  urological, or  other clinical chemistry
parameters.  Liver aminopyrine  N-demethylase  activity was increased in
all  permethrin-treated  animals.  Bone  marrow  smears of  the animals
showed  no  unusual findings.   Gross  and microscopic  examination  of
tissues and organs was performed after 1 and 2 years, and  all  animals
that  died with neoplastic changes  were examined.  Liver weights  were
higher  after 1 year of  dosing in male  and female rats  that received
permethrin at 2500 mg/kg than in the control animals.   After  2 years,
the  liver weight and  liver-to-body weight ratios  were higher in  all
permethrin-treated  males than in  the corresponding controls.   In the
females, higher values of absolute and relative liver weights, compared
to  the  controls,  were recorded only in the group of animals dosed at
1000 mg/kg.   Kidney weight was also increased, predominantly in males,
at all dose levels.  Hepatocyte vacuolation was seen at 1 year in males
fed at the highest dose level only and in females at all  dose  levels.
The  smooth endoplasmic reticulum  showed significant increases  at  52
weeks in both males and females at all dietary levels.  At the  end  of
the study, notable endoplasmic reticulum increases were  detected  only
at  the highest dose  levels, although non-significant  increases  were
noted at all dose levels in both males and females.  Examination of the
sciatic  nerve  showed  no  effects  attributable  to  permethrin.   No
oncogenic effects were noted at any dose level (Ishmael  &  Litchfield,
1988).

    Long-Evans  rats (60 males and 60 females per group) fed permethrin
in  the diet at dose levels of 0, 20, 100, or 500 mg/kg for 2 years did
not  reveal any mortality or  adverse effects on growth,  food consump-
tion,  or behaviour attributable  to the administration.   Haematology,

clinical  chemistry,  and  urinalysis measurements  were  performed  at
either  6 months  or  1 year and at the end of the study. There were no
compound-related  effects on a wide variety of parameters examined, and
ophthalmological examination indicated no abnormalities.  Blood glucose
levels  were higher in the  highest-dose males at 24 months  and in the
highest-dose  females  at  18 months, compared  to  the  values of  the
control  animals. Two independent evaluations  of the histopathological
data  concluded that there was  no oncogenic potential for  permethrin.
While there was a dose-dependent increase in gross liver weight in both
males  and  females,  these values  are  small  and  not  statistically
significant.  The NOEL for general toxicity in this study was estimated
to be 100 mg/kg (Braun & Rinehart, 1977; Billups 1978a, b).

7.6  Carcinogenesis

    Summaries by Paynter et al. (1982) of toxicological data from seven
long-term  chronic  toxicity/oncogenicity  studies (four  in  mouse and
three in rat) carried out by ICI, FMC, and Burroughs-Welcome (BW)  have
been made available by the US EPA.  One rat study and one  mouse  study
performed  by ICI were recently published (Ishmael & Litchfield, 1988),
and one rat study and one mouse study carried out by BW were  cited  in
FAO/WHO  (1988).  A report of the FIFRA Scientific Advisory Panel which
reviewed  this data was also  made available (US EPA,  1981).  Table 13
summarizes the basic design of each of these studies, some of which are
also discussed in section 7.5.

7.6.1  Mouse

    One  of the four mouse  studies referenced in Table 13  (FMC I) was
not considered for evaluation because of dose level changes in the mid-
and high-level groups and problems in histopathological methodology.

7.6.1.1  ICI study

    Relevant  non-oncogenic effects observed during the study consisted
of increased mortality, increased liver aminopyrine- N-demethylase   ac-
tivity, increased liver weight, and eosinophilia of hepatocytes in both
males  and females at 2500 mg/kg  diet.  The liver changes  observed in
this  study  were  considered to  be  related  in large  measure to the
induction of liver microsomal enzyme activity.  Minimal  liver  changes
were  also observed  at 1000 mg/kg,  but not  at 250 mg/kg.   A  slight
increase in lung adenomas was observed in male mice at the highest dose
level.  However, there was some uncertainty as to whether this increase
was related to permethrin ingestion.

7.6.1.2  FMC II study

    Relevant  non-oncogenic effects observed during the study consisted
of  increased mortality in  males at 2000 mg/kg  diet, increased  liver
weight  in females  at 2500 mg/kg  and 5000 mg/kg,  and increased  lung
weight  in  females  at 5000 mg/kg.   Histopathologically, dose-related
"focal alveolar cell proliferation"  (increased  numbers of lung cells)
was  observed  in  permethrin-treated females.   As  regards  oncogenic
effects, there was an increased incidence of bronchio-alveolar adenomas
in  female mice only.  The  number of female mice  with adenomas and/or

carcinomas  (15/74, 24/72, 35/74,  and 44/75 at  the four dose  levels)
revealed  a statistically significant dose-response relationship.  Male
mice  did not show this  effect.  However, some doubt  was expressed by
the  FIFRA Scientific  Advisory Panel  concerning the  conduct of  this
study.

7.6.1.3  BW study

    Non-oncogenic  effects  observed  during  the  study  consisted  of
slightly  decreased mortality in females  at 50 and 250 mg/kg  per day,
increased  liver weights  in males,  and increased  kidney  weights  in
females  at 250 mg/kg per day.  Histopathologically, an increased inci-
dence  in cuboidal/columnar metaplasia  of the alveolar  epithelium was
observed in the lungs of male and female mice at the highest dose.  The
oncogenicity data indicated a dose-related trend in females, but not in
males,  for adenomatous tumours in  the lungs.  No notable  pattern was
observed for other neoplasms at any dose level.

7.6.1.4  Appraisal of mouse studies on carginogenicity

    Consistent findings in the above three mouse studies at  high  dose
levels  were liver changes known to be associated with the induction of
the  liver microsomal enzyme  system.  Other histopathological  effects
observed  in liver, not  usually associated with  microsomal induction,
included multifocal hepatocytomegaly and hepatocytic pigmentation.  The
incidence of lung adenomas for each of the three mouse studies is given
in Table 14.

    Among  the three  long-term mouse  studies, there  was evidence  of
permethrin oncogenicity in the lungs in one strain (CD-1  female  only)
at the highest dose level only.

    Although  there was a  difference between the  control and  treated
groups  in terms of lung  adenomas in these studies,  these differences
were not significant when compared with historical control values.  The
oncogenicity potential, as evaluated by the FIFRA  Scientific  Advisory
Panel, was considered to be very weak.


Table 13.  Chronic toxicity and carcinogenicity studies in mice and rats
------------------------------------------------------------------------------------------------------
Study
performed  Species  Strain         No. of   Duration  Dose                 Reference
by                                 animals  (weeks)   (mg/kg diet)
------------------------------------------------------------------------------------------------------
ICI        mouse    Alderly Park   70       98        0, 250, 1000, 2500   Ishmael & Litchfield (1988)
                    (SPF)

FMC I      mouse    CD-1           75       104       0, 20, 500, 4000     Hogan & Rinehart (1977); 
                                                                           Rapp (1978)

FMC II     mouse    CD-1           75       104       M:0, 20, 500, 4000   Bio Dynamics (1979)
                                                      F:0, 20, 2500, 5000

BW         mouse    CFLP           75       92        0a, 10a, 50b, 250b   James et al. (1980)

ICI        rat      Wistar         60       104       0, 500, 1000, 2500   Ishmael & Litchfield (1988)

FMC        rat      Long-Evans     60       104       0, 20, 100, 500      Braun & Rinehart (1977);
                                                                           Billups (1978a,b)

BW         rat      Wistar         60       104       0, 10b, 50b, 250b    McSheehy & Finn (1980)
------------------------------------------------------------------------------------------------------
a   100 animals as control.
b   mg/kg body weight; permethrin 25% cis, 75% trans.
Table 14.  Comparison of lung adenomas (%) in three mouse studies
------------------------------------------------------------------------
                        Male                          Female
              control low    mid    high    control  low    mid    high
                      dose   dose   dose             dose   dose   dose
------------------------------------------------------------------------
ICI study     20      12     26     32      22       16     20     30

FMC II study  22      23     28     25      16(20a)  17     35     35

BW study      26      19     23     22      3(20b)   7      10     20
------------------------------------------------------------------------
a   Historical control values ranged from 23 to 60%, with a mean 
    of 20.4%.
b   Historical control values ranged from 7.5 to 30.0%, with a mean 
    of 20.4%.

7.6.2  Rat

    One  of the three  long-term rat studies  referred to in  Table 13,
i.e.  the  FMC  rat study,  was  excluded  from examination  because of
serious flaws in histopathological methodology.

7.6.2.1  ICI study

    Relevant  non-oncogenic  effects  observed consisted  of  increased
mortality  in males and  decreased mortality in  females at  2500 mg/kg
diet,  increased liver weights  in both males  and females at  1000 and
2500 mg/kg and in males only at 500 mg/kg, increased liver aminopyrine-
N-demethylase    activity in both  males and females  at 1000 and  2500
mg/kg, and hepatocyte vacuolization or hypertrophy in males and females
at  1000 and 2500 mg/kg.   Additional effects observed  were  increased
kidney  weight in males at all treatment levels and increased pituitary
weight in males at 1000 and 2500 mg/kg.

    No  tumours related to the ingestion of permethrin were observed in
this study.

7.6.2.2  BW study

    Non-oncogenic  effects observed at 250 mg/kg per day were increased
mortality in males, occasional body tremors in males and  females,  in-
creased  liver weight in males, hepatocyte hypertrophy in males and fe-
males, and focal changes of the thyroid follicles in males and females.
The  microscopic  liver and  thyroid changes were  also observed at  50
mg/kg per day in both sexes.

    With respect to tumours (including rare, unusual, or malignant neo-
plasms),  none  of the  tumour types observed  in this study  were con-
sidered to be related to the ingestion of permethrin.

7.6.2.3  Appraisal of rat studies on carcinogenicity

    No evidence of oncogenicity was observed in the rat studies.

7.7  Mutagenicity

7.7.1  Microorganism and insects

    The mutagenic activity of permethrin was evaluated using  the  Ames
test.   There was no  increase in the  number of revertant  colonies at
doses  up to 2500 µg   permethrin/plate  in five strains of  Salmonella
typhimurium (TA1535, TA1537, TA1538, TA98, and TA100) with  or  without
S9-mix  prepared from rat  liver or S9  prepared from PCB-treated  mice
(Longstaff, 1976; Newell & Skinner, 1976; Simmon, 1976; Suzuki, 1977).

    Permethrin  and  six other  synthetic  pyrethroids were  tested for
mutagenicity in S. typhimurium TA98 and TA100 strains in  the  presence
and absence of a metabolic-activation system.  All  pyrethroids  tested
gave negative results (Pluijmen et al., 1984).

    Two reverse-mutation tests in  Escherichia coli WP2 also gave nega-
tive results (Newell & Skinner, 1976; Simmon, 1976).

    When tested for mutagenicity in V79 Chinese hamster cells, permeth-
rin and five other synthetic pyrethroids were shown to be non-mutagenic
(Pluijmen et al., 1984).

    In  a host-mediated assay,  permethrin (200 mg/kg body  weight) was
orally administered to ICR mice. The indicator organism, S. typhimurium
G46, harvested from the abdominal cavity of mice 3 h  after  treatment,
did not reveal any mutagenic effect (Shirasu et al., 1979).  In another
host-mediated  assay employing a similar test system, (+)- trans-permethrin
at dose levels of 600 and 3000 mg/kg body weight and  (+)- cis-permethrin
at 21 and 54 mg/kg body weight gave negative results (Miyamoto, 1976).

    Permethrin  was  tested  for its  ability  to  induce complete  and
partial  chromosome  loss  in  Drosophila melanogaster males  by  adding
5 mg/litre  (soaked  onto  a filter  paper)  to  the feeding  solution.
Treated  males  were mated  with  mus-302 repair-defective  females  to
detect  chromosome loss in  the zygotes.  Permethrin  did not induce  a
significant  increase in chromosome loss, compared to negative controls
(Woodruff et al., 1983).

7.7.2  Mammals

    An  in vivo cytogenetic test was performed in Alderly Park  rats  to
assess  the  ability of  permethrin  to induce  chromosomal aberration.
Permethrin was administered to groups of eight males by a single intra-
peritoneal injection or by five daily injections at doses of 600, 3000,
or  6000 mg/kg.  The cytogenetic effect on bone marrow cells was evalu-
ated  24 h after the single  injection and 6 h after  the last multiple
dosing.   No differences were observed in the rate of chromosomal aber-
rations between any permethrin-treated groups and the vehicle controls.
Two positive controls (trimethyl phosphate and mitomycin C)  produced a
significantly  higher incidence of chromosomal  aberrations (Anderson &
Richardson, 1976).

    Permethrin  (25:75) gave a  negative response when  mouse  lymphoma
L5178Y cells were treated with permethrin (up to 125 µg/ml)    with  or
without activation (Clive, 1977).

    In  dominant lethal studies, permethrin  dissolved in corn oil  was
administered  orally for five successive days to groups of male CD mice
(15 per group) at doses of 15, 48, or 150 mg/kg.  Each male  was  mated
with  16 virgin females, and on  the 12th day of gestation  the females
were killed.  There was no dose-related effect on pregnancy or early or
late fetal deaths.  Administration of permethrin thus had  no  dominant
lethal  effect on male mice.   On the other hand,  the positive control
(ethylmethanesulfonate)  induced pre-implantation losses and  the early
death  of embryos  (McGregor &  Wickramaratne, 1976a;  Chesher et  al.,
1975b).

7.8   Teratogenicity and Reproduction Studies

7.8.1  Teratogenicity studies

7.8.1.1  Mouse

    In studies by Kohda et al. (1976b), groups of pregnant ICR mice (27
to  32 mice per  group) were  orally administered  permethrin  at  dose
levels of 0, 15, 50, or 150 mg/kg body weight from day 7 to  day 12  of
pregnancy.   On day 18, two-thirds of  the animals were sacrificed  and
examined  for implantation and resorption sites.  Viable offspring were
examined  for somatic and skeletal abnormalities, and, after 3 weeks of
lactation,  pups  were examined  for  behavioral abnormalities  and for
differentiation and growth.  At 6 weeks of age, all animals were sacri-
ficed and subjected to internal and external examination. There were no
effects  on maternal toxicity over the course of the study.  Growth and
differentiation  of pregnant females  were not affected  by permethrin,
nor  were  the number  of implantation sites  or litter size  adversely
affected.   The size  of individual  pups and  the incidence  of  gross
external,  internal, and skeletal abnormalities  were not significantly
different from those in the control mice.  Permethrin, at  dose  levels
up to and including 150 mg/kg, did not appear to affect  those  animals
allowed  to  bear  and wean young.  The growth of young animals did not
appear to differ from control values, and, 3 weeks after  weaning,  the
surviving animals did not differ from controls with respect  to  growth
or  major organ changes.  There  was no teratogenicity associated  with
permethrin  in this mouse bioassay, although the duration of dosing was
a  little too short  to cover both  the early and  late stage of  organ
development  (Kohda et al., 1976b).

7.8.1.2  Rat

    In  studies by McGregor &  Wickramaratne (1976b), pregnant CD  rats
(20 rats  per group) were orally administered permethrin at dose levels
of 0, 22.5, 71.0, or 225 mg/kg from day 6 to day 16 of  gestation.   On
day 20,  the animals were sacrificed  and the corpora lutea  were exam-
ined.   Somatic  and  skeletal  investigations  were  performed  on the
fetuses. No adverse toxicological response was seen at the highest dose
used.   There were no abortions  or maternal deaths and  no significant
differences in pregnancy frequency, corpora lutea, or total  number  of

implantations  between treated and  control rats.  Placental  and fetal
weights were similar to those of the controls and no skeletal or struc-
tural abnormalities were observed.  Based upon the standard teratologi-
cal rat bioassay, permethrin did not show any teratological potential.

    Pregnant  Sprague-Dawley  rats  (29-34 rats per  group) were orally
administered permethrin at dose levels of 0, 10, 20, or  50 mg/kg  body
weight from day 9 to day 14 of pregnancy. On day 20, approximately two-
thirds of the pregnant females were sacrificed and the  remaining  rats
were  allowed to deliver and wean pups.  After lactation, the pups were
examined  for behaviour and for growth and differentiation before being
sacrificed  at 6 weeks of  age and examined  for internal and  external
gross malformations.  Pregnant females fed at the highest  dose  showed
toxic  signs  of  poisoning, including  ataxia,  tremor,  and a  slight
reduction  in body weight.  There was no mortality, although fetal loss
at  the highest dose level was slightly higher than that in the control
animals.   A slightly higher  incidence of non-ossified  sternebra  was
noted at 50 mg/kg. The number of implantation sites and the litter size
were  not affected, and growth and differentiation were similarly unaf-
fected.  Internal and external examination showed that, with the excep-
tion  of the slight skeletal variation noted at 50 mg/kg, there were no
permethrin-associated  changes.  In those  animals allowed to  bear and
wean pups, there were no notable differences from control  values  with
respect to gestation, implantation sites, delivery, and numbers of live
young.  Growth and differentiation of the offspring did not  appear  to
be affected by permethrin, and there were no abnormalities with respect
to gross pathology or in the weights of major tissues and organs at the
conclusion of the study. Permethrin did not elicit a teratogenic effect
in this bioassay (Kohda et al., 1976a).

    In  a study by  Metker et al.  (1977), permethrin (4,  41,  and  83
mg/kg/diet), aspirin (200 mg/kg diet), and corn oil (2 ml/kg diet) were
each  administered to groups of  20 pre-impregnated Sprague-Dawley rats
from  day 6 to day 16 of gestation.  The animals were sacrificed on day
20  of gestation, and the  fetuses were removed and  examined for gross
abnormalities,  sex, weight, and  body length.  The  administration  of
aspirin  (the positive control)  resulted in significantly  lower  body
weight and length and a variety of abnormalities including craniorachi-
oschisis  in the foetuses.   Permethrin, administered to  pregnant rats
during  gestation by intragastric intubation, did not appear to present
a teratogenic or lethal hazard to the developing fetus.

    When groups of 22 female Wistar rats received permethrin (25:75) at
0  or 200 mg/kg body weight in corn oil by daily oral gavage on days 6-
16 (inclusive) of pregnancy, treatment was without apparent  effect  on
maternal  body weight  gain or  general conditions.   The animals  were
sacrificed  on day 20 so that their uterine contents could be examined.
Treatment  had no effect on the number of corpora lutea, implantations,
live  fetuses, early  and late  fetal deaths,  or fetal  abnormalities.
Examination  of  the fetuses,  which  included dissection  and skeletal
staining,  showed no morphological effects of treatment.  These results
indicate  that permethrin (25:75) at  200 mg/kg body weight per  day is
not fetotoxic to rats (James, 1974).

7.8.1.3  Rabbit

    Mated  female Dutch rabbits (18 per group) were orally administered
permethrin (at dose levels of 0, 600, 1200, or 1800 mg/kg  body  weight
per  day) in  0.5% v/v aqueous  Tween 80 from  days 6-18  inclusive  of
pregnancy.   On day 29 of pregnancy  the animals were killed  and their
uteri were examined for resorptions and live implantations. The fetuses
were  examined for gross abnormalities of skeleton and soft tissue.  At
all  dose levels, permethrin depressed  body weight gain during  dosing
and  was  embryotoxic  at the two highest dose levels.  It was toxic to
the dams at 1800 mg/kg body weight per day, but no teratogenic activity
was detectable at any dose level (Richards et al., 1980).

7.8.2  Reproduction Studies

7.8.2.1  Rat

    Groups  of Long-Evans rats (10 males and 20 females per group) were
fed  permethrin at dose  levels of 0,  20, and 100 mg/kg  diet in a  3-
generation  (two litters per generation) reproduction study.  There was
no  effect on  mortality, mating,  pregnancy, or  fertility,  with  the
exception of the F2 mating  index, which was reduced in  both  controls
and  treatment groups.  Pup survival and growth were unaffected. Haema-
tological evaluations of F2 adults  between the second and third mating
showed no unusual effects. This study indicated that dietary permethrin
does  not  adversely  affect  reproduction  in  the  rat  (Schroeder  &
Rinehart, 1977).

    In  studies by Hodge et al. (1977), groups of Wistar rats (12 males
and 24 females per group) were fed permethrin at dose levels of 0, 500,
1000, and 2500 mg/kg diet for 12 weeks.  At 12 weeks the  animals  were
mated  to initiate a standard 3-generation (two litters per generation)
reproduction  study.  Clinical signs of acute poisoning (tremors, etc.)
were  noted, predominantly in  females given the  highest dose.   There
were  no effects attributable  to permethrin on  fertility,  gestation,
viability  of pups, sex ratio, litter size, or lactation.  Ten male and
female  weanlings from  the second  litter of  the F3 generation   were
examined  for histopathological changes.  Centrilobular hypertrophy and
cytoplasmic  eosinophilia were observed at  all dose levels, the  inci-
dence and severity of which appeared to be dose dependent.  Rats in the
third  litter of the F3 generation   were sacrificed on day 12  of ges-
tation for teratogenic examination, but no abnormalities were observed.
Based  on the  results of  this study,  permethrin does  not appear  to
induce reproductive toxicity in rats.

    Spencer  and Berhance (1982)  fed female Sprague-Dawley  rats  (5-8
rats per group) permethrin in the diet at levels of 0, 500, 1000, 1500,
2000,  2500, 3000, 3500,  and 4000 mg/kg diet  from day 6 to  day 15 of
pregnancy.   Laparotomy was performed on  day 20 of gestation, and  the
number  of live  fetuses was  determined.  Placentae  were excised  and
cleaned of extraneous connective tissue.  Analysis of the  protein  and
glycogen  contents of the  placentae on day 16  of pregnancy  indicated
that  they were  only influenced  by very  high doses  (2500-4000 mg/kg
diet)  of permethrin.  Analysis  of variance indicated  no  significant
effect  on protein level, but  the treatment did decrease  the glycogen

concentration.   No significant dose-related effects  on implantational
sites/intrauterine  fetuses were observed.   These results appeared  to
confirm that permethrin possesses low mammalian toxicity.

    In  a 3-generation reproduction study, groups of 20 male and 20 fe-
male  Wistar COBS rats received permethrin (25:75) in the diet at 0, 5,
30, and 180 mg/kg body weight per day during growth, mating, gestation,
parturition,  and  lactation  for  three  generations,  each  with  two
litters.   Fetal toxicity and teratogenicity was assessed in the second
pregnancy  of the F2 generation.   Treatment with permethrin had no ef-
fect  on general behaviour or condition, food intake, body weight gain,
or  pregnancy rate of the  dams, or on parturition,  sex ratio, or  pup
weight.   A  small number  of rats of  each group developed  eye abnor-
malities, including ocular haemorrhage and chronic glaucoma,  but  this
was not related to the treatment.  Examination of  F3b fetuses   showed
no  treatment-related effect on sex  ratio, body weight, or  the occur-
rence of visceral or skeletal abnormalities.  This study indicated that
permethrin (25:75) has no effect on the reproduction of rats  at  doses
up to 180 mg/kg body weight per day (James, 1979).

7.9  Neurotoxicity

7.9.1  Rat

    When male and female Charles River rats (six of each sex per group)
were  fed  permethrin  at dose levels of 0 or 6000 mg/kg diet for up to
14 days,  severe clinical signs  of poisoning were  evident in all  the
permethrin-treated rats.  Only one permethrin-treated male survived the
14-day  trial.  Fragmented and swollen  sciatic nerve axons and  myelin
degeneration  were observed in four out of five permethrin-treated ani-
mals (Hend & Butterworth, 1977).

    In a short-term study designed to assess the effects of  high  con-
centrations  of permethrin on the  sciatic nerve, male Wistar  rats (10
per group) were fed permethrin at dose levels of 0, 2500,  3000,  3750,
4500, 5000, and 7000 mg/kg diet for 14 days.  Clinical signs  of  acute
poisoning  and death occurred in the animals that were dosed at 5000 or
7000 mg/kg. Some rats that received the lower dose levels showed slight
to  moderate tremors, and food  consumption and growth were  reduced in
these animals. At the two lowest dose levels, clinical signs of poison-
ing  disappeared within  the first  week whereas,  at the  higher  dose
levels,  signs  of  poisoning  persisted  throughout  the  study.  Rats
receiving  permethrin  at doses  of up to  4500 mg/kg showed no  ultra-
structural  changes in their sciatic  nerve.  A variety of  mild ultra-
structural  changes, such as  vacuolation and swelling  of unmyelinated
fibres and hypertrophy of Schwann cells, were observed in the nerves of
rats receiving 5000 mg/kg (Glaister et al., 1977).

    A  detailed morphological evaluation of the nervous system was per-
formed on rats in two long-term feeding studies.  In the  first,  Long-
Evans rats were fed diets containing permethrin at concentrations of 0,
20, 100, or 500 mg/kg diet for 2 years, and five male and  five  female
randomly  selected survivors  from each  group were  examined.  In  the
second study, Long-Evans rats were fed diets containing  permethrin  at

concentrations  of 0, 20, or 100 mg/kg diet for three successive gener-
ations,  and  five  male and five female rats from each group were ran-
domly selected from the third generation parental animals.  Examination
of central and peripheral nerves and of extensive morphometric data and
teased myelinated fibers of distal sural and tibial nerves and  of  the
maxillary  division  of  the fifth  cranial  nerve  did not  reveal any
changes  attributable  to the  feeding of the  pesticide (Dyck et  al.,
1984).

    When groups of 10 male and 10 female Sprague-Dawley rats were given
permethrin (25:75) (94.5% pure) at 4000, 6000, or 9000 mk/kg  diet  for
21 days,  all animals developed severe trembling and lost weight.  Some
of the highest-dose rats of each sex died.  Subsequent  examination  of
brain,  spinal cord, trigeminal and  dorsal root ganglia, proximal  and
distal root trunks, and terminal motor and sensory nerves  revealed  no
consistent histopathological abnormalities (Dayan, 1980).

7.9.2  Hen

    Hens  were administered permethrin orally (cis:trans=1:1) (as a 40%
w/v solution in dimethylsulfoxide) at a daily dose level of 1 g/kg body
weight for 5 days.  After 3 weeks, the dosing regimen was repeated, and
the  animals were maintained for an additional period of 3 weeks before
being sacrificed.  There were no signs of neurological  disturbance  or
mortality in any of the animals. All hens treated with tri- ortho-cresyl phos-
phate  (TOCP) (positive control) displayed clinical and histopathologi-
cal  evidence of neurotoxicity,  whereas none of  the birds dosed  with
permethrin  showed any signs of intoxication.  Histological examination
of nerve tissues revealed no lesions.  Hence, permethrin was considered
to  have no delayed neurotoxic  potential such as that  associated with
certain organophosphates (Millner & Butterworth, 1977).

    In  studies by Ross  & Prentice (1977),  15 adult hens were  orally
administered  permethrin at 9 g/kg body weight and again 21 days later.
After a further 21 days, they were sacrificed.  All  positive   control
animals (given TOCP at 500 mg/kg) showed signs of delayed neurotoxicity
ranging  from slight muscular incoordination to paralysis.  No signs of
ataxia  were recorded in any  of the hens in  the permethrin-treated or
negative  control groups.  Histopathological examination of the nervous
tissues of permethrin-treated animals revealed none of the degenerative
changes noted in the tissues of the positive controls.

7.10  Behavioural Effects

    Behavioural observations were carried out on immature male Sprague-
Dawley rats habituated to inhalation of permethrin  aerosols.   Habitu-
ation was carried out by exposing three groups of rats (five per group)
to  aerosols of permethrin firstly  at 500 mg/m3 for  21 days, then  at
1000 mg/m3 for  an additional 21 days. Three other groups of rats (five
per group) served as controls; they were similarly treated but were not
exposed  to  permethrin. At  the end of  this conditioning period,  all
rats, including the controls, were exposed to a permethrin  aerosol  at
5000 mg/m3 for   4 h.  At the end of the habituation period, there were
no  differences in retention  of avoidance training  or the ability  to
learn  the same task between controls and aerosol-exposed groups.  How-
ever,  after exposure to permethrin at 5000 mg/m3,   the non-habituated

control  group of rats  showed significantly lower  retention  capacity
compared with the habituated rats or with their own  pre-exposure  per-
formances.   The non-habituated control  rats also showed  decreases in
coordination and balance and a higher incidence of  conflict  behaviour
and  tremors.  The performance of the rats in the habituated groups was
not changed (Sherman, 1979).

7.11  Miscellaneous Studies

    The  pharmacological action of permethrin  on nictitating membrane,
blood  pressure, respiration, heart rate, and isolated ileum was inves-
tigated  in the rabbit,  guinea-pig, and cat.   Permethrin reduced  the
incidence  and amplitude of  contraction of isolated  rabbit ileum  but
induced no changes in a similar preparation from the guinea-pig. Intra-
venous administration of permethrin at doses of 4 mg/kg or more  affec-
ted  blood pressure and  respiration in all  animals.  The  hypotensive
effect  was not affected by  pretreatment with atropine or  propanolol.
Permethrin was shown to produce slight contraction of  the  nictitating
membrane.  An increase in pulse rate was observed in the electrocardio-
gram  (ECG)  of the  rabbit at dose  levels above 4 mg/kg,  but was not
accompanied by changes in the wave pattern (Nomura & Segawa, 1979).

    In  the Japanese White  rabbit, the intravenous  administration  of
lethal doses of permethrin caused changes in  the  electroencephalogram
(EEG) tracings.  Spike waves and an increased amplitude of  slow  waves
were  induced  at 100 mg/kg  body weight.  At  a sub-lethal dose  of 30
mg/kg,  permethrin did not induce changes in the EEG (Takahashi et al.,
1979).

    There  was no change in  hexobarbital-induced sleeping time in  ICR
mice  intraperitoneously administered a  single dose of  permethrin  at
dose levels of up to 2000 mg/kg body weight (Takahashi et al., 1979).

    Sprague-Dawley  rats (three groups of 10 rats each) were pretreated
for four consecutive days with an intraperitoneal injection  of  either
sodium  phenobarbital at 100 mg/kg (positive control group), permethrin
at  575 mg/kg (test group), or  corn oil at 2.0 ml/kg  (solvent control
group).   On the fifth  test day the  rats received an  intraperitoneal
injection of hexobarbital (220 mg/kg).  The hexobarbital-induced sleep-
ing  times of the  permethrin-treated rats were  significantly  shorter
than  those of the solvent control animals but were similar to those of
the phenobarbital positive control (Metker et al., 1977).

    Permethrin  and cypermethrin were  evaluated for their  ability  to
alter  microsomal cytochrome P-450 and  NADPH cytochrome  c reductase in
Long-Evans  rats. When permethrin (cis:trans = 80:20) was orally admin-
istered  to rats at  50 mg/kg body weight  per day, it  increased cyto-
chrome P-450 after 4, 8, or 12 days of administration and  NADPH  cyto-
chrome  c reductase after 8 or 12 days, whereas cypermethrin (alpha-cyano
analogue of permethrin) did not induce either cytochrome P-450  or  the
reductase.   Neither of the  two pyrethroids altered  body weight  gain
(Carlson & Schoening, 1980).

7.12  Mechanism of Toxicity (Mode of Action)

    Based on the signs of toxicity to mammals (Verschoyle  &  Aldridge,
1980;  Lawrence &  Casida, 1982)  and to  cockroaches (Gammon  et  al.,
1981), pyrethroids may be classified into two types: Type I and Type II
compounds (see Appendix I).  1R- cis-  and 1R- trans-permethrin   belong
to  Type I.   Electrophysiological  recordings from  dosed  cockroaches
reveal  trains of cercal  sensory spikes and,  sometimes, spike  trains
from the cercal motor nerves and the central nervous system.  The signs
of  poisoning caused by  Type I pyrethroid compounds  are restlessness,
incoordination,  hyperactivity,  prostration, and  paralysis (Gammon et
al., 1981).

    1RS- cis-permethrin   and 1RS- trans-permethrin   cause tremor (known
as T-syndrome) when injected intravenously into rats at a dose level of
more than 270 mg/kg body weight. The onset of the T-syndrome is usually
rapid. Rats suffering from T-syndrome exhibit aggressive  sparring  be-
haviour and increased sensitivity to external stimuli. This is followed
by  the  appearance of  a slight tremor,  which gradually becomes  more
severe  and finally reaches a  state of prostration and  vigorous whole
body tremor.  The core temperature is markedly increased during poison-
ing;  this may result from  the excessive muscular activity  associated
with tremor (Verschoyle & Aldridge, 1980).

    Exposure of sensory nerve fibres from clawed frogs  (Xenopus laevis)
to  permethrin (10-7 to  10-5 mol/litre)  resulted in marked repetitive
activity.   This heightened  activity was  not observed  in  the  motor
fibres  of frogs  that were  similarly tested.  Treatment  of  isolated
lateral-line preparations of frogs with permethrin (5 x 10-6 mol/litre)
also resulted in pronounced repetitive activity (Van  den   Bercken   &
Vijverberg, 1980b).

    Permethrin (cis, trans, and technical grade) and  deltamethrin,  as
representatives   of  the  non-cyano-  and   cyano-containing  classes,
respectively,  of synthetic pyrethroids, were  examined regarding their
major site of action on the  mammalian  nervous  system  in  mice.  ED50
values  for  the ability  of both types  of pyrethroids to  cause pros-
tration  and loss of  righting reflex were  estimated following  either
intravenous  or  intracerebroventricular  injections.  The  comparative
potencies  of the four  pyrethroids (deltamethrin >   cis-permethrin   >
technical grade permethrin >  trans-permethrin)  were the same following
either route of administration. All four compounds tested showed a much
greater  potency  (>  200-fold for  deltamethrin,  cis-permethrin,   and
technical  grade  permethrin, and  85-fold for  trans-permethrin)  after
intracerebroventricular  administration  than after  intravenous admin-
istration.  In addition, the poisoning symptoms seen  following  direct
central  injection were almost identical to those obtained with periph-
eral  administration.  These results  suggest that poisoning  from both
classes  of pyrethroids  in mammals  is due  predominantly  to  central
mechanisms (Staatz et al., 1982).

8.  EFFECTS ON HUMANS

    Although  permethrin has been used for many years, no human poison-
ing cases have been reported.

8.1  Occupational Exposure

    Data  on permethrin human  toxicity are scanty.   Studies of  occu-
pational  exposure  to permethrin  were  reported in  Sweden (Kolmodin-
Hedman et al., 1982).  In the first study, six forestry  workers  using
an aqueous emulsion of permethrin (trans:cis=75:25)  were studied.  The
duties  of  these workers  involved dipping conifer  seedlings in a  2%
aqueous  emulsion  of  permethrin  (one  worker)  and   packaging   the
permethrin-treated  seedlings  (five workers).   The permethrin concen-
trations in the breathing zones of these workers varied  between  0.011
and  0.085 mg/m3.     One  person excreted  permethrin  metabolites  at
0.26 µg/ml    urine the following morning,  but the same afternoon  the
urinary  excretion of permethrin residues was below the detection limit
of 0.1 µg/ml.   The urine from other workers did not contain detectable
amounts  of permethrin residues.   No symptoms of  permethrin poisoning
were  reported in this field study.  The second study, performed on the
basis of a questionnaire and interviews, was conducted 1-2 months after
the planting season.  It involved 87 persons at various plant nurseries
that used the insecticide (trans:cis=60:40 or 75/25). This study showed
that the major work-related symptoms amongst workers  were  irritative,
such  as itching and burning of the skin, and itching and irritation of
the  eyes.  Irritative symptoms in the skin and upper respiratory tract
were  reported  in  63%  of  workers  who  were exposed  to  permethrin
(trans:cis=75:25)  and  33%  who were  exposed  to  permethrin  with  a
different isomeric composition (trans:cis=60:40). The frequency of each
symptom  was  about 10%  in each case.   Increased nasal secretion  was
reported by 13% of the workers handling permethrin (trans:cis= 75:25).

    Le  Quesne et al. (1980) examined 23 laboratory workers involved in
field  trials, formulation, or general laboratory work with permethrin,
cypermethrin,  fenvalerate,  and  fenpropathrin.   The  study  involved
electrophysiological  monitoring and interviews to ascertain subjective
symptoms.   The most frequently reported symptom was a facial sensation
described as tingling, burning, or nettle rash by workers who  had  ex-
perienced it on one or more occasions.  This sensation usually occurred
about  30 min to 3 h after exposure and lasted for about 30 min to 8 h.
Apparently  this did not occur when permethrin alone was involved.  All
the  workers were examined neurologically and no abnormal findings were
recorded.   Electro-physiological measurements from these  workers were
compared  with those of an age-matched control group.  No difference in
response was found between the two groups.

    Studies  of pesticide contamination of  clothing worn by crop  con-
sultants during permethrin application to soybean fields were performed
to  assess the extent of  dermal exposure to the  pesticide.  The suits
and T-shirts were removed and wrapped in aluminum foil, placed  on  ice
and  transported to the  laboratory where they  were held in  a freezer
until residue analysis was performed.  Specimens from the  thigh,  arm,
and  chest of each suit and from the arm and chest of each T-shirt were

collected,  extracted with hexane  and analyzed by  GC-ECD.  Measurable
residues  of permethrin were detected  only in leg specimens  (Cloud et
al., 1987).

    As part of an evaluation of permethrin (25:75) (5% wettable powder)
in Nigeria, medical surveillance, including urinalysis of staff engaged
in  bagging,  mixing, or  spraying,  was undertaken.   Medical history,
pulse, and blood pressure were recorded and urine was  collected  twice
daily.   This surveillance revealed no effects attributable to permeth-
rin.   Despite the use of protective clothing, up to 2 mg of permethrin
was excreted within 24 h of exposure (Rishikesh et al., 1978).

8.2  Clinical Studies

    Flannigan  & Tucker (1985) and  Flannigan et al. (1985a,b)  studied
the  difference in the  degree of paraesthesia  induced by a  number of
pyrethroids.   On five occasions, 0.05 ml  of field-strength-formulated
permethrin  (0.13 mg/cm2)   was applied  to a 4 cm2 area   of  earlobe.
The  opposite earlobe received distilled water.  Participant evaluation
after each application continued for 48 h and involved  description  of
the  cutaneous  sensations.  Each  participant  was treated  after each
application  with one of the remaining compounds.  Permethrin, like the
other pyrethroids, induced skin sensations. Paraesthesia developed with
a latency period of approximately 30 min, peaked by 8 h,  and  deterio-
rated  within 24 h.  In  the case of  permethrin these sensations  were
approximately four times less marked than those induced by cypermethrin
and  fenvalerate, which both contain an alpha-cyano-group. It was  also
found that local application of  dl-alpha-tocopheryl   acetate markedly
inhibited the occurrence of skin sensations.

    To assess the safety of permethrin dusts for the control  of  human
body  lice, approximately 350 people were individually dusted with 50 g
of powder containing either 2.5 or 5.0 g permethrin/kg.  Urine samples,
taken at the time of treatment and subsequently, indicated that maximal
absorption of permethrin was 39 µg/kg,   24 h after  treatment  (Nassif
et al., 1980).

    In  a study to assess the degree of dermal absorption of permethrin
from  impregnated clothing, a group  of 10 male volunteer soldiers  for
48 h  wore military clothing that  had previously been treated  with an
aqueous  suspension  of  permethrin (0.2%  w/v).   Subsequent  analysis
showed  that the mean permethrin  (25:75)  concentration of the  shirts
and  trousers  was  0.32 g/100 g.   However,  the  average   individual
exposure  to permethrin was  3.8 mg/day.  No volunteers  complained  of
irritation  and there were no abnormal findings on physical examination
(Farquhar et al., 1981a).

    When  dermally  exposed  to permethrin  [(25:75)  1%  w/w  in  soft
paraffin] for up to 9 days using a patch test, 2 out of  17  volunteers
developed mild erythema (Pegum & Doughty, 1978).

    To  assess  the human  tolerance,  absorption, and  persistence  of
permethrin when used against human lice, 10 adult volunteers (four men,
six women) were treated with 15-40 ml of permethrin (25:75)  (1%)  head
louse  solution.  Their  hair was  allowed to  dry naturally  and  then
washed with baby shampoo.  Urine samples were collected at 0-24, 24-48,
120-144,  and 336-360 h to measure dermal absorption.  On assessment, 3
out  of  10 volunteers developed  mild,  patchy erythema,  which  faded
between  days 4-7.  Permethrin excretion during the first 24 h was only
about 1% of the applied dose, while the cumulative maximum over 14 days
was only about 5.5 mg (Farquhar et al., 1981b).

9.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    The  Joint FAO/WHO Meeting  on Pesticide Residues  (JMPR) discussed
and evaluated permethrin in 1979, 1980, 1981, 1982, 1983,  1984,  1985,
and  1987  (FAO/WHO,  1980a,b;  1981a,b;  1982a,b;  1983a,b;   1984a,b;
1985a,b; 1986a,b; 1987).

    An  acceptable  daily  intake  (ADI)  of  0-0.05 mg/kg  body weight
(cis:trans ratios of 40:60 and 27:75) was established in 1985.

    Maximum residue limits of 0.01-50 mg/kg for specified foods and 20-
100 mg/kg  dry weight for specified  feed have been proposed  (FAO/WHO,
1986).

    In  the  WHO recommended  classification  of pesticides  by hazard,
permethrin as a technical product is classified in class II  (i.e.,  as
moderately  hazardous) (WHO, 1988).  A WHO/FAO data sheet on permethrin
exists (WHO/FAO, 1984).

REFERENCES

AGNIHOTRI, N.P., JAIN, H.K., & GAJBHIYE, V.T.  (1986)   Persistence  of
some  synthetic pyrethroid insecticides in  soil, water and sediment  -
Part I.  J. entomol. Res., 10: 147-151.

ALINIAZEE,  M.T.  &  CRANHAM, J.E.  (1980)   Effect  of four  synthetic
pyrethroids  on  a  predatory mite,  Typhlodromus  pyri, and  its  prey,
 Panonychus  ulmi, on apples in southeast England.  Environ. Entomol., 9:
436-439.

ANDERSON,   D.   &   RICHARDSON,  C.R.    (1976)    Permethrin  (PP557):
cytogenetic  study  in the  rat  (Report No.  CTL/P/296)  (Unpublished
report submitted to WHO by ICI Central Toxicology Laboratory).

ANDERSON,  R.L.  (1982)   Toxicity  of  fenvalerate  and  permethrin to
several  nontarget aquatic invertebrates.  Environ.  Entomol., 11: 1251-
1257.

BAKER,  P.G.  &  BOTTOMLEY, P.  (1982)   Determination  of residues  of
synthetic pyrethroids in fruit and vegetables by gas-liquid  and  high-
performance liquid chromatography.  Analyst, 107: 206-212.

BATTELLE (1982)   Pesticide programme of research and  market  planning.
 Part I: Insecticides, Geneva, Institut Battelle (October 1982).

BATTELLE  (1986)    World  Pesticide Programme,  Insecticide  II,  1984,
Geneva, Institut Battelle.

BILLUPS,  L.H.  (1978a)  Histopathologic   examination of a  twenty-four
 month toxicity/carcinogenicity study of compound FMC33297 in rats, (Un-
published  report submitted to  WHO by FMC  Corporation,  Environmental
Pathology Services).

BILLUPS,  L.H.   (1978b)    Twenty-four  month  toxicity/carcinogenicity
 study  of compound FMC33297 in  rats  (Unpublished report submitted  to
WHO by FMC Corporation, Environmental Pathology Services).

BIO-DYNAMICS   (1979)  Twenty-four  month toxicity/carcinogenicity study
 of  permethrin  in  mice   (Bio-Dynamics  Inc.  Project  No. 76-1695/9)
(Unpublished report submitted to WHO by FMC Corporation).

BORTHWICH,  P.W. & WALSH, G.E. (1981)  Initial  toxicological assessment
 of  Ambush,  Bolero, Bux,  Dursban,  Fentrifanil, Larvin,  and  Pydrin:
 Static   acute   toxicity   tests  with   selected   estuarine   algae,
 invertebrates,  and  fish,   Springfield, Virginia,  National Technical
Information Service, pp. 1-9 (EPA-600/4-81-076).

BRADBROOK,  C.,  BANHAM,  P.B.,  GORE,  C.W.,  PRATT,  I.,  &   WEIGHT,
T.M.    (1977)    PP557:   A  study  of  the  reversibility  of  hepatic
 biochemical  and  ultrastructural  changes  in  the  rat  (Report  No.
CTL/P/354) (Unpublished Data submitted to WHO by ICI Central Toxicology
Laboratory).

BRAUN,  W.G.  &  KILLEEN, J.C.   (1975)   Acute   oral toxicity  in rat:
 compound no.  FMC33297 (Bio-Dynamics Inc. Project) (Unpublished report
submitted to WHO by FMC Corporation).

BRAUN,  W.G.  &  RINEHART,  W.E.   (1977)   A   twenty-four  month  oral
 toxicity/carcinogenicity  study of FMC33297 in rats  (Bio-Dynamics Inc.
Project) (Unpublished report submitted to WHO by FMC Corporation).

BRAUN,  H.E. & STANEK, J. (1982)  Application of the AOAC multi-residue
method  to determination of synthetic pyrethroid residues in celery and
animal products.  J. Assoc. Off. Anal. Chem., 65: 685-689.

BUTTERWORTH,  S.T.G. &  HEND, R.W.   (1976)  Toxicity   studies  on  the
 insecticide  WL43470: a five week   feeding study in rats  (Report No.
TLGR.0056.76)  (Unpublished  data submitted  to  WHO by  Shell Research
Ltd).

CARLSON, G.P. & SCHOENIG, G.P.  (1980)  Induction of  liver  microsomal
NADPH cytochrome c reductase and cytochrome P-450 by some new synthetic
pyrethroids.   Toxicol. appl. Pharmacol., 52: 507-512.

CARROLL,   B.R.,  WILLIS,  G.H.,  &  GRAVES,  J.B.  (1981)   Permethrin
concentration of cotton plants, persistence in soil and loss in runoff.
 J. environ. Qual., 10:  497-500.

CHESHER,  B.C. & MALONE, J.C.  (1974a)   10-day cumulative oral toxicity
 study   with   21Z73   in  rabbits,   Berkhamsted,  Wellcome  Research
Laboratories  (Report  No. HEFG  74-7)  (Unpublished data  submitted to
WHO).

CHESHER,  B.C. & MALONE, J.C.  (1974b)  Guinea  pig sensitization  study
 with  21Z73 using the  maximisation test method, Berkhamsted,  Wellcome
Research   Laboratories  (Report  No.  HEFG   74-3)  (Unpublished  data
submitted to WHO).

CHESHER,  B.C. & MALONE, J.C.   (1974c)   Occular irritancy of  21Z73 in
rabbits, Berkhamsted,  Wellcome Research Laboratories (Report  no. HEFG
74-6) (Unpublished data submitted to WHO).

CHESHER,  B.C.,  CLAMPITT,  R.C.,  &  MALONE,  J.C.   (1975)   21Z73   -
 Preliminary investigations into the cumulative oral toxicity  on  dogs,
Berkhamsted,  Wellcome  Research  Laboratories (Report  no.  HEFG 75-9)
(Unpublished data submitted to WHO).

CLAPP,  M.J.L., BANHAM, P.B.,  CHART, I.S., GLAISTER,  J., GORE, C.,  &
MOYES,  A.  (1977a)  PP557:  28  day feeding study in  rats (Report No.
CTL/P/355) (Unpublished data submitted to WHO by ICI Central Toxicology
Laboratory).

CLAPP,  M.J.L., BANHAM,  P.B., GLAISTER,  J.R., &  MOYES,  A.   (1977b)
 PP557:    28   day  feeding  study  in  mice   (Report  No.  CTL/P/354)
(Unpublished   data  submitted  to   WHO  by  ICI   Central  Toxicology
Laboratory).

CLARK, D.G.  (1978)  Toxicology  of WL 43479: acute toxicity of WL43479,
Sittingbourne,    Shell  Research  Ltd   (Report  No.  TLGR.   0043.78)
(Unpublished data submitted to WHO).

CLIVE,  C.D.   (1977)    Mutagenicity  of  BW21Z73  in  L5178Y/TK  mouse
 lymphoma  cells with and  without  exogenous  metabolic activation, Re-
search   Triangle  Park,  NC,   Burroughs  Wellcome  Co.   (Report  No.
TTEP/77/0011) (Unpublished data submitted to WHO).

CLOUD,  R.M., ZIMPFER,  M.L., YANES,  J.JR., BOETHEL,  D.J., BUCO,  P.,
& HARMON, C.W.  (1987)  Insecticide residues on clothing worn  by  crop
consultants in soybean fields treated with non-conventional application
technology.  Bull. environ. Contam. Toxicol., 38: 277-282.

COATS,   J.R.  &  O'DONNELL-JEFFERY,  N.L.  (1979)   Toxicity  of  four
synthetic  pyrethroid  insecticides  to rainbow  trout.  Bull.  environ.
 Contam. Toxicol., 23: 250-255.

COX, R.L. & WILSON, W.T.  (1984)  Effects of permethrin on the behavior
of  individually  tagged  honey bees,  Apis  mellifera  L. (Hymenoptera:
Apidae).  Environ. Entomol., 13: 375-378.

CRIDLAND, J.S. & WEATHERLEY, B.C.  (1977a)   Urinary excretion in man of
 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane  carboxylic acid ("CVA")
 after  oral ingestion of permethrin (NRDC 143) - A first report, Bech-
enham,   Wellcome   Research   Laboratories  (Report   No.   BDPE-77-1)
(Unpublished data submitted to WHO).

CRIDLAND, J.S. & WEATHERLEY, B.C.  (1977b)   An estimate  of  permethrin
 (NRDC 143; OMS1821) absorbed by people employed in a field trial of the
 insecticide, Bechenham,  Wellcome  Research  Laboratories  (Report  No.
BDPE-77-3) (Unpublished data submitted to WHO).

DAYAN,  A.D.  (1980)  21-day  neuropathological study in  the  Sprague-
Dawley   rat  of  permethrin   (212732J)  administered  in   the  diet,
Berkhamsted,  Wellcome  Research  Laboratories (Report  No.  BP  80-48)
(Unpublished report submitted to WHO by Wellcome Foundation Ltd).

DOYLE,  R.D.,  KAUFMAN,  D.D.,  BURT,  G.W.,  &  DOUGLASS,  L.   (1981)
Degradation  of  cis-permethrin  in soil  amended with sewage  sludge or
dairy manure.  J. agric. food Chem., 29: 412-414.

DYCK,  P.J., SHIMONO, M.,  SCHOENING, G.P., LAIS,  A.C., OVIATT,  K.F.,
&  SPARKS, M.F.  (1984)  The  evaluation of a new  synthetic pyrethroid
pesticide  (permethrin) for neurotoxicity.  J. environ. Pathol. Toxicol.
 Oncol., 5: 109-117.

EDWARDS,  D.B.,  OSBORN,  B.E.,  DENT,  N.J.,  &  KINCH,  D.A.   (1976)
 Toxicity   study in beagle dogs (oral administration for three months),
Inveresk,    United   Kingdom,  Inveresk   Research  International  Ltd
(Submitted to WHO by ICI Ltd).

EDWARDS, M.J. & ISWARAN, T.J.  (1977)  Permethrin:  residue transfer and
 toxicology  study  with  cows  fed  treated  grass   nuts (Report   No.
TMJ1519/B) (Unpublished report submitted to WHO by ICI Plant Protection
Division).

ELLIOTT,  M.  (1977)   Synthetic pyrethroids,  Washington, DC, American
Chemical Society, p. 229 (ACS Symposium Series 42).

ELLIOTT,    M.,   FARNHAM,   A.W.,   JANES,    N.F.,   NEEDHAM,   P.H.,
PULMAN,  D.A.,  &  STEVENSON,  J.H.  (1973)  A  photostable pyrethroid.
 Nature (Lond.), 246: 169-170.

ELLIOTT,  M.,  JANES,  N.F., PULMAN,  D.A.,  GAUGHAN,  L.C., UNAI,  T.,
&  CASIDA, J.E. (1976) Radiosynthesis and metabolism in rats of the 1R-
isomers of the insecticide permethrin.  J. agric. food  Chem., 24:  270-
276.

EVANS,  M.H. (1976)  End-plate potentials  in frog muscle exposed  to a
synthetic pyrethroid Pestic.  Biochem. Physiol., 6: 547-550.

EVERTS,   J.W.,   KORTENHOFF,   B.A.,   HOOGLAND,   H.,   VLUG,   H.J.,
JOCQUE, R., & KOEMAN, J.H.  (1985)  Effects on  non-target  terrestrial
arthropods  of synthetic pyrethroids used for the control of the tsetse
fly   (Glossina   spp.) in settlement areas of the southern Ivory Coast,
Africa.  Arch.  environ. Contam. Toxicol., 14: 641-650.

FAO     (1982)  Second   Government   Consultation    on   International
 Harmonization  of  Pesticide  Registration  Requirements,  Rome,  11-15
 October  1982, Rome, Food and  Agriculture Organization of  the  United
Nations.

FAO/WHO  (1980a)   Pesticide residues in food.  Report of the 1979 Joint
 Meeting of the FAO Panel of Experts on Pesticide Residues in  Food  and
 the Environment and the WHO Expert Group on  Pesticide  Residues, Rome,
Food and Agriculture Organization of the United Nations, pp. 52-55 (FAO
Plant Production and Protection Paper 20).

FAO/WHO (1980b) 1979   Evaluations of some pesticide residues  in  food,
Rome,   Food  and  Agriculture  Organization  of  the  United  Nations,
pp. 369- 425 (FAO Plant Production and Protection Paper 20 Sup).

FAO/WHO  (1981a)   Pesticide residues in food.  Report of the 1980 Joint
 Meeting of the FAO Panel of Experts on Pesticide Residues in  Food  and
 the Environment and the WHO Expert Group on  Pesticide  Residues, Rome,
Food and Agriculture Organization of the United Nations, pp. 50-51 (FAO
Plant Production and Protection Paper 26).

FAO/WHO  (1981b)  1980    Evaluations  of  some  pesticide  residues  in
 food, Rome, Food and Agriculture Organization of the  United  Nations,
pp. 360-393 (FAO Plant Production and Protection Paper 26 Sup).

FAO/WHO    (1982a)   Pesticide  residues in  food.  Report  of the  1981
 Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food
 and  the Environment and  the WHO Expert  Group on Pesticide  Residues,
Rome,   Food and Agriculture  Organization of the  United Nations,  pp.
37-39 (FAO Plant Production and Protection Paper 37).

FAO/WHO   (1982b)   1981 Evaluations of some pesticide residues in food,
Rome,   Food  and  Agriculture  Organization  of  the  United  Nations,
pp. 385-425 (FAO Plant Production and Protection Paper 42).

FAO/WHO   (1983a)  Pesticide residues in food.  Report of the 1982 Joint
 Meeting  of the  FAO Panel  of Experts  on Pesticide  Residues in  Food
 and  the Environment and  the WHO Expert  Group on Pesticide  Residues,
Rome,  Food and Agriculture Organization of the United Nations, pp. 36-
38 (FAO Plant Production and Protection Paper 46).

FAO/WHO   (1983b)   1982 Evaluations of some pesticide residues in food,
Rome,   Food  and  Agriculture  Organization  of  the  United  Nations,
pp. 329-350 (FAO Plant Production and Protection Paper 49).

FAO/WHO    (1984a)   Pesticide  residues in  food.  Report  of the  1983
 Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food
 and  the Environment and the  WHO  Expert  Group on Pesticide Residues,
Rome,   Food and Agriculture Organization of the United Nations, p. 38,
57, 62, 65 (FAO Plant Production and Protection Paper 56).

FAO/WHO  (1984b)  1983 Evaluations of  some pesticide residues  in food,
Rome,   Food  and  Agriculture  Organization  of  the  United  Nations,
pp. 307-313, 501 (FAO Plant Production and Protection Paper 61).

FAO/WHO   (1985a)  Pesticide residues in food.  Report of the 1984 Joint
 Meeting of the FAO Panel of Experts on Pesticide Residues in  Food  and
 the Environment and the WHO Expert Group on  Pesticide  Residues, Rome,
Food and Agriculture Organization of the United Nations, pp. 63, 85, 93
(FAO Plant Production and Protection Paper 62).

FAO/WHO  (1985b)  1984 Evaluations of some pesticide residues  in  food,
Rome,   Food  and  Agriculture  Organization  of  the  United  Nations,
pp. 441-444, 723 (FAO Plant Production and Protection Paper 67).

FAO/WHO  (1985c)   Guide to  Codex recommendations concerning  pesticide
 residues.  Part 8. Recommendations for methods of analysis of pesticide
 residues, 3rd ed., Rome, Codex Committee on Pesticide Residues.

FAO/WHO  (1986a)   Pesticide residues in food.  Report of the 1985 Joint
 Meeting of the FAO Panel of Experts on Pesticide Residues in  Food  and
 the Environment and the WHO Expert Group on  Pesticide  Residues, Rome,
Food  and Agriculture Organization  of the United  Nations, p. 37  (FAO
Plant Production and Protection Paper 68).

FAO/WHO   (1986b)   1985 Evaluations of some pesticide residues in food,
 Part  I -  Residues, Rome, Food  and Agriculture  Organization  of  the
United  Nations, pp. 201-203 (FAO Plant Production and Protection Paper
No 72/1).

FAO/WHO  (1986c)   Codex Maximum Limits for pesticide residues, 2nd ed.,
Rome,  Food and Agriculture Organization  of the United Nations,  Joint
FAO/WHO   Food  Standards  Programme,  Codex  Alimentarius  Commission,
(CAC XIII).

FAO/WHO  (1987)   Pesticide residues in food. Report of the  1987  Joint
 Meeting of the FAO Panel of Experts on Pesticide residues in  Food  and
 the Environment and the WHO Expert Group on  Pesticide  Residues, Rome,
Food  and Agriculture Organization  of the United  Nations, p. 33  (FAO
Plant Production and Protection Paper 84).

FAO/WHO   (1988)  Permethrin. In:  Pesticide residues in food. Part II -
 Toxicology, Rome,  Food  and  Agriculture Organization  of  the  United
Nations, pp. 101-110 (FAO Plant Production and Protection Paper 86/2).

FARQUHAR,   J.A.,   HUTCHINSON,   D.B.A.,  PERIAM,   A.W.,  &  SPARKES,
R.G.   (1981a)   An investigation into the absorption of permethrin from
 impregnated clothing, Bechenham, Wellcome Research Laboratories (Report
No. BKDL/81/1) (Unpublished data submitted to WHO).

FARQUHAR,   J.A.,   HUTCHINSON,   D.B.A.,  PERIAM,   A.W.,  &  SPARKES,
R.G.   (1981b)   An  investigation of  tolerance to  absorption  of  and
 persistence  of  permethrin  applied as  a  1%  lotion to  human  hair,
Bechenham,   Wellcome  Research  Laboratories  (Report  No.  BKDL/81/2)
(Unpublished data submitted to WHO).

FLANNIGAN,   S.A.  &  TUCKER,  S.B.   (1985)   Variation  in  cutaneous
sensation  between  synthetic  pyrethroid insecticides.  Contact  Derma-
 titis, 13: 140-147.

FLANNIGAN,    S.A.,   TUCKER,   S.B.,   MARCUS,   M.K.,   ROSS,   C.E.,
FAIRCHILD,  E.J.,  GRIMES,  B.A.,  &  HARRIST,  R.B.   (1985a)  Primary
irritant  contact  dermatitis  from  synthetic  pyrethroid  insecticide
exposure.  Arch.  Toxicol., 56, 288-294.

FLANNIGAN,  S.A.,  TUCKER,  S.B.,  KEY,  M.M.,  ROSS,  C.E., FAIRCHILD,
E.J.,  GRIMES,  B.A., &  HARRIST,  R.B.  (1985b)   Synthetic pyrethroid
insecticides:  a dermatological evaluation.  Br. J.  ind. Med., 42: 363-
372.

FRIESEN,  M.K.,  GALLOWAY, T.D.,  &  FLANNAGAN, J.F.  (1983)   Toxicity
of  the insecticide permethrin in  water and sediment to  nymphs of the
burrowing  mayfly  Hexagenia  rigida (Ephemeroptera:  Ephemeridae).  Can.
 Entomol., 115: 1007-1014.

GAMBRELL,  R.P.,  REDDY,  C.N., COLLARD,  V.,  GREEN,  G.,  &  PATRICK,
W.H.,  Jr.  (1981)   Behavior of DDT, kepone and permethrin in sediment-
 water  systems under different  oxidation-reduction and pH  conditions,
Washington,   DC,  US  Environmental Protection  Agency  (EPA 600/3-81-
038).

GAMMON,  D.W.  & CASIDA,  J.E. (1983)  Pyrethroids  of the most  potent
class  antagonize GABA action  at the crayfish  neuromuscular junction.
 Neurosci. Lett., 40: 163-168.

GAMMON,  D.W.,  BROWN,  M.A., &  CASIDA,  J.E.  (1981)  Two  classes of
pyrethroid  action  in  the cockroach.    Pestic. Biochem. Physiol., 15:
181-191.

GAMMON,  D.W.,  LAWRENCE,  L.J.,  &  CASIDA,  J.E.  (1982)   Pyrethroid
toxicology:   Protective effects of  Diazepam and phenobarbital  in the
mouse and the cockroach.   Toxicol. appl. Pharmacol., 66: 290-296.

GAUGHAN,  L.C.  &  CASIDA, J.E.  (1978)  Degradation of  trans- and  cis-
permethrin  on cotton and bean plants.  J. agric. food  Chem., 26:  525-
528.

GAUGHAN,  L.C., UNAI, T., &  CASIDA, J.E. (1977) Permethrin  metabolism
in rats.   J. agric. food Chem., 25: 9-17.

GAUGHAN,  L.C., ROBINSON, R.A.,  & CASIDA, J.E.  (1978b)   Distribution
and  metabolic  fate  of  trans- and  cis-permethrin  in  laying hens.  J.
 agric. food Chem., 26: 1374-1380.

GAUGHAN,  L.C.,  ACKERMAN,  M.E., UNAI,  T.,  &  CASIDA,  J.E.  (1978a)
Distribution  and metabolism of  trans- and  cis-permethrin  in lactating
Jersey cows.   J. agric. food Chem., 26: 613-618.

GERIG,  L. (1985) Testing the toxicity of synthetic pyrethroid insecti-
cides to bees.   Pestic. Sci., 16: 206-207.

GLAISTER,  J.R.,  PRATT, I.,  & RICHARDS, D.   (1977)   Effects of  high
 dietary  levels of PP557 on clinical behaviour and structure of sciatic
 nerves  in rats (Report No.  CTL/P/317) (Unpublished data  submitted to
WHO by ICI Central Toxicology Laboratory).

GLICKMAN, A.H. & CASIDA, J.E. (1982)  Species and structural variations
affecting  pyrethroid neurotoxicity.  Neurobehav. Toxicol. Teratol., 4:
(6) 793-799.

GLICKMAN,  A.H.  &  LECH,  J.J.  (1981)  Hydrolysis  of  permethrin,  a
pyrethroid  insecticide, by rainbow trout and mouse tissues  in vitro : A
comparative study.   Toxicol. appl. Pharmacol., 60: 186-192.

GLICKMAN, A.H., SHONO, T., CASIDA, J.E., & LECH, J.J.  (1979)  In vitro
metabolism   of permethrin  isomers by  carp and  rainbow  trout  liver
microsomes.   J. agric. food Chem., 27: 1038-1041.

GLICKMAN,  A.H.,  HAMID,  A.AR., RICKERT,  D.E.,  &  LECH, J.J.  (1981)
Elimination  and  metabolism of  permethrin  isomers in  rainbow trout.
 Toxicol. appl. Pharmacol., 57: 88-98.

GLICKMAN, A.H., WEITMAN, S.D., & LECH, J.J.  (1982)  Different toxicity
of  trans-permethrin  in rainbow trout and mice. I. Role of biotransfor-
mation.   Toxicol. appl. Pharmacol., 66: 153-161.

HAGLEY,  E.A.C.,  PREE,  D.J., &  HOLLIDAY,  N.J.  (1980)  Toxicity  of
insecticides to some orchard carabids  (Coleoptera carabidae). Can. Entomol.,
112: 457-462.

HALLS, G.R.H. (1981)   The fate of permethrin residues on wheat during 9
 months  storage in Australia (Report  No. HEFH 81-1)  (Unpublished data
submitted to WHO by Wellcome Research Laboratories).

HALLS, G.R.H. & PERIAM, A.W. (1980)   The fate of permethrin residues on
 wheat during storage and after milling and baking - results after 9, 12
 and 15 months storage (Report HEFH 80-3) (Unpublished data submitted to
WHO by Wellcome Research Laboratories).

HANSEN,  D.J.,  GOODMAN,  L.R., MOORE,  J.C.,  &  HIGDON, P.K.   (1983)
Effects  of  the  synthetic pyrethroids  AC  222,  705, permethrin  and
fenvalerate  on sheepshead  minnows in  early life  stage  of  toxicity
tests.   Environ. Toxicol. Chem., 2: 251-258.

HART,  D.,  BANHAM,  P.B.,  GORE,  C.W.,  PRATT,  I.,  &  WEIGHT,  T.M.
(1977c)   PP557:  Liver hypertrophy study in rats-dietary administration
 over 26 weeks (Report No. CTL/P/360) (Unpublished data submitted to WHO
by ICI Central Toxicology Laboratory).

HELSON,  B.V., KINGSBURY,  P.D., &  DE GROOT,  P.  (1986)   The use  of
bioassays to assess aquatic arthropod mortality from  permethrin  drift
deposits.   Aquat. Toxicol., 9: 253-262.

HEND, R.W. & BUTTERWORTH, S.T.G.  (1977)   Toxicity of  insecticides:  a
 short-term  feeding study of WL 43379 in rats (Report No. TLGR.0108.77)
(Unpublished data submitted to WHO by Shell Research Ltd).

HENRIET,  J.,  MARTIJN, A.,  &  POLVISEN, H.H.  (1985)  CIPAC  Handbook.
 Volume  1C: Analysis of technical and formulated pesticides,  Hertford-
shire,  Collaborative International Pesticides Analytical  Council Ltd,
pp. 2172-2173.

HILL,  E.F. &  CAMARDESE, M.B.  (1986)   Lethal  dietary  toxicities  of
 environmental  contaminants and pesticides to Coturnix, Washington, DC,
United  States Department of the  Interior, Fish and Wildlife  Service,
p.111 (Fish and Wildlife Technical Report No. 2).

HODGE,   M.C.E.,   BANHAM,   P.B.,  GLAISTER,   J.R.,   RICHARDS,   D.,
TAYLOR, K., & WEIGHT, T.M. (1977)   PP557: Three generation reproduction
 study  in  rats (Unpublished   report submitted to  WHO by ICI  Central
Toxicology Laboratory).

HOGAN,  G.K.  &  RINEHART,  W.E.   (1977)    A  twenty-four  month  oral
 carcinogenicity  study of FMC 33297 in mice (Bio-Dynamics Inc. Project)
(Unpublished report submitted to WHO by FMC Corporation).

HOLDWAY,  D.A. & DIXON, D.G.   (1988)  Acute toxicity of  permethrin or
glyphosate pulse exposure to larval white sucker   (Catostomus   commer-
 soni) and juvenile flagfish  (Jordanella  floridae) as modified by age
and ration level.  Environ. Toxicol. Chem., 7: 63-68.

HOLMSTEAD,  R.L.,  CASIDA,  J.E., RUZO,  L.O.,  &  FULLER, D.G.  (1978)
Pyrethroid  photodecomposition:  Permethrin.  J. agric.  food Chem., 26:
590-595.

HORIBA,   M.,   KOBAYASHI,  A.,   &   MURANO,  A.   (1977)   Gas-liquid
chromatographic  determination of a new pyrethroid, permethrin (S-3151)
and its optical isomers.  Agric. biol. Chem., 41: 581-586.

HOY,   M.A.,  FLAHERTY,   D.,  PEACOCK,   W.,  &   CULVER,  D.   (1979)
Vineyard  and  laboratory  evaluations  of  methomyl,  dimethoate,  and
permethrin  for a  grape pest  management program  in the  San  Joaquin
Valley of California.   J. econ. Entomol., 72: 250-255.

HOYT,  S.C.,  WESTIGARD,  P.H., &  BURTS,  E.C.  (1978) Effects  of two
synthetic  pyrethroids on the  codling moth, pear  psylla, and  various
mite species in northwest apple and pear orchards.  J.  econ.  Entomol.,
71: 431-434.

HUNT, L.M. & GILBERT, B.N. (1977) Distribution and excretion  rates  of
14C-labelled   permethrin isomers administered orally to four lactating
goats for 10 days.   J. agric. food Chem., 25: 673-676.

HUNT,   L.M.,  GILBERT,  B.N.,   &  LEMEILLEUR,  C.A.   (1979)  Distri-
bution  and depletion of  radioactivity in hens  treated dermally  with
14C-labelled permethrin.   Poult. Sci., 58: 1197-1201.

ISHMAEL,   J.  &  LITCHFIELD,   M.H.   (1988)   Chronic   toxicity  and
carcinogenic  evaluation of permethrin in rats and mice.   Fundam. appl.
 Toxicol., 11: 308-311.

IVIE, G.W. & HUNT, L. (1980) Metabolites of  cis- and  trans-permethrin
in lactating goats.  J. agric. food Chem., 28: 1131-1138.

JAGGERS, S.E. & PARKINSON, G.R.  (1979)   Permethrin: summary and review
 of  acute  toxicities  in  laboratory  species (Report  No.  CTL/P/461)
(Unpublished   data  submitted  to   WHO  by  ICI   Central  Toxicology
Laboratory).

JAMES,  J.A.  (1974)   Fetal toxicity  study of 21Z73 (NRDC  143) in the
 rat (Report  No. BPAT 74-10) Bechenham,  Wellcome Research Laboratories
(Unpublished data submitted to WHO).

JAMES,  J.A.,  (1979)   A  multigeneration reproduction study  of  21Z73
 (permethrin)  in  the rat (Report  No.  BPAT 79-3)  Bechenham, Wellcome
Research Laboratories (Unpublished data submitted to WHO).

JAMES, J.A., TAYLOR, P.E., & ROE, F.J.C.  (1980)   Carcinogenicity study
 in  mice with permethrin,  Bechenham, Wellcome Research  Laboratories,
(Report No.  HEFG 80-29) (Unpublished data submitted to WHO).

JOLLY,  A.L., Jr.,  AVAULT, J.W.,  Jr., KOONCE,  K.L., &  GRAVES,  J.B.
(1978)  Acute toxicity of permethrin to several aquatic animals.  Trans.
 Am. Fish. Soc., 107: 825-827.

JORDAN,  E.G.  &  KAUFMAN, D.D.  (1986)  Degradation of  cis- and  trans-
permethrin in flooded soil.  J. agric. food Chem., 34: 880-884.

JORDAN, E.G., KAUFMAN, D.D., & KAYSER, A.J. (1982) The effect  of  soil
temperature  on the degradation of  cis-,   trans-permethrin  in soil.  J.
 environ. Sci. Health, B 17: 1-17.

KADOTA,  T., MIYAMOTO, J.,  & ITO, N.  (1975)   Six-month subacute  oral
 toxicity  of NRDC in Sprague-Dawley rats (Unpublished data submitted to
WHO by Sumitomo Chemical Co.).

KANEKO,  H.,  OHKAWA,  H.,  &  MIYAMOTO,  J.  (1978)  Degradation   and
movement of permethrin isomers in soil.  J. Pestic. Sci., 3: 43-51.

KAUFMAN,  D.D.,  HAYES,  S.C., JORDAN,  E.G.,  &  KAYSER, A.J.   (1977)
Permethrin degradation in soil and microbial cultures. In: Elliott, M.,
ed.  Synthetic  pyrethroids, Washington, DC, American  Chemical Society,
pp. 147-161 (ACS symposium series 42).

KAUFMAN,  D.D., RUSSEL,  B.A., HELLING,  C.S., &  KAYSER,  A.J.  (1981)
Movement   of   cypermethrin,   deltamethrin,  permethrin   and   their
degradation products in soil.   J. agric. food Chem., 29: 239-245.

KAUSHIK,   N.K.,  STEPHENSON,  G.L.,   SOLOMON,  K.R.,  &   DAY,   K.E.
(1985)    Impact   of   permethrin  on   zooplankton   communities   in
limnocorrals.  Can.  J. Fish. aquat. Sci., 42: 77-85.

KILLEEN,  J.C. & RAPP, W.R.  (1976a)  A  three month oral toxicity study
 of FMC 33297 in Beagle dogs  (Bio-Dynamics Inc.  Project)  (Unpublished
report submitted to WHO by FMC Corporation).

KILLEEN,  J.C. & RAPP, W.R.  (1976b)   A three month oral toxicity study
 of  FMC 33297 in  rats (Bio-Dynamics Inc. Project)  (Unpublished report
submitted to WHO by FMC Corporation).

KINGSBURY,  P.D. (1976)  Effects of  an aerial application of  the syn-
thetic pyrethroid permethrin on a forest stream.  Manitoba Entomol., 10:
9-17.

KINGSBURY,  P.D.  &  KREUTZWEISER,  D.P.  (1980a)  Environmental  impact
 assessment  of  a  semi-operational permethrin  application. Sault Ste.
Marie, Ontario, Canada, Forest Pest Management Institute.   Report  No.
FPM-X 30: pp.47.

KINGSBURY,  P.D.  &  KREUTZWEISER, D.P.  (1980b)  Dosage-effect  studies
 on  the  impact  of permethrin  on  trout  streams. Sault  Ste. Marie,
Ontario, Canada, Forest Pest Management Institute Report No. FPM-X 31.

KINGSBURY,  P.D. & KREUTZWEISER, D.P.  (1987)  Permethrin treatments in
Canadian forests. Part 1: Impact on fish.  Pestic. Sci., 19: 35-48.

KOHDA,  H., KADOTA, T., & MIYAMOTO, J.  (1976a)   Teratogenic evaluation
 with  permethrin  in  rats (Unpublished  report  submitted  to  WHO  by
Sumitomo Chemical Co.).

KOHDA, H., KADOTA, T., & MIYAMOTO, J.   (1976b)  Teratogenic  evaluation
 with  permethrin  in  mice (Unpublished  report  submitted  to  WHO  by
Sumitomo Chemical Co.).

KOHDA,  H., KADOTA, T., & MIYAMOTO, J.  (1979a)   Acute oral, dermal and
 subcutaneous  toxicities  of  permethrin in  rats  and mice (Unpblished
report submitted to WHO by Sumitomo Chemical Co.).

KOHDA,  H.,  KANEDO,  H.,  OHKAWA,  H.,  KADOTA,  T.,  &  MIYAMOTO,  J.
(1979b)    Acute  intraperitoneal toxicity of  permethrin metabolites in
 mice (Unpublished report submitted to WHO by Sumitomo Chemical Co.).

KOLMODIN-HEDMAN,    B.,   SWENSSON,   A.,   &   AKERBLOM,   M.   (1982)
Occupational  exposure  to  some synthetic  pyrethroids (permethrin and
fenvalerate).   Arch. Toxicol., 50: 27-33.

KREUTZWEISER, D.P. (1982)  The effects of permethrin on the invertebrate
 fauna of a Quebec forest. Sault Ste Marie, Ontario, Canada, Forest Pest
Management Institute, Report No. FPM-X 50: pp.44.

KREUTZWEISER,  D.P.  &  KINGSBURY, P.D.   (1987)  Permethrin treatments
in  Canadian forests.  Part 2:  Impact on stream invertebrates.  Pestic.
 Sci., 19: 49-60.

KUMARAGURU,   A.K.  &  BEAMISH,   F.W.H.  (1981)  Lethal   toxicity  of
permethrin (NRDC-143) to rainbow trout,  Salmo gairdneri, in relation to
body weight and water temperature.  Water Res., 15: 503-505.

KUMARAGURU,   A.K.,   BEAMISH,   F.W.H.,  &   FERGUSON,   H.W.   (1982)
Direct   and  circulatory  paths   of  permethrin  (NRDC-143)   causing
histopathological   changes  in  the  gills   of  rainbow  trout,  Salmo
 gairdneri Richardson.  J.  Fish Biol., 20: 87-91.

LAWRENCE,  L.J.  & CASIDA,  J.E.  (1982) Pyrethroid  toxicology:  Mouse
intracerebral structure-toxicity relationship.  Pestic. Biochem. Physiol.,
18: 9-14.

LAWRENCE,   L.J.  &  CASIDA,  J.E.  (1983)   Stereospecific  action  of
pyrethroid   insecticides  on  the  gamma-aminobutyric  acid  receptor-
ionophore complex.   Science, 221: 1399-1401.

LAWRENCE,  L.J., GEE, K.W.,  & YAMAMURA, H.I.  (1985)  Interactions  of
pyrethroid  insecticides  with  chloride  ionophore-associated  binding
sites.   Neurotoxicology,  6: 87-98.

LEAHEY,  J.P.   (1985)    The pyrethroid  insecticides, London, Taylor &
Francis Ltd, p. 440.

LEAHEY,  J.P.  &  CARPENTER, P.K.  (1980)  The  uptake  of  metabolites
of  permethrin  by  plants  grown in soil treated with [14C]permethrin.
 Pestic. Sci., 11: 279-289.

LEAHEY,  J.P., BEWICK, D.W.,  & SAUNDERS, R.  (1977)   Accumulation  and
 depletion  of radioactive residues in  the tissues of Mallard  duck and
 Japanese quail following daily dosing with  14 C-permethrin (Unpublished
report submitted to WHO by ICI Plant Protection Division).

LE   QUESNE,   P.N.,  MAXWELL,   I.C.,   &  BUTTERWORTH,   T.G.  (1980)
Transient  facial  sensory  symptoms following  exposure  to  synthetic
pyrethroids: a clinical and electorophysiological assessment.  Neurotoxi-
 cology, 2: 1-11.

LINDEN,   E.,  BENGTSSON,  B.-E.,   SVANBERG,  O.,  &   SUNDSTROM,   G.
(1979)  The acute toxicity of  78 chemicals and pesticide  formulations
against two brackish water organisms, the Bleak  (Alburnus alburnus) and
the  Nitocra spinipes.  Chemosphere, 11/12: 843-851.

LINDQUIST, R.K., KRUEGER, H.R., & POWELL, C.C., Jr.   (1987)   Airborne
and  surface  residues  of  permethrin  after  high-   and   low-volume
applications in greenhouses.   J. environ. Sci. Health, B22: 15-27.

LITCHFIELD,  M.H.  (1983)  Characterisation of  the principal mammalian
toxicological  and  biological  actions of  synthetic  pyrethroids. In:
Miyamoto,  J. & Kearney,  P.C., ed.  Pesticide chemistry:  human welfare
 and  the environment. II. Natural products, Oxford, Pergamon Press, pp.
207-211.

LONGSTAFF,  E.   (1976)   Permethrin:  short-term  predictive  tests for
 carcinogenicity:  results  from  the Ames  test (Report  No. CTL/P/301)
(Unpublished   data  submitted  to   WHO  by  ICI   Central  Toxicology
Laboratory).

LORD,   K.A.,   MCKINLEY,  M.,  &  WALKER,  N.  (1982)  Degradation  of
permethrin in soils.  Environ. Pollut. A29: 81-90.

LUND,  A.E.  &  NARAHASHI,  T.  (1983)   Kinetics  of  sodium   channel
modification  as the  basis for  the variation  in the  nerve  membrane
effects of pyrethroids and DDT analogs.   Pestic. Biochem. Physiol., 20:
203-216.

MCGREGOR,   D.B.  &  WICKRAMARATNE,  G.A.,  de  S.   (1976a)    Dominant
 lethal  study in mice of  ICI-PP557 (Report No. 623, Inveresk  Research
International Project No. 406722) (Unpublished data submitted to WHO by
ICI Ltd).

MCGREGOR,  D.B.  &  WICKRAMARATNE,  G.A.,  de  S.    (1976b)     Terato-
 genicity  study in rats  of ICI-PP557 (Inveresk Research  International
Project No. 404898) (Unpublished data submitted to WHO by ICI Ltd.).

MCLEESE,  D.W.,  METCALFE,  C.D.,  &  ZITKO,  V.  (1980)  Lethality  of
permethrin, cypermethrin and fenvalerate to salmon, lobster and shrimp.
 Bull. environ. Contam. Toxicol., 25: 950-955.

MACPHEE,  A.,  GAUL, S.,  & RAGAB, M.T.H.  (1982) Control of  blueberry
thrips,  Frankliniella  vaccinii Morga,  with  permethrin and  effect on
yield and residue in fruit.  J. environ. Sci. Health, B17: 183-193.

MCSHEEHY,  T.W.  &  FINN, J.P.   (1980)    21Z:  Potential toxicity  and
 oncogenicity  in  dietary administration  to rats for  a period of  104
 weeks (Report  No. HEFG 80-33)  (Unpublished data of  Wellcome Research
Laboratories).

MAREI,  A.E.M.,  RUZO,  L.O., &  CASIDA,  J.E.   (1982)   Analysis  and
persistence  of permethrin, cypermethrin, deltamethrin  and fenvalerate
in the fat and brains of treated rats.  J. agric. food  Chem., 30:  558-
562.

MATHUR,  S.P.,  BELANGER,  A., HAMILTON,  H.A.,  &  KHAN,  S.U.  (1980)
Influence  on microflora and  persistence of field-applied  disulfoton,
permethrin and prometryne in an organic soil.    Pedobiologia, 20:  237-
242.

MAYER,  F.L.,  Jr.  (1987)   Acute  toxicity  handbook  of chemicals  to
 estuarine    organisms, Springfield,   Virginia,   National   Technical
Information Service, p. 158 EPA/600/8-87/017.

MAYER, F.L., Jr. & ELLERSIECK, M.R. (1986)   Manual of  acute  toxicity:
 Interpretation  and  data  base for  410  chemicals  and 66  species of
 freshwater  animals, Washington,  DC,  United States  Department of the
Interior, Fish and Wildlife Service, pp.377-378.

MEISTER, R.T., BERG, G.L., SINE, C., MEISTER, S., & POPLYK,  J.  (1983)
 Farm   chemicals handbook. Section C. Pesticide dictionary, Wilboughby,
Ohio, Meister Publishing Co., pp. C180-C181.

METKER,  L.W.  (1978)  Subchronic  inhalation  toxicity  of  3-(phenoxy-
 phenyl)methyl(+)-cis,trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopro-
 panecarboxylate  (permethrin), Aberdeen  Proving Ground,  Maryland, US
Army Environmental Hygiene Agency (Report No. 75-51-0026-80).

METKER,   L.W.,  ANGERHOFER,  R.A.,   POPE,  C.R.,  &   SWENTZEL,  K.C.
(1977)  Toxicology evaluation of 3-(phenoxyphenyl)methyl(+)-cis,trans-3-
 (2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate (permethrin),
Environmental Hygiene Agency (Report No. 75-51-0837-78).

MILLNER,  C.K. & BUTTERWORTH,  S.T.G.  (1977)   Toxicity  of  pyrethroid
 insecticides:  investigation of the neurotoxic potential of WL 43479 to
 adult  hens, (Report No. TLGR.0069.77)  (Unpublished data submitted  to
WHO by Shell Research Ltd).

MIYAMOTO, J. (1976) Degradation, metabolism and toxicity  of  synthetic
pyrethroids.  Environ. Health Perspect., 14: 15-28.

MIYAMOTO, J.  (1981)  The chemistry, metabolism and residue analysis of
synthetic pyrethroids,  Pure appl. Chem., 53: 1967-2022.

MIYAMOTO,  J. & KEARNEY, P.C.  (1983)  Pesticide chemistry-human welfare
 and the environment. Proceedings of the Fifth International Congress of
 Pesticide  Chemistry, Kyoto, Japan, 29 August-4 September 1982, Oxford,
Pergamon Press, Vol. 1-4.

MULLA,  M.S.,  DARWAZEH, H.A.,  & MAJORI, G.  (1975) Field efficacy  of
some  promising  mosquito  larvicides  and  their  effect  on nontarget
organisms.   Mosq. News, 35: 179-185.

MULLA,   M.S.,   NAVVAB-GOJRATI,   H.A.,  &   DARWAZEH,   H.A.  (1978a)
Toxicity   of  mosquito  larvicidal  pyrethroids  to  four  species  of
freshwater fishes.   Environ. Entomol., 7: 428-430.

MULLA,   M.S.,   NAVVAB-GOJRATI,   H.A.,  &   DARWAZEH,   H.A.  (l978b)
Biological  activity and longevity of new synthetic pyrethroids against
mosquitoes and some nontarget insects.  Mosq. News, 38: 90-96.

MULLA,  M.S.,  DARWAZEH,  H.A.,  &  DHILLON,  K.S.  (1981)  Impact  and
joint  action of decamethrin  and permethrin and  freshwater fishes  on
mosquitoes.  Bull. environ. Contam. Toxicol., 26: 689-695.

NASSIF,  M., BROOKE, J.P.,  HUTCHINSON, D.B.A., &  KAMEL, O.M.   (1980)
Studies with permethrin against body lice in  Egypt.  Pestic.  Sci., 11:
679-684.

NEWELL,  G.W.  &  SKINNER  W.A.   (1976)    In   vitro   microbiological
 mutagenicity  study of an FMC  corporation compound (Unpublished report
submitted to WHO by FMC Corporation).

NOMURA, Y. & SEGAWA, T.  (1979)   Pharmacological study  of  permethrin:
 effects  of  isolated  ileum, nictitating  membrane, respiration, blood
 pressure  and electrocardiography (Unpublished report submitted  to WHO
by Sumitomo Chemical Co.).

OHKAWA,   H.,  KANEKO,  H.,  &   MIYAMOTO,  J.  (1977)  Metabolism   of
permethrin in bean plants.  J. Pestic. Sci., 2: 67-76.

OHSHIMA,  M., TAKIMOTO,  Y., &  MATSUDA, T.   (1988)   Accumulation  and
 metabolism  of 14 C-permethrin   in carp  (Cyprinus carpio) (Unpublished
data submitted to WHO by Sumitomo Chemical Co.).

OKUNO,  Y.,  MIYAGAWA, H.,  HOSOI, R., &  KADOTA, T.  (1976)    Skin and
 eye  irritation  study  of permethrin  (S-3151) in rabbits (Unpublished
report submitted to WHO by Sumitomo Chemical Co.).

PARKINSON, G.R. (1978)  Permethrin: acute toxicity to male rats  (Report
No.  CTL/P/388)  (Unpublished  data submitted  to  WHO  by ICI  Central
Toxicology Laboratory).

PARKINSON,  G.R.,  BERRY,  P.N.,  GLAISTER,  J.,  GORE,  C.W., LEFEVRE,
V.K., & MURPHY, J.A.  (1976)   PP557 (Permethrin): acute  and  sub-acute
 toxicity, (Report  No. CTL/P/225) (Unpublished data submitted to WHO by
ICI Central Toxicology Laboratory).

PAYNTER, O.C., BUDD, E.R., & LITT, B.D.  (1982)  Permethrin.  Assessment
 of chronic and oncogenic effects: A summary, Washington, DC, Toxicology
Branch,  Hazard Evaluation Division,  Office of Pesticide  Programs, US
Environmental Protection Agency (Unpublished data submitted to WHO).

PEGUM,  J.S.  &  DOUGHTY, B.J.   (1978)    Human  skin patch  test  with
 pyrethrins,  kadethrin,  permethrin and  decamethrin, Berkhamsted Hill,
Wellcome   Group  Research  and  Development  (Report  No.  NEFJ  78-2)
(Unpublished data submitted to WHO).

PIERCY, D.W.T., REYNOLDS, J., & JAMES, J.A.  (1976)   Effects of diet on
 the acute toxicity of permethrin in the female  rat, Berkhamsted  Hill,
Wellcome  Research and Development (Report no. 77-11) (Unpublished data
submitted to WHO).

PIKE,  K.S., MAYER, D.F.,  GLAZER, M., &  KIOUS, C. (1982)   Effects of
permethrin  on mortality and foraging  behavior of honey bees  in sweet
corn.   Environ. Entomol., 11: 951-953.

PLAPP,  F.W., Jr & BULL,  D.L. (1978) Toxicity and  selectivity of some
insecticides  to  Chrysopa  carnea, a  predator of  the tobacco budworm.
 Environ. Entomol., 7: 431-434.

PLAPP,  F.W., Jr & VINSON,  S.B. (1977) Comparative toxicities  of some
insecticides  to  the tobacco  budworm  and its  ichneumonid  parasite,
 Campoletis sonorensis. Environ. Entomol., 6: 381-384.

PLUIJMEN,    M.,   DREVON,   C.,   MONTESANO,   R.,   MALAVEILLE,   C.,
HAUTEFEUILLE,  A.,  &  BARTSCH, H.   (1984)   Lack  of mutagenicity  of
synthetic  pyrethroids in Salmonella typhimurium strains in V79 Chinese
hamster cells.  Mutat. Res., 137: 7-15.

RACEY,  P.A.  & SWIFT,  S.M.  (1986)  The  residual effect of  remedial
timber treatments on bats.  Biol. Conserv., 35: 205-214.

RAPP,  W.R.  (1978)   Twenty-four month oral toxicity/oncogenicity study
 of  FMC33297 in mice.  Histopathology report (Unpublished data  of  FMC
Corporation).

REYNOLDS,   J.,   PIERCY,   D.W.T.,  CLAMPITT,   R.B.,   JAMES,   J.A.,
THOMPSON,    P.M.,   FAREBROTHER,   D.A.,   &   DAYAN,   A.D.    (1978)
 Permethrin  oral administration to dogs for 6 months, Berkhamsted Hill,
Wellcome  Research Laboratories (Report  No. HEFG 78-14)   (Unpublished
data submitted to WHO).

RICHARDS,  D., BANHAM,  P.B., KILMARTIN,  M., &  WEIGHT,  T.M.   (1980)
 Permethrin:   Teratogenicity study in the rabbit (Report No. CTL/P/523)
(Unpublished report submitted to WHO by ICI Ltd).

RISHIKESH,  N., CLARKE, J.L., MATHIN,  H.L., KING, J.S., &  PEARSON, J.
(1978)    Evaluation  of  decamethrins and  permethrin against Anopheles
 gambiae   and   Anopheles  funestus  in  a  village  trial  in  Nigeria
(WHO/VBC/78.679)   (Unpublished  report  of Division  of Vector Biology
Control, World Health Organization).

ROBERTS, T.R. & WRIGHT, A.N. (1981) The metabolism  of  3-phenoxybenzyl
alcohol,  a  pyrethroid  metabolite, in  plants.  Pestic. Sci., 12: 161-
169.

ROCK, G.C. (1979) Relative toxicity of two synthetic pyrethroids  to  a
predator  Amblyseius fallacis and its prey  Tetranychus urticae. J. econ.
 Entomol., 72: 293-294.

ROSS,  D.B. & PRENTICE,  D.E. (1977)  Examination of  permethrin (PP557)
 for  neurotoxicity in the domestic hen, Huntingdon, Huntingdon Research
Centre (Report No. ICI/157-NT/77468) (Unpublished data submitted to WHO
by FMC Corporation and ICI Ltd).

ROSS,  D.B., CAMERON,  D.M., &  ROBERTS, N.L.  (1976a)  The  acute  oral
 toxicity  (LD50 )   of PP557 (permethrin)  to Mallard ducks, Huntingdon,
Huntingdon  Research  Centre  (Report No.  ICI 68/WL/7639) (Unpublished
data submitted to WHO by ICI Ltd).

ROSS,  D.B., CAMERON,  D.M., &  ROBERTS, N.L.  (1976b)    The  sub-acute
toxicity  (LC50 )   of PP557  (permethrin) to Mallard  ducks, Huntingdon,
Huntingdon  Research Centre (Report  No. ICI 68/WL/75837)  (Unpublished
data submitted to WHO by ICI Ltd).

ROSS,  D.B.,  CAMERON, D.M.,  & ROBERTS, N.L.  (1976c)   The acute  oral
 toxicity   (LD50 )    of  PP557  (permethrin)  to  Starling, Huntingdon,
Huntingdon  Research  Centre  (Report No.  ICI 68/WL/7637) (Unpublished
data submitted to WHO by ICI Ltd).

ROSS,  D.B., CAMERON,  D.M., &  ROBERTS, N.L.  (1976d)    The  sub-acute
 toxicity   (LC50 )    of  PP557  (permethrin)  to  Starling, Huntingdon,
Huntingdon  Research  Centre  (Report No.  ICI 68/WL/7636) (Unpublished
data submitted to WHO by ICI Ltd).

ROSS,  D.B., CAMERON,  D.M., &  ROBERTS, N.L.  (1976e)    The  sub-acute
 toxicity  (LC50 )    of  PP557  (permethrin)  to  Ring-necked  pheasant,
Huntingdon,   Huntingdon Research Centre  (Report No. ICI  68/WL/75839)
(Unpublished data submitted to WHO by ICI Ltd).

ROSS,  D.B.,  CAMERON, D.M.,  & ROBERTS, N.L.  (1977a)   The acute  oral
 toxicity  (LD50 )    of  PP557  (permethrin)  to  Ring-necked  pheasant,
Huntingdon,   Huntingdon Research Centre  (Report No. ICI  68/WL/77154)
(Unpublished data submitted to WHO by ICI Ltd).

ROSS,  D.B.,  PRENTICE,  D.E.,  MAJEED,  S.K.,  GIBSON,  W.A., CAMERON,
D.M., CAMERON, M. McD., & ROBERTS, N.L.  (1977b)  The  incorporation  of
 permethrin  in the diet of laying hens (part I), Huntingdon, Huntingdon
Research  Centre (Report No. ICI 152/77387) (Unpublished data submitted
to WHO by ICI Ltd).

ROUSH,  R.T. & HOY,  M.A. (1978) Relative  toxicity of permethrin  to a
predator,  Metaseiulus  occidentalis, and its prey,  Tetranychus urticae.
 Environ. Entomol., 7: 287-288.

RUIGT,  G.S.F. & VAN DEN BERCKEN, J. (1986)  Action of pyrethroids on a
nerve-muscle  preparation of the clawed  frog,  Xenopus laevis.  Pestic.
 Biochem. Physiol., 25: 176-187.

SASINOVICH,  L.M. & PANSHINA, T.N.  (1987)  [Substantiation of hygienic
rules for synthetic pyrethroid content in the work zone air].   Gig. Tr.
 prof. Zabol., 8: 48-50 (in Russian).

SCHROEDER,   R.E.  &  RINEHART,   W.E.   (1977)    A   three  generation
 reproduction  study  of  FMC33297 in  rats (Bio-Dynamics  Inc  Project)
(Unpublished report submitted to WHO by FMC Corporation).

SHAH,  P.V., MONROE, R.J., & GUTHRIE, F.E. (1981)  Comparative rates of
dermal  penetration of insecticides in mice.  Toxicol. appl. Pharmacol.,
59: 414-423.

SHAROM,    M.S.   &   SOLOMON,   K.R.   (1981)   Adsorption-desorption,
degradation,  and  distribution  of permethrin  in  aqueous systems.  J.
 agric. food Chem., 29: 1122-1125.

SHERMAN,  R.A. (1979)  Preliminary behavioural assessment of habituation
 to  the insecticide permethrin, Aberdeen  Proving Ground, Maryland,  US
Army Environmental Hygiene Agency (Report No. 75-51-002679).

SHIRASU, Y., MORIYA, M., & OTA, T.  (1979)   Mutagenicity of  S-3151  in
 bacterial test systems (Unpublished report submitted to WHO by Sumitomo
Chemical Co.).

SHONO, T., OHSAWA, K., & CASIDA, J.E. (1979)  Metabolism  of  trans- and
 cis-permethrin,  trans- and  cis-cypermethrin,      and   decamethrin  by
microsomal enzymes.  J. agric. food Chem., 27: 316-325.

SHOUR, M.H. & CROWDER, L.A. (1980) Effects of  pyrethroid  insecticides
on the common green lacewing.  J. econ. Entomol., 73: 306-309.

SIEGEL,  M.M., HILDEBRAND, B.E., &  HALL, D.R. (1980) Determination  of
permethrin  in environmental waters by  gas chromatography-selected ion
monitoring-mass  spectroscopy  using  ion counting  detection.  Int.  J.
 environ. anal. Chem., 8: 107-126.

SIMMON, V.F.  (1976)   In vitro  microbiological mutagenicity study of an
 FMC  corporation  compound, Menlo  Park, Stanford  Research  Institute,
(Report No. LSC-4768) (Unpublished report submitted to WHO).

SIMONAITIS,  R.A. & CAIL, R.S. (1977) Gas chromatographic determination
of  residues of the synthetic pyrethroid FMC33297. In: Elliott, M., ed.
 Synthetic   pyrethroids, Washington,  DC,  American  Chemical  Society,
pp. 211-223 (ACS Symposium Series U2).

SODERLUND, D.M. & CASIDA, J.E. (1977) Effects of  pyrethroid  structure
on  rate of hydrolysis and oxidation by mouse liver microsomal enzymes.
 Pestic. Biochem. Physiol., 7: 391-401.

SPENCER,  F. & BERHANCE, Z. (1982) Uterine and fetal characteristics in
rats  following  a  post-implantational exposure  to  permethrin.  Bull.
 environ. Contam.  Toxicol., 29: 84-88.

STAATZ,  C.G., BLOOM,  A.S., &  LECH, J.J.   (1982)  A  pharmacological
study  of pyrethroid neurotoxicity in  mice.  Pestic. Biochem. Physiol.,
17: 287-292.

STEVENSON,  J.H.,  NEEDHAM,  P.H.,  &  WALKER,  J.  (1978)  Poisoning of
 honeybee  by  pesticides:  Investigation  of  the  changing  pattern in
 Britain  over 20 years. Rothamsted Experimental  Station Report (1977),
Part 2: 55-72.

STRATTON,  G.W. & CORKE, C.T.   (1981)  Interaction of permethrin  with
 Daphnia   magna in the presence  and absence of  particulate  material.
 Environ. Pollut., A24: 135-144.

STRATTON,  G.W. &  CORKE, C.T.   (1982)  Toxicity  of  the  insecticide
permethrin   and   some   degradation  products   towards   algae   and
cyanobacteria.   Environ. Pollut. A29: 71-80.

SUNDARAM,   K.M.S.,   DE   GROOT,   P.,   &   SUNDARAM,    A.    (1987)
Permethrin  deposits and airborne concentrations downwind from a single
swath  application  using a  back pack mist  blower.   J. environ.  Sci.
 Health, B22: 171-193.

SUZUKI,  H.  (1977)   Studies on the mutagenicity of some pyrethroids on
 salmonella  strains  in  the presence  of  mouse  hepatic S9  fractions
(Unpublished report submitted to WHO by Sumitomo Chemical Co.).

SWAINE, H. & SAPIETS, A.  (1981a)   Cypermethrin: residue transfer study
 with  dairy cows fed on  a diet containing the  insecticide (Report No.
RJ0186B) (Unpublished data submitted to WHO by ICI Ltd).

SWAINE,  H. & SAPIETS, A.  (1981b)   Cypermethrin: residue levels of the
 major metabolites of the insecticide in the milk and tissues  of  dairy
 cows  fed  on a  diet containing cypermethrin  at 50 mg/kg (Report  No.
RJ0198B) (Unpublished data submitted to WHO by ICI Ltd).

SWAINE,  H.,  EDWARD,  M.J.,  &  USSARY,  J.P.  (1978)  Permethrin  crop
 protection  study (Report No. TMV 0378B) (Unpublished data submitted to
WHO by ICI Ltd).

TAKAHASHI,   K.,   OKUDA,  No.,  &  SHIRASU,  Y.   (1979)    Effects  of
 permethrin on hexobarbital induced sleeping time in mice  and  electro-
 encephalography  in  rabbits (Unpublished  report submitted  to  WHO by
Sumitomo Chemical Co.).

TYLER, J.F.C. (1987)  Gas chromatographic method for  determination  of
permethrin  in  pesticide formulations:  Collaborative study.  J. Assoc.
 Off. Anal. Chem., 70(1): 53-55.

US  EPA  (1981)    Advisary  opinion  on  the  oncogenic  potential   of
 permethrin, Washington,   DC,   US   Environmental  Protection   Agency
(Unpublished report submitted to WHO).

USSARY,  J.P.  (1979)   Permethrin  residues on sweet  corn (Report  No.
TMU0438B) (Unpublished data submitted to WHO by ICI Americas Inc.).

USSARY,  J.P.  (1978)   Permethrin  residues on sweet  corn (Report  No.
TMU0413B) (Unpublished data submitted to WHO by ICI Americas Inc.).

USSARY, J.P. & BRAITHWAITE, G.B.  (1980)   Residues of permethrin and 3-
 phenoxy-benzyl  alcohol in cow  tissues (Trial No. 35NC79-001.   Report
No.  TMU0493B)  (Unpublished  data submitted  to  WHO  by ICI  Americas
Inc.).

VAN DEN BERCKEN, J. (1977)  The action of allethrin on  the  peripheral
nervous system of the frog.  Pestic. Sci., 8: 692-699.

VAN  DEN  BERCKEN,  J. &  VIJVERBERG,  H.P.M.  (1980a)   Voltage  clamp
studies on the effects of allethrin and DDT on the sodium  channels  in
frog  myelinated nerve membrane. In:  Insect  neurobiology and pesticide
 action, London, Society of Chemical Industry, pp. 79-85.

VAN   DEN  BERCKEN,  J.  &   VIJVERBERG,  H.P.M.  (1980b)  Effects   of
insecticides  on the sensory system of Xenopus. In:  Insect neurobiology
 and  pesticide  action, London,  Society of  Chemical Industry, pp.391-
397.

VAN   DEN   BERCKEN,   J.,  AKKERMANS,   L.M.A.,   &   VAN  DER   ZALM,
J.M.,  (1973)  DDT-like  action of  allethrin in  the  sensory  nervous
system of  Xenopus laevis. Eur. J. Pharmacol., 21: 95-106.

VAN   DEN   BERCKEN,   J.,   KROESE,   A.B.A.,   &   AKKERMANS,  L.M.A.
(1979)   Effect of  insecticides on  the sensory  nervous  system.  In:
Narahashi,  T., ed.   Neurotoxicology   of insecticides and  pheromones,
New York, London, Plenum Press, pp. 183-210.

VERSCHOYLE,   R.D.   &   ALDRIDGE,   W.N.   (1980)   Structure-activity
relationship of some pyrethrins to rats.  Arch. Toxicol., 45: 325-329.

VIJVERBERG,   H.P.M.  &  VAN   DEN  BERCKEN,  J.   (1979)    Frequency-
dependent  effects of the  pyrethroid insecticide decamethrin  in  frog
myelinated nerve fibres.  Eur. J. Phamacol., 58: 501-504.

VIJVERBERG,   H.P.M.   &  VAN   DEN  BERCKEN,  J.   (1982)   Action  of
pyrethroid  insecticides on the vertebrate nervous system.  Neuropathol.
 appl.  Neurobiol., 8: 421-440.

VIJVERBERG,  H.P.M.,  RUIGT,  G.S.F., &  VAN  DEN  BERCKEN, J.  (1982a)
Structure-related  effects of pyrethroid  insecticides on the  lateral-
line sense organ and on peripheral nerves of the  clawed  frog,  Xenopus
 laevis. Pestic.  Biochem. Physiol., 18: 315-324.

VIJVERBERG,  H.P.M.,  VAN  DER  ZALM,  J.M.,  &  VAN  DEN  BERCKEN,  J.
(1982b)   Similar  mode  of action  of  pyrethroids  and DDT  on sodium
channel gating in mylinated nerves.  Nature (Lond.), 295: 601-603.

VIJVERBERG,  H.P.M.,  VAN  DER  ZALM,  J.M.,  VAN  KLEEF,  R.G.D.M.,  &
VAN  DEN  BERCKEN,  J.  (1983)   Temperature  and   structure-dependent
interaction  of pyrethroids with  the sodium channels  in frog node  of
Ranvier.  Biochim.  Biophys. Acta, 728: 73-82.

WALLWORK,  L.M.  &  MALONE,  J.C.   (1974)    21Z73  (25:75)  effect  of
 different  solvents on  the rat  oral toxicity (Report  No. HEFG  75-4)
Berkhamsted, Wellcome Research Laboratories (Unpublished data submitted
to WHO).

WALLWORK,  L.M.,  CLAMPITT,  R.B.,  &  MALONE,  J.C.   (1974a)    10-day
 cumulative  oral  toxicity  study  with  21Z73  in   mice, Berkhamsted,
Wellcome  Research  Laboratories  (Report No.  HEFG  74-9) (Unpublished
data submitted to WHO).

WALLWORK,  L.M.,  CLAMPITT,  R.B.,  &  MALONE,  J.C.   (1974b)    10-day
 cumulative  oral  toxicity  study  with  21Z73  in   rats, Berkhamsted,
Wellcome Research Laboratories (Unpublished report submitted to WHO).

WELLS,  D., GRAYSON,  B.T., &  LANGNER, E.  (1986) Vapour  pressure  of
permethrin.   Pestic. Sci., 17: 473-476.

WHO  (1979)   WHO  Technical  Report  Series,  No.  634  (Safe  use  of
pesticides.  Third Report of the WHO Expert Committee on Vector Biology
and Control), pp. 18-23.

WHO   (1988)    The  WHO  recommended  classification  of  pesticides by
 hazard:   Guidelines  to  classification 1988-89, Geneva,  World Health
Organization (Unpublished report VBC/88.953).

WHO/FAO  (1984)  Data  sheet  on pesticides No.  51: Permethrin, Geneva,
World Health Organization (VBC/DS/84.51).

WILLIAMS,  I.H. & BROWN, M.J.  (1979) Persistence of permethrin  and WL
43775 in soil.  J. agric. food Chem., 27: 130-132.

WOODRUFF, R.C., PHILLIPS, J.P., & IRWIN, D.  (1983)   Pesticide-induced
complete and partial chromosome loss in screens  with  repair-defective
females of  Drosophila melanogaster.  Environ. Mutagen., 5: 835-846.

WOOD, MACKENZIE & Co. (1980) Pyrethroids.  Agrochem. Monit., 9: 3-14.

WOOD, MACKENZIE & Co. (1981) Pyrethroids.  Agrochem. Monit., 15: 3-27.

WOOD, MACKENZIE & Co. (1982) Pyrethroids.  Agrochem. Monit., 21: 3-17.

WOOD, MACKENZIE & Co. (1983) Pyrethroids.  Agrochem. Monit., 27: 3-12.

WOOD, MACKENZIE & Co. (1984) Pyrethroids.  Agrochem. Monit., 33: 2-12.

WORKMAN, R.B. (1977) Pesticides toxic to striped earwig,  an  important
insect predator.  Proc. Florida State Hortic. Soc., 90: 401-402.

WORTHING,  C.R. & WALKER,  S.B. (1983)  The pesticide  manual, 7th  ed.,
Croydon, British Crop Protection Council, p. 427.

WORTHING,  C.R. & WALKER,  S.B. (1987)  Permethrin.  In:  The  pesticide
 manual, 8th  ed., Croydon, British  Crop Protection Council,  pp.  647-
648.

WOUTERS, W. & VAN DEN BERCKEN, J. (1978)  Action  of  pyrethroids.  Gen.
 Pharmacol., 9: 387-398.

ZITKO,   V.,   CARSON,  W.G.,  &  METCALFE,  C.D.  (1977)  Toxicity  of
pyrethroids   to  juvenile  atlantic  salmon.  Bull.   environ.  Contam.
 Toxicol., 18: 35-41.

ZITKO,  V.,  MCLEESE,  D.W., METCALFE,  C.D.,  &  CARSON,  W.G.  (1979)
Toxicity  of permethrin, decamethrin, and related pyrethroids to salmon
and lobster.  Bull. environ. Contam. Toxicol., 21: 338-343.

APPENDIX I

    On  the basis of electrophysiological studies with peripheral nerve
preparations  of  frogs  ( Xenopus  laevis;  Rana  temporaria, and  Rana
 esculenta ),   it  is  possible to  distinguish  between  2  classes  of
pyrethroid insecticides: (Type I and Type II).  A  similar  distinction
between  these  2  classes of pyrethroids has been made on the basis of
the  symptoms of toxicity  in mammals and  insects (Van den  Bercken et
al., 1979; WHO, 1979; Verschoyle & Aldridge, 1980; Glickman  &  Casida,
1982;  Lawrence  & Casida,  1982).  The same  distinction was found  in
studies on cockroaches (Gammon et al., 1981).

    Based  on the binding assay  on the gamma-aminobutyric acid  (GABA)
receptor-ionophore   complex,   synthetic   pyrethroids  can   also  be
classified into two types: the alpha-cyano-3-phenoxybenzyl  pyrethroids
and  the non-cyano pyrethroids (Gammon  et al., 1982; Gammon  & Casida,
1983; Lawrence & Casida, 1983; Lawrence et al., 1985).

Pyrethroids   that  do  not  contain  an  alpha-cyano group (allethrin,
d-phenothrin,  permethrin, tetramethrin, cismethrin, and bioresmethrin)
(Type I: T-syndrome)

    The pyrethroids that do not contain an alpha-cyano  group give rise 
to pronounced repetitive activity in sense organs and in sensory  nerve
fibres  (Van den  Bercken et  al., 1973).   At room  temperature,  this
repetitive  activity usually consists  of trains of  3-10 impulses  and
occasionally  up to 25  impulses.  Train duration  is between 10  and 5
milliseconds.

    These  compounds also induce  pronounced repetitive firing  of  the
presynaptic motor nerve terminal in the neuromuscular junction (Van den
Bercken,  1977).  There was no significant effect of the insecticide on
neurotransmitter  release  or on  the  sensitivity of  the  subsynaptic
membrane,  nor on the  muscle fibre membrane.   Presynaptic  repetitive
firing was also observed in the sympathetic ganglion treated with these
pyrethroids.

    In  the lateral-line sense organ  and in the motor  nerve terminal,
but not in the cutaneous touch receptor or in sensory nerve fibres, the
pyrethroid-induced  repetitive  activity increases  dramatically as the
temperature  is lowered, and a decrease of 5°C in temperature may cause
a  more than 3-fold increase  in the number of  repetitive impulses per
train.  This effect is easily reversed by raising the temperature.  The
origin   of  this  "negative  temperature  coefficient"  is  not  clear
(Vijverberg et al., 1983).

    Synthetic pyrethroids act directly on the axon through interference
with  the sodium channel gating mechanism that underlies the generation
and  conduction of each nerve  impulse.  The transitional state  of the
sodium  channel is controlled by 2 separately acting gating mechanisms,
referred  to as the activation  gate and the inactivation  gate.  Since
pyrethroids   only  appear  to   affect  the  sodium   current   during
depolarization, the rapid opening of the activation gate and  the  slow
closing of the inactivation gate proceed normally.  However,  once  the
sodium channel is open, the activation gate is restrained in  the  open

position  by  the  pyrethroid  molecule.   While  all  pyrethroids have
essentially  the same basic mechanism  of action, however, the  rate of
relaxation differs substantially for the various pyrethroids (Flannigan
& Tucker, 1985).

    In the isolated node of Ranvier, allethrin causes  prolongation  of
the  transient increase in  sodium permeability of  the nerve  membrane
during excitation (Van den Bercken & Vijverberg, 1980a,b).  Evidence so
far  available  indicates that  allethrin  selectively slows  down  the
closing  of the activation  gate of a  fraction of the  sodium channels
that  open during depolarization of the membrane.  The time constant of
closing  of the activation gate  in the allethrin-affected channels  is
about  100 milliseconds compared with less than 100 microseconds in the
normal sodium channel, i.e., it is slowed down by a factor of more than
100.   This results  in a  marked prolongation  of the  sodium  current
across  the nerve membrane during excitation, and this prolonged sodium
current  is directly responsible for the repetitive activity induced by
allethrin (Vijverberg et al., 1983).

    The  effects of  cismethrin on  synaptic transmission  in the  frog
neuromuscular  junction,  as  reported  by  Evans  (1976),  are  almost
identical to those of allethrin, i.e., presynaptic  repetitive  firing,
and no significant effects on transmitter release or on the subsynaptic
membrane.

    Interestingly,  the action of  these pyrethroids closely  resembles
that  of the insecticide  DDT in the  peripheral nervous system  of the
frog.   DDT also causes pronounced repetitive activity in sense organs,
in  sensory  nerve  fibres, and  in  motor  nerve terminals,  due  to a
prolongation  of the transient increase  in sodium permeability of  the
nerve membrane during excitation.  Recently, it was  demonstrated  that
allethrin and DDT have essentially the same effect on  sodium  channels
in frog myelinated nerve membrane.  Both compounds slow down  the  rate
of  closing  of  a  fraction  of  the  sodium  channels  that  open  on
depolarization  of the membrane  (Van den Bercken  et al., 1973,  1979;
Vijverberg et al., 1982b).

    In  the  electrophysiological  experiments  using  giant  axons  of
crayfish,  the  type  I pyrethroids  and  DDT  analogues retain  sodium
channels  in a  modified open  state only  intermittently, cause  large
depolarizing after-potentials, and evoke repetitive firing with minimal
effect on the resting potential (Lund & Narahashi, 1983).

    These results strongly suggest that permethrin and cismethrin, like
allethrin, primarily affect the sodium channels in the  nerve  membrane
and   cause   a  prolongation  of  the  transient  increase  in  sodium
permeability of the membrane during excitation.

    The  effects  of  pyrethroids  on  end-plate  and   muscle   action
potentials were studied in the pectoralis nerve-muscle  preparation  of
the  clawed frog ( Xenopus  laevis ).   Type I  pyrethroids  (allethrin,
cismethrin,  bioresmethrin,  and  1R,  cis-phenothrin)  caused  moderate
presynaptic  repetitive  activity,  resulting  in  the  occurrence   of
multiple end-plate potentials (Ruigt & Van den Bercken, 1986).

Pyrethroids with an alpha-cyano  group on the  3-phenoxybenzyl  alcohol
(deltamethrin,     cypermethrin,    cyhalothrin,    lambda-cyhalothrin,
fenvalerate, and fenpropanate) (Type II:  CS-syndrome)

    The pyrethroids with an alpha-cyano group cause an intense repetitive
activity in the lateral line organ in the form of  long-lasting  trains
of impulses (Vijverberg et al., 1982a).  Such a train may last  for  up
to  1 min  and contains  thousands of  impulses.  The  duration of  the
trains  and  the  number of  impulses  per  train increase  markedly on
lowering  the  temperature.   Cypermethrin does  not  cause  repetitive
activity in myelinated nerve fibres.  Instead, this pyrethroid causes a
frequency-dependent depression of the nervous impulse, brought about by
a progressive depolarization of the nerve membrane as a result  of  the
summation  of  depolarizing  after-potentials during  train stimulation
(Vijverberg & Van den Bercken, 1979; Vijverberg et al., 1983).

    In  the  isolated node  of  Ranvier, cypermethrin,  like allethrin,
specifically  affects the  sodium channels  of the  nerve membrane  and
causes  a long-lasting prolongation of the transient increase in sodium
permeability  during excitation, presumably by slowing down the closing
of  the  activation gate  of the sodium  channel (Vijverberg &  Van den
Bercken,  1979; Vijverberg et al., 1983).  The time constant of closing
of  the  activation  gate  in  the  cypermethrin-affected  channels  is
prolonged  to more than 100 milliseconds.  Apparently, the amplitude of
the  prolonged sodium current after cypermethrin is too small to induce
repetitive  activity in nerve  fibres, but is  sufficient to cause  the
long-lasting repetitive firing in the lateral-line sense organ.

    These results suggest that alpha-cyano pyrethroids primarily affect
the  sodium  channels in  the nerve membrane  and cause a  long-lasting
prolongation  of the transient increase  in sodium permeability of  the
membrane during excitation.

    In  the  electrophysiological  experiments  using  giant  axons  of
crayfish,  the Type II pyrethroids retain sodium channels in a modified
continuous  open state persistently, depolarize the membrane, and block
the   action  potential  without  causing  repetitive  firing  (Lund  &
Narahashi, 1983).

    Diazepam,  which facilitates GABA  reaction, delayed the  onset  of
action   of  deltamethrin  and  fenvalerate,  but  not  permethrin  and
allethrin, in both the mouse and cockroach.  Possible mechanisms of the
Type II pyrethroid syndrome include action at the GABA receptor complex
or a closely linked class of neuroreceptor (Gammon et al., 1982).

    The  Type II syndrome  of intracerebrally administered  pyrethroids
closely   approximates  that  of   the  convulsant  picrotoxin   (PTX).
Deltamethrin  inhibits the binding  of [3H]-dihydropicrotoxin   to  rat
brain   synaptic  membranes,  whereas   the  non-toxic  R   epimer   of
deltamethrin is inactive.  These findings suggest a  possible  relation
between  the Type II pyrethroid  action and the GABA  receptor complex.
The   stereospecific  correlation  between  the  toxicity  of  Type  II
pyrethroids and their potency to inhibit the [35S]-TBPS    binding  was
established  using  a radioligand,  [35S]- t-butyl-bicyclophosphoro-
thionate  [35S]-TBPS.     Studies  with  37  pyrethroids  revealed   an
absolute correlation, without any false positive or  negative,  between

mouse  intracerebral toxicity and  in vitro inhibition:  all toxic cyano
compounds  including  deltamethrin, 1R, cis-cypermethrin,    1R, trans-
cypermethrin, and [2S,alphaS]-fenvalerate  were  inhibitors, but  their 
non-toxic stereoisomers were not; non-cyano pyrethroids were  much less
potent or were inactive (Lawrence & Casida, 1983).

    In   the   [35S]-TBPS     and  [3H]-Ro     5-4864   (a   convulsant
benzodiazepine  radioligand) binding assay, the inhibitory potencies of
pyrethroids  were closely related  to their mammalian  toxicities.  The
most  toxic pyrethroids of Type  II were the most  potent inhibitors of
[3H]-Ro    5-4864 specific binding to rat brain membranes.  The [3H]-
dihydropicrotoxin  and  [ 35S]-TBPS   binding studies  with pyrethroids
strongly indicated that Type II effects of pyrethroids are mediated, at
least  in part, through an  interaction with a GABA-regulated  chloride
ionophore-associated binding site.  Moreover, studies with [3H]-Ro   5-
4864  support  this  hypothesis and,  in  addition,  indicate that  the
pyrethroid-binding site may be very closely related to  the  convulsant
benzodiazepine site of action (Lawrence et al., 1985).

    The  Type  II pyrethroids  (deltamethrin, 1R,  cis-cypermethrin  and
[2S,alphaS]-fenvalerate)  increased  the  input  resistance of crayfish 
claw opener muscle fibres bathed in GABA.  In contrast, two non-insect-
icidal stereoisomers and Type I pyrethroids   (permethrin,  resmethrin,
allethrin)  were  inactive.  Therefore,  cyanophenoxybenzyl pyrethroids
appear  to act on the GABA receptor-ionophore complex (Gammon & Casida,
1983).

    The  effects  of  pyrethroids  on  end-plate  and   muscle   action
potentials were studied in the pectoralis nerve-muscle  preparation  of
the  clawed frog ( Xenopus  laevis).  Type II pyrethroids (cypermethrin
and deltamethrin) induced trains of repetitive muscle action potentials
without  presynaptic  repetitive  activity.  However,  an  intermediate
group  of  pyrethroids  (1R-permethrin, cyphenothrin,  and fenvalerate)
caused  both types of  effect.  Thus, in  muscle or nerve  membrane the
pyrethroid induced repetitive activities due to a prolongation  of  the
sodium  current.  But no  clear distinction was  observed between  non-
cyano and alpha-cyano pyrethroids (Ruigt & Van den Bercken, 1986).

 Appraisal

    In  summary, the results strongly  suggest that the primary  target
site of pyrethroid insecticides in the vertebrate nervous system is the
sodium channel in the nerve membrane. Pyrethroids without an alpha-cyano
group  (allethrin, d-phenothrin, permethrin,  and cismethrin)  cause  a
moderate  prolongation of the transient increase in sodium permeability
of  the nerve membrane during  excitation.  This results in  relatively
short  trains of  repetitive nerve  impulses in  sense organs,  sensory
(afferent) nerve fibres, and, in effect, nerve terminals.  On the other
hand, the alpha-cyano pyrethroids cause a long-lasting  prolongation of
the  transient increase in  sodium permeability of  the nerve  membrane
during excitation.  This results in long-lasting trains  of  repetitive
impulses  in sense organs and  a frequency-dependent depression of  the
nerve  impulse in  nerve fibres.   The difference  in  effects  between
permethrin  and cypermethrin, which have identical molecular structures
except for the presence  of an alpha-cyano  group on the  phenoxybenzyl
alcohol, indicates that it is this alpha-cyano group that is responsible
for the long-lasting prolongation of the sodium permeability.

    Since the mechanisms responsible for nerve impulse  generation  and
conduction are basically the same throughout the entire nervous system,
pyrethroids may also induce repetitive activity in various parts of the
brain.  The  difference  in   symptoms  of  poisoning   by  alpha-cyano
pyrethroids,   compared   with   the  classical   pyrethroids,  is  not
necessarily  due  to an  exclusive central site  of action.  It  may be
related  to the long-lasting  repetitive activity in  sense organs  and
possibly in other parts of the nervous system, which, in a more advance
state  of  poisoning,  may  be  accompanied  by  a  frequency-dependent
depression of the nervous impulse.

    Pyrethroids  also  cause  pronounced  repetitive  activity  and   a
prolongation  of the transient increase  in sodium permeability of  the
nerve   membrane  in  insects   and  other  invertebrates.    Available
information  indicates that the sodium channel in the nerve membrane is
also  the most important target site of pyrethroids in the invertebrate
nervous system (Wouters & Van den Bercken, 1978; WHO, 1979).

    Because  of  the universal  character  of the  processes underlying
nerve  excitability, the action of pyrethroids should not be considered
restricted  to particular animal species, or to a certain region of the
nervous system.  Although it has been established that sense organs and
nerve endings are the most vulnerable to the action of pyrethroids, the
ultimate  lesion that causes death  will depend on the  animal species,
environmental  conditions, and on  the chemical structure  and physical
characteristics  of  the  pyrethroid  molecule  (Vijverberg  &  Van den
Bercken, 1982).

RESUME, EVALUATION, CONLUSIONS ET RECOMMANDATIONS

1.  Résumé et Evaluation

1.1  Identité, propriétés physicochimiques et méthodes d'analyse

    La  perméthrine, un pyréthroide photostable, a été synthétisée pour
la  première fois en 1973 et commercialisée en 1977.  C'est un ester de
l'analogue  dichloré  de  l'acide  chrysanthémique,  à  savoir  l'acide
(dichloro-2,2 vinyl)-3 diméthyl-2,2 cyclopropanecarboxylique (Cl2CA) et
de l'alcool phénoxy-3 benzylique. Les produits techniques se présentent
sous  la  forme  d'un  mélange  de  quatre  stéréoisomères  ayant   les
configurations  [1R,trans], [1R,cis], [1S,trans]  et  [1S,cis] dans les
proportions  approximatives  de  3:2:3:2.  Le  rapport  cis/trans   est
d'environ deux tiers, les isomères 1R et 1S étant présents en quantités
égales (racémique). C'est l'isomère [1R,cis] qui est  l'insecticide  le
plus actif; vient ensuite l'isomère [1R,trans].

    La  perméthrine de qualité technique se présente sous la forme d'un
liquide  brun ou brun jaunâtre qui peut partiellement cristalliser à la
température  ambiante. Son point  de fusion est  d'environ 35°C et  son
point d'ébullition de 220°C sous 0,05 mmHg. La densité est  de 1,214  à
25°C  et la tension de  vapeur de 1,3 µPa à 20°C.   La  perméthrine est
pratiquement insoluble dans l'eau (moins de 0,2 mg par litre  à  25°C),
mais  elle  est  soluble dans  certains  solvants  organiques tels  que
l'acétone, l'hexane et le xylène.  Elle est stable à la lumière et à la
chaleur, mais instable en milieu alcalin.

    Le dosage des résidus et les analyses  écotoxicologiques  s'effect-
uent  par chromatographie en phase  gazeuse avec détection par  capture
d'électrons  (concentration  minimale décelable  de 0,005 mg/kg).  Pour
l'analyse des produits techniques, on a recours à la chromatographie en
phase gazeuse avec détection par ionisation de flamme.

1.2  Production et usage

    On  utilise  actuellement  dans  le  monde  environ  600 tonnes  de
perméthrine par an, essentiellement en agriculture. Ce produit pourrait
être utilisé pour la protection des céréales ensilées et  on  l'emploie
en  épandage  aérien  pour la  protection  des  forêts, la  lutte anti-
vectorielle,   la  destruction  des  insectes   incommodants  dans  les
habitations, le déparasitage des bestiaux, la destruction des  poux  du
corps et l'imprégnation des moustiquaires.

    La  perméthrine  est  présentée  en  concentré  émulsionnable,   en
concentré  pour application à très bas volume, en poudre mouillable, en
poudre pour poudrage et en aérosols.

1.3  Exposition humaine

    Les  teneurs  en  résidus  des  diverses  récoltes  diminuent assez
lentement,  le temps de demi-élimination allant de une à trois semaines
selon  les plantes.  Toutefois,  lorsqu'elle est utilisée  conformément
aux  recommandations, la perméthrine  ne donne pas  lieu à une  accumu-
lation de résidus, même après plusieurs traitements.

    Pour  ce  qui  est de  la  population  dans son  ensemble,  la voie
d'exposition à la perméthrine est essentiellement alimentaire. Les taux
de  résidus dans les  plantes correctement cultivées  sont généralement
faibles.   L'exposition  qui pourrait  en  résulter pour  la population
générale  est  vraisemblablement  faible,  mais  on  manque  de données
précises provenant d'études sur la ration totale.

    On  est très peu  documenté sur l'exposition  professionnelle à  la
perméthrine.

1.4  Destinée dans l'environnement

    On  a montré en laboratoire  que la perméthrine se  dégrade dans le
sol  avec une demi-vie d'environ 28 jours. L'isomère trans se décompose
plus rapidement que l'isomère cis, la principale réaction  de  décompo-
sition initiale étant le clivage du groupement ester.   Cette  réaction
donne naissance à des composés qui subissent une oxydation plus poussée
aboutissant à l'anhydride carbonique comme produit final.  On a montré,
en  étudiant le  potentiel de  lessivage de  la perméthrine  et de  ses
produits  de  dégradation, que  toutes  ces substances  pénétraient peu
profondément dans le sol.

    La perméthrine déposée sur les végétaux se dégrade avec  une  demi-
vie d'environ 10 jours. La principale voie de dégradation  comporte  le
clivage du groupement ester et la conjugaison de l'acide et de l'alcool
qui  en résultent.  Il se produit également une hydroxylation en divers
points  de la molécule  ainsi qu'une interconversion  cis-trans  photo-
induite.

    Dans  l'eau et à la  surface du sol, la  perméthrine est décomposée
par le rayonnement solaire. Là encore, le clivage du  groupement  ester
et l'interconversion cis-trans sont les principales réactions.

    En  général, ce processus de décomposition environnementale conduit
à des produits de moindre toxicité.

    La  perméthrine  disparaît  rapidement de  l'environnement,  en six
à  24 heures dans les étangs et les cours d'eau, en sept jours dans les
sédiments  des  étangs,  et en 58 jours dans les feuilles et le sol des
forêts. On a constaté que 30% du composé disparaissaient en une semaine
des feuilles d'une plantation de cotonniers.

    En  conditions d'aérobiose dans le sol, la perméthrine se décompose
avec une demi-vie de 28 jours.

    La  perméthrine  se  déplace peu  dans  l'environnement  et il  est
improbable qu'elle s'y accumule en quantité notable.

1.5  Cinétique et métabolisme

    Administrée  à  des  mammifères,  la  perméthrine  est   rapidement
métabolisée  et  presqu'entièrement excrétée  dans  les urines  et  les
matières  fécales en l'espace  de 12 jours. L'isomère  trans,  beaucoup
plus sensible à l'attaque par l'estérase que l'isomère  cis,  s'élimine
plus  rapidement que ce dernier. Les principales réactions métaboliques
sont le clivage du groupement ester et l'oxydation, particulièrement au

niveau du cycle aromatique terminal, du reste phénoxybenzylique  et  du
groupe  diméthyle  géminé du  cycle  cyclopropane, réactions  qui  sont
suivies  d'une conjugaison.  On a  retrouvé moins  de 0,7%  de la  dose
initiale  dans  le  lait  de  chèvres et  de  vaches à  qui  l'on avait
administré de la perméthrine par voie orale.

1.6  Effets sur les êtres vivants dans leur milieu naturel

    Des  épreuves de laboratoire  ont montré que  la perméthrine  était
extrêmement toxique pour les arthropodes aquatiques, la CL50 allant  de
0,018 µg/litre pour la larve d'un crabe comestible à 1,26 µg/litre pour
un cladocère. Elle est également très  toxique  pour  les poissons,  la
CL50 à   96 heures allant de  0,62 µg/litre   pour la  larve de  truite
arc-en-ciel à 314 µg/litre   pour la truite adulte.  La dose sans effet
observable au début du cycle évolutif du vairon est 10 µg/litre  sur 28
jours,  la dose chronique étant  de 0,66 à 1,4 µg/litre   pour un autre
cyprinidé,  Pimephas  promelas. La perméthrine  est moins toxique  pour
les mollusques aquatiques et les amphibiens, les valeurs de la CL50   à
96 heures  se  situant  respectivement  à  plus  de  1000 µg/litre   et
7000 µg/litre.

    Lors d'essais sur le terrain et en utilisation normale, cette forte
toxicité  potentielle ne  se manifeste  pas. Il  existe  une  abondante
littérature sur les effets de la perméthrine utilisée  en  agriculture,
dans les exploitations forestières ainsi que pour la lutte antivectori-
elle dans de nombreuses régions du monde. Il y a une certaine mortalité
pour les arthropodes aquatiques, notamment lorsque l'on traite les eaux
en  surface, mais les  effets sur les  populations ne sont  que tempor-
aires.  Il  n'y  a pas eu de cas de mortalité chez les poissons.  Cette
moindre toxicité qui se manifeste sur le terrain provient de  la  forte
adsorption du composé par les sédiments et de sa décomposition rapide.

    La  perméthrine  fixée  sur les  sédiments  est  toxique  pour  les
organismes  fouisseurs,  mais là  encore,  l'effet est  temporaire.  La
perméthrine est extrêmement toxique pour les abeilles. La DL50 topique est
de 0,11 µg   par abeille mais le fort effet répulsif qu'elle exerce sur
l'insecte  en  réduit  les effets  toxiques  dans  la  pratique.   Rien
n'indique  qu'il  puisse y  avoir une forte  mortalité des abeilles  en
utilisation  normale. La perméthrine est plus toxique pour les acariens
prédateurs que pour les espèces nuisibles visées.

    La   perméthrine   est  très  peu  toxique  pour  les  oiseaux,  en
administration  orale ou  par voie  alimentaire. La  DL50    aiguë  est
supérieure   à   3000 mg par kg  de   poids   corporel  en   une  seule
administration  et supérieure à 5000 mg  par kg de nourriture  quand le
produit  est mêlé à la ration. Elle n'a aucun effet sur la reproduction
de la poule à la dose de 40 mg/kg de nourriture.

    Les  organismes aquatiques accumulent facilement la perméthrine, le
facteur  de concentration allant  de 43 à 750 selon  les espèces.  Chez
tous  les  organismes  aquatiques  étudiés,  la  perméthrine  disparaît
rapidement  lorsque les  animaux sont  remis en  eau propre.  Il n'y  a
aucune  accumulation chez les oiseaux.  On peut donc considérer  que ce
composé ne présente en pratique aucune tendence à la bioaccumulation.

1.7 Effets   sur  les  animaux   d'expérience  et  sur   les   systèmes
d'épreuve  in vitro 

    La  perméthrine n'a qu'une faible toxicité aiguë pour les rats, les
souris,  les  lapins  et  les  cobayes,  encore  que  la  DL50    varie
considérablement selon le véhicule utilisé et le rapport  des  isomères
cis/trans.  Les signes d'intoxication aiguë apparaissent en deux heures
et  persistent jusqu'à trois jours. Les isomères [1R,cis] et [1R,trans]
appartiennent aux pyréthroïdes du type-I dont les  effets  caractérist-
iques  sont les  tremblements (syndrome  T) la  perte de  coordination,
l'hyperactivité,  la prostration et la  paralysie.  L'intoxication pro-
voque une augmentation notable de la température centrale.

    Aucun  des métabolites de la  perméthrine ne présente une  toxicité
aiguë  (par voie orale  ou intrapéritonéale) supérieure  à celle de  la
perméthrine elle-même.

    La  perméthrine a provoqué une légère irritation de la peau intacte
ou abrasée chez le lapin, mais il n'y a pas eu  d'irritation  d'origine
photochimique  après exposition aux rayons ultra-violets de zones de la
peau traitées par cet insecticide. Elle ne suscite en  revanche  aucune
réaction de sensibilisation chez le cobaye.

    Des  études de  toxicité orale  subaiguë et  subchronique  ont  été
effectuées  chez  le  rat et  la  souris  à des  doses  allant  jusqu'à
10 000 mg/kg de nourriture et pendant des périodes s'étendant de  14  à
26 semaines.  A la dose la plus forte, on a observé une augmentation du
rapport poids du foie/poids du corps, une hypertrophie du foie  et  des
signes cliniques d'intoxication tels que des tremblements. Chez le rat,
la dose sans effet observable varie de 20 mg/kg de nourriture (pour les
études  de  90 jours ou  de six mois)  à 150 mg/kg de  nourriture (lors
d'une étude de six mois).

    Chez  le chien, ces valeurs  ont été trouvées égales  à 50 mg/kg de
poids corporel et à 100 mg/kg de poids corporel,  respectivement,  lors
de deux études de trois mois.

    Des études à long terme sur des souris et des rats ont  révélé  une
augmentation  du poids du foie, vraisemblablement liée à l'induction du
système enzymatique des microsomes hépatiques.

    Une étude de deux ans sur des rats a fait ressortir une  dose  sans
effet  observable de  100 mg/kg de  nourriture, soit  5 mg/kg de  poids
corporel.

    D'après  trois  études à  long terme sur  la souris, il  semblerait
qu'il  existe un certain pouvoir cancérogène au niveau des poumons pour
au  moins  une  souche de souris (uniquement des femelles) à la dose la
plus élevée étudiée, soit 5 g/kg de nourriture.  Aucun  effet  oncogène
n'a été observé chez des rats des deux sexes.

    La perméthrine n'est mutagène ni  in vivo ni  in vitro .

    Les études de mutagénicité ainsi que des études à long terme sur la
souris  et le rat indiquent  que le pouvoir oncogène  de la perméthrine
est  très faible, qu'il se  limite aux souris femelles  et qu'il s'agit
probablement d'un phénomène épigénétique.

    La  perméthrine n'est pas tératogène  pour le rat, la  souris ou le
lapin, à des doses allant respectivement jusqu'à 225, 150 et 1800 mg/kg
de poids corporel.

    La  perméthrine n'a  pas produit  d'effet indésirable  à des  doses
allant  jusqu'à 2500 mg/kg  de nourriture  lors d'une  étude de  repro-
duction portant sur trois générations.

    Administrée  à  des  rats  à  forte  dose  (6600  à  7000 mg/kg  de
nourriture) pendant 14 jours, l'insecticide a provoqué des  lésions  au
niveau du nerf sciatique; cependant une autre étude n'a pas confirmé la
présence d'altérations ultrastructurales à ce niveau.  Chez la poule on
n'a pas observé de neurotoxicité retardée.

1.8  Effets sur l'homme

    La  perméthrine peut provoquer un  certain nombre de sensations  au
niveau  de  la peau  ainsi que des  parésthésies chez les  travailleurs
exposés,  symptômes  qui  apparaissent  après  une  période  de latence
d'environ  30 minutes, passent par un maximum au bout de huit heures et
disparaissent  en 24 heures. Parmi  les symptômes les  plus fréquemment
signalés,  figurent  un  engourdissement, des  démangeaisons, des four-
millements et des sensations de brûlure.

    Aucun cas d'intoxication n'a été signalé.

    La  probabilité  d'effets  oncogènes chez  l'homme  est extrêmement
faible, voire nulle.

    Rien n'indique que la perméthrine puisse exercer des effets indési-
rables  sur l'homme si  elle est utilisée  conformément aux  recommand-
ations.

2.  Conclusions

2.1  Population générale

    La  population  dans son  ensemble  est vraisemblablement  très peu
exposée  à la perméthrine. Cet  insecticide ne devrait présenter  aucun
danger s'il est utilisé conformément aux recommandations.

2.2  Exposition professionnelle

    Utilisée  de  manière  raisonnable et  moyennant  certaines mesures
d'hygiène  et de sécurité,  la perméthrine ne  devrait présenter  aucun
danger  pour  les  personnes  qui  lui  sont  exposées  de   par   leur
profession.

2.3  Environnement

    La  perméthrine ou ses produits  de décomposition ne devraient  pas
atteindre dans le milieu des concentrations critiques dans la mesure où
l'insecticide  est utilisé aux  doses recommandées. Au  laboratoire, la
perméthrine  est extrêmement toxique pour les poissons, les arthropodes
aquatiques  et les abeilles. Toutefois il est improbable que des effets
indésirables durables se produisent en situation réelle  si  l'insecti-
cide est utilisé conformément aux recommandations.

3.  Recommandations

    Les   concentrations   alimentaires  résultant   d'une  utilisation
conforme  aux recommandations sont  en principe faibles,  toutefois  il
serait bon de confirmer cette hypothèse en étendant la  surveillance  à
la perméthrine.

    La  perméthrine  est  utilisée  depuis  de  nombreuses  années sans
qu'aucun  effet  indésirable  n'ait  été  signalé  à  la  suite   d'une
exposition   humaine.   Néanmoins  il  serait  bon  de  poursuivre  les
observations sur ce type d'exposition.





    See Also:
       Toxicological Abbreviations
       Permethrin (HSG 33, 1989)
       Permethrin (ICSC)
       Permethrin (PDS)
       PERMETHRIN (JECFA Evaluation)
       Permethrin (Pesticide residues in food: 1979 evaluations)
       Permethrin (Pesticide residues in food: 1980 evaluations)
       Permethrin (Pesticide residues in food: 1981 evaluations)
       Permethrin (Pesticide residues in food: 1982 evaluations)
       Permethrin (Pesticide residues in food: 1983 evaluations)
       Permethrin (Pesticide residues in food: 1984 evaluations)
       Permethrin (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Permethrin (JMPR Evaluations 1999 Part II Toxicological)
       Permethrin (UKPID)
       Permethrin (IARC Summary & Evaluation, Volume 53, 1991)