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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY


    ENVIRONMENTAL HEALTH CRITERIA 96



    d-PHENOTHRIN










    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
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    WHO Library Cataloguing in Publication Data

    d-Phenothrin.

        (Environmental health criteria ; 96)

        1.Pyrethrins   I.Series

        ISBN 92 4 154296 9        (NLM Classification: WA 240)
        ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR d-PHENOTHRIN

INTRODUCTION            

1. SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

    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. Identity    
    2.2. Physical and chemical properties    
    2.3. Analytical methods  

3. SOURCES AND LEVELS OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Industrial production   
    3.2. Use patterns    
    3.3. Residues in food    
    3.4. Residues in the environment 

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION   

    4.1. Transport and distribution between media    
    4.2. Photodegradation    
    4.3. Degradation in plants and soils 
    4.4. Degradation on stored foods 

5. KINETICS AND METABOLISM 

    5.1. Metabolism in mammals   
    5.2. Enzymatic systems for biotransformation 

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT 

    6.1. Aquatic organisms   
    6.2. Terrestrial organisms   

7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS       

    7.1. Single and short-term exposures 
    7.2. Long-term exposures and carcinogenicity 
         7.2.1. Rat 
         7.2.2. Mouse   
         7.2.3. Dog 
    7.3. Mutagenicity    
    7.4. Reproduction, embryotoxicity, and teratogenicity    
         7.4.1. Embryotoxicity and teratogenicity   
         7.4.2. Reproduction studies    
    7.5. Neurotoxicity   
    7.6. Miscellaneous effects   
    7.7. Mechanism of toxicity - mode of action  

8. EFFECTS ON HUMANS   

    8.1. 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 D-PHENOTHRIN

 Members

Dr V. Benes, Toxicology and Reference Laboratory, Institute 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 
   Programme, US Environmental Protection Agency, Washington DC, 
   USA  (Chairman) 

Dr S.K. Kashyap, National Institute of Occupational Health 
   (I.C.M.R.) Ahmedabad, India  (Vice Chairman) 

Dr Yu. I. Kundiev, Research Institute of Labour, Hygiene, and 
   Occupational 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, Tokyo, 
   Japan 

 Representatives of other Organizations

Dr M. Ikeda, International Commission on Occupational Health, 
   Department 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 

Dr N. Punja, Groupement International des Associations Nationales 
   de Fabricants de Produits Agrochimiques (GIFAP), ICI Plant 
   Protection Division, Fenhurst, Haslemere, United Kingdom 

 Observers

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

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

 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 publication.  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 Programme on Chemical Safety, World 
Health Organization, Geneva, Switzerland, 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-
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 para. 82-84 and recommendations 
para. 90 of the Second FAO Government Consultation (1982). 


ENVIRONMENTAL HEALTH CRITERIA FOR D-PHENOTHRIN


    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 Institute 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-General of NIHS welcomed the participants to the 
institute.  Dr M. Mercier, Manager of the IPCS, welcomed the 
participants on behalf of the three IPCS cooperating organizations 
(UNEP/ILO/WHO).  The group reviewed and revised the draft monograph 
and made an evaluation of the risks for human health and the 
environment from exposure to d-phenothrin. 

    The first draft of this document was prepared by Dr J. MIYAMOTO 
and Dr 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 this draft. The second draft was prepared by Dr J. SEKIZAWA, 
NIHS, Tokyo, incorporating 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, in 
making available to the IPCS and the Task Group their toxicological 
proprietary information on d-phenothrin is gratefully acknowledged.  
This allowed the Task Group to make its evaluation on this basis of 
more complete data. 

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 biological 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 
    addition 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, kadethrin, and tellallethrin (usually 
    for household insects), fenpropathrin, tralomethrin, 
    cyhalothrin, lambda-cyhalothrin, tefluthrin, cufluthrin, 
    flucythrinate, fluvalinate, and biphenate (for agricultural 
    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 rapidly, 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 organophosphorus 
    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, 
    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 tendency to accumulate in tissues.  In the environment, 
    synthetic pyrethroids 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 environment.  The toxicity of synthetic 
    pyrethroids in birds and domestic animals is low. 

10. In addition to the evaluation documents of FAO/WHO, there are 
    several 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, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

1.1.  Summary and Evaluation

1.1.1.  Identity, physical and chemical properties, analytical methods

    Racemic phenothrin was first synthesized in 1969.  Chemically, 
it is an ester of chrysanthemic acid (2,2-dimethyl-3-(2,2-
dimethylvinyl)-cyclopropanecarboxylic acid) and 3-phenoxybenzyl 
alcohol (PBalc).  It is a mixture of four stereoisomers, i.e., the 
[1R,trans], [1R,cis], [1S,trans], and [1S,cis] isomers.  
d-Phenothrin is the 1:4 mixture of the [1R,cis] and [1R,trans] 
isomers and is nowadays the only technical product commercially 
available.  The [1R,trans] isomer is the most insecticidally active 
isomer, followed by the [1R,cis] isomer. 

    Technical grade d-phenothrin is a pale yellow to yellow-brown 
liquid and is 92.5-94.5% pure.  The specific gravity is 1.058-1.061 
at 25°C, and the vapour pressure is 0.16 mPa at 20°C.  It is 
sparingly soluble in water (2 mg/litre at 25°C) but is soluble in 
organic solvents such as acetone, xylene, and hexane.  It is 
fairly stable in air but is unstable to light, although it is not 
photodegraded as rapidly as natural pyrethrins.  It is unstable in 
alkaline media. 

    Residue analysis can be carried out by determination using 
high-performance liquid chromatography with UV detector, the 
minimum detectable concentration being 0.05 mg/kg.  A gas 
chromatograph equipped with flame ionization detector is used for 
the analysis of the technical product. 

1.1.2.  Production and use

    d-Phenothrin has been in use since 1977.  It is estimated that 
70-80 tonnes of d-phenothrin are used annually worldwide, mainly to 
control noxious insects in the household and insects of public 
health concern and to protect stored grain.  It is used either 
alone or in combination with other insecticides and/or synergists, 
and it is formulated in aerosols, oil, dust formulations, and 
emulsifiable concentrate.  d-Phenothrin is also used to control 
human lice, in which case it is formulated as a powder, shampoo, or 
lotion. 

1.1.3.  Human exposure

    Conventional household aerosol spraying is not expected to lead 
to aerial levels of d-phenothrin greater than 0.5 mg/m3.  Residues 
of up to 4 mg/kg might be present in stored wheat, but this 
decreases, after milling, to 0.8 mg/kg in flour and to 0.6 mg/kg 
after baking. 

    To control lice, d-phenothrin is applied to human hair, e.g., 
three doses of 32 mg at 3-day intervals.  No data are available on 
occupational exposure to d-phenothrin. 

    The exposure of the general population is expected to be very 
low, but precise data are lacking. 

1.1.4.  Environmental fate

    Phenothrin degrades readily, with a half-life of less than 1 
day, on plants and other surfaces.  There is little translocation 
of d-phenothrin or its degradation products to the untreated parts 
of the plants.  Limited uptake of radiolabelled products into bean 
plants took place from soils treated with 14C-phenothrin.  When 
soils were treated with [1R, trans ]- or [1R, cis ]-phenothrin 
(1 mg/kg), both isomers decomposed rapidly with initial half-lives 
of 1-2 days, but under flooded conditions the degradation was much 
slower, with initial half-lives of 2-4 weeks (trans isomer) and 1-2 
months (cis isomer).  Very little movement (approximately 2%) of 
either  trans-  or  cis-  phenothrin was observed through soil 
columns when leaching was started immediately or 14 days after 
treatment with the insecticide. 

    In general, the degradative processes that occur in the 
environment lead to less toxic products. 

1.1.5.  Kinetics and metabolism

    After rats were given single or repeated oral exposure or 
dermal treatment with radiolabelled phenothrin, the radiolabel was 
rapidly and almost completely excreted in urine and faeces within 
3-7 days. The major metabolic pathways of both  trans- and  cis-
phenothrin in rats were ester cleavage and oxidation at the 4'-
position of the alcohol moiety or the isobutenyl group of the acid 
moiety.  Ester-cleaved metabolites (excreted mainly in the urine) 
were the principal products of the trans isomer, whereas ester-form 
metabolites (excreted mainly in the faeces) were mostly formed from 
the cis isomer. 

1.1.6.  Effects on organisms in the environment

    Phenothrin has been tested on few groups of non-target 
organisms and on only a few species within each group.  The 96-h 
LC50 for racemic phenothrin and (1R) stereoisomers in fish ranged 
from 17 to 200 µg/litre.  A single study on aquatic invertebrates 
demonstrated 3-h LC50 values for  Daphnia pulex of 25-50 mg/litre 
for all isomers and for racemic phenothrin. 

    A single field study applying phenothrin to ponds showed no 
effect on aquatic arthropods. 

    Toxicity to birds is low with an acute oral LD50 for bobwhite 
quail of >2500 mg/kg body weight and a dietary LC50 for mallard 
duck and bobwhite quail of >5000 mg/kg diet. 

    Since phenothrin breaks down rapidly in sunlight and is used 
principally on stored grain, environmental exposure is expected to 
be very low.  Therefore, effects on the environment are extremely 
unlikely. 

1.1.7.  Effects on experimental animals and  in vitro test systems

    The acute toxicity of d-phenothrin is extremely low, the LD50 
being >5000 mg/kg body weight in the rat and mouse (via the oral, 
subcutaneous, dermal, and intraperitoneal routes) and the 
inhalation LC50 >3760 mg/m3 in the rat.  d-Phenothrin causes a 
poisoning syndrome of hyperexcitability, prostration, tremor, 
ataxia, and paralysis.  From these symptoms and the results of 
electrophysiological studies of cockroach cercal sensory nerves, it 
is classified as a Type I pyrethroid. 

    When rats were exposed to d-phenothrin by inhalation at 
concentrations of up to 210 mg/m3 for 4 h per day for 4 weeks or 
orally for 5 consecutive days at a dose level of 5000 mg/kg body 
weight, no adverse toxicological effects were observed. 

    Several feeding studies of phenothrin (racemic or d-phenothrin 
from 200 to 10 000 mg/kg diet) in rats and mice, with exposure 
periods of 6 months to 2 years, have been performed.  The no-
observed-effect levels (NOEL) obtained in these studies were 300-
1000 mg/kg diet, which correspond to approximately 40-160 mg/kg 
body weight per day.  In two studies on dogs in which d-phenothrin 
was given at doses of 100-3000 mg/kg diet, with exposure periods of 
26-52 weeks, the NOEL was 300 mg/kg diet, corresponding to 7-8 
mg/kg body weight per day. 

    d-Phenothrin is not mutagenic in a variety of  in vivo and  in 
 vitro systems that test for gene mutations, DNA damage, DNA repair, 
and chromosomal effects. 

    In 2-year studies, d-phenothrin was not oncogenic to rats and 
mice at dietary levels of up to 3000 mg/kg diet. 

    Neither teratogenicity nor embryotoxicity was observed in 
fetuses of rabbits and mice orally administered d-phenothrin at up 
to 1000 and 3000 mg/kg body weight, respectively.  In a 2-
generation rat reproduction study, the NOEL was 1000 mg/kg diet. 

    Rats exposed by inhalation to very high doses of d-phenothrin 
(up to 3760 mg/m3) for 4 h or orally to a dose of 5000 mg/kg body 
weight per day for 5 days showed no myelin degeneration or axon 
disruption in the sciatic nerve. 

1.1.8.  Effects on human beings

    Although d-phenothrin has been in use for more than 10 years, 
no cases of human poisoning have been reported. 

    There are no indications that d-phenothrin, when used as 
recommended, has an adverse effect on human beings. 

1.2.  Conclusions

1.2.1.  General population

    The exposure of the general population to d-phenothrin is 
expected to be very low and is not likely to present a hazard when 
it is used as recommended. 

1.2.2.  Occupational exposure

    With reasonable work practices, hygiene measures and safety 
precautions, d-phenothrin is unlikely to be an occupational hazard. 

1.2.3.  Environment

    The rapid breakdown of phenothrin in sunlight and its use 
principally on stored grain imply that environmental exposure 
should be very low.  Environmental effects of the compound are, 
therefore, extremely unlikely. 

1.3.  Recommendations

    When d-phenothrin is used as recommended, exposure levels are 
expected to be very low.  However, monitoring studies should be 
continued. 

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

Molecular formula:  C23H26O3

Chemical Structure

    Racemic phenothrin was first synthesized by Itaya et al.  
(1969). It is prepared by esterifying (1RS, cis,trans )-2,2-
dimethyl-3-(2,2-dimethylvinyl)cyclopropanecarboxylic acid 
(chrysanthemic acid) with 3-phenoxybenzyl alcohol (Fujimoto et al., 
1973).  Phenothrin is thus a mixture of four stereoisomers (Fig. 1).  
The cis:trans isomer ratio is 1:4 and the optical ratio of 1R:1S is 
1:1 (racemic).  Thus the isomers 1, 2, 3, and 4 are present in the 
approximate ratio of 4:1:4:1 (Table 1).  d-Phenothrin is the 
(1R,cis,trans) preparation (i.e., a mixture of isomers 2 and 1), 
the cis:trans ratio being 1:4.  The technical grade is 92.5-94.5% 
pure.  The major impurities found in seven d-phenothrin 
preparations (average purity, 94.0%) were ethyl chrysanthemate 
(2.31%), 3-phenoxy-6-bromobenzyl  cis,trans-chrysanthemate (0.66%), 
3-phenoxytoluene (0.43%), and 4-phenoxybenzyl  cis,trans-
chrysanthemate (0.39%) (Miyamoto et al., 1984). 

FIGURE 1


Table 1.  Chemical identity of racemic phenothrin and d-phenothrin
--------------------------------------------------------------------------------------------
Common name/          CAS Index name (9CI)/                   Stereoisomeric   Synonyms and
CAS Registry no./     Stereospecific nameb,c                  compositiond     trade names
RTECS Registry no.a
--------------------------------------------------------------------------------------------
Phenothrin (racemic)  Cyclopropanecarboxylic acid,            (1):(2):(3):(4)  Phenoxythrin, 
26002-80-2            2,2-dimethyl-3-(2-methyl-1-propenyl)-,  =4:1:4:1         S-2539
GZ1975000             (3-phenoxyphenyl)methyl ester

                      3-Phenoxybenzyl (1RS,  cis, trans )-,
                      2,2-dimethyl-3-(2,2-dimethylvinyl)-
                      cyclopropanecarboxylate
                                 or
                      3-Phenoxybenzyl (1RS,  cis, trans )-
                      chrysanthemate

(+) -cis, trans-       Cyclopropanecarboxylic acid,            (1):(2)          Sumithrin, 
Phenothrin            2,2-dimethyl-3-(2-methyl-1-propenyl)-,  =4:1             S-2539 Forte
GZ2002000             (3-phenoxyphenyl)methyl ester                            d-Phenothrin

                      3-Phenoxybenzyl (1R,  cis, trans )-
                      chrysanthemate
--------------------------------------------------------------------------------------------
a   (NIOSH, 1983).
b   (1R), d, (+) or (1S), l, (-) in the acid part of the compound signify the same 
    stereospecific conformation, respectively.
c   Chrysanthemic acid is a name of the acid which forms the acid part of the compound.
d   Numbers in parentheses identify the structures shown in Fig. 1.
 
2.2.  Physical and Chemical Properties

    Certain physical and chemical properties of d-phenothrin are 
given in Table 2.  It is poorly soluble in water, but is soluble in 
organic solvents.  d-Phenothrin is fairly stable in air but 
unstable to light and in alkaline media.  However, it is not 
photodegraded as rapidly as the natural pyrethrins (FAO/WHO, 1980; 
Worthing & Walker, 1987). 

Table 2.  Some physical and chemical properties of 
d-phenothrin
-------------------------------------------------------
Physical state             liquid                      

Colour                     pale yellow to yellow-brown 

Relative molecular mass    350.5                       

Water solubility (25°C)    2 mg/litre                  
                                                       
Solubility in organic      solublea                    
solvents                                               
                            25                         
Relative density           d  1.058-1.061              
                            25                         
                                                       
Vapour pressure (20°C)     0.16 mPa                    
-------------------------------------------------------
a   Hexane (>1 kg/kg), acetone, methanol (>1 kg/kg), 
    xylene (>1 kg/kg).

2.3.  Analytical Methods

    Examples of residue and product analyses of racemic phenothrin 
and d-phenothrin are shown in Table 3. 

    To analyse technical grade racemic phenothrin or various 
formulations, Sakaue et al. (1981) dissolved the product in 
acetone, together with di-(2-ethylhexyl) phthalate (an internal 
standard), and injected the solution into a gas chromatograph 
equipped with a flame ionization detector (GC-FID).  d-Phenothrin 
was separated as a single peak in the analysis of formulations by a 
high-performance liquid chromatography with UV detector (HPLC-UV) 
system (utilizing a µ-Bondapak phenyl column eluted with 
acetonitrile as water mobile phase). Murano (1972) and 
Papadopoulou-Mourkidou et al. (1981) analyzed technical grade 
phenothrin, and separated the cis and trans isomers of racemic or 
d-phenothrin by GC-FID with a AW-DMCS chromosorb W column or by 
HPLC-IR with a Partisil 10 column, respectively. 

    The Joint FAO/WHO Codex Alimentarius Committee has published 
recommendations for methods of analysis of d-phenothrin residues 
(FAO/WHO, 1985b). 


Table 3.  Analytical methods for racemic phenothrin
--------------------------------------------------------------------------------------------------------------------
Sample      Sample preparation                            Determination            MDCb     % Recovery        Refer-
            Extraction  Partition        Clean up         GLC or HPLC condition;   (mg/kg)  (fortification    enced
            solvent                                       detector, column,                 level, mg/kg)c       
                                    column      elution   carrier flow,         
                                                          retention time        
--------------------------------------------------------------------------------------------------------------------
 Residue analysis

apple        n-hexane    ext.sol.a   silica gel  CH2Cl2    HPLC UV-206nm, 25cm      0.05     62(0.1), 92(1.0)  1
            acetone     /H2O                              ODS, propan-2-o1,                    
            (1/1)                                         1 ml/min
pear                                silica gel  CH2Cl2    as for apple             0.05     85(0.1), 96(1.0) 
cabbage                             silica gel  CH2Cl2    as for apple             0.05     72(0.1), 88(1.0)
potato                              silica gel  CH2Cl2    as for apple             0.05     77(0.1), 98(1.0)

wheat                   methanol     n-hexane    alumina   HPLC, 235nm, 30cm,                87(2.0)           2
grain                                                     µBondapak C18,
                                                          methanol/H2O
                                                          (4/1), 2.5ml/min
                                                                                            
cooked                  petroleum                         colorimetric method,              87(3.1)           3
rice                    ether                             680nm                             91(1.9)
                        ethanol                                                                               

 Product analysis

Technical               acetone                           FID-GC, 1m, 2% PEG-20M                              4
grade                                                     210°C
--------------------------------------------------------------------------------------------------------------------

Table 3 (contd.)
--------------------------------------------------------------------------------------------------------------------
Sample      Sample preparation                            Determination            MDCb     % Recovery        Refer-
            Extraction  Partition        Clean up         GLC or HPLC condition;   (mg/kg)  (fortification    enced
            solvent                                       detector, column,                 level, mg/kg)c       
                                    column      elution   carrier flow,         
                                                          retention time        
--------------------------------------------------------------------------------------------------------------------
Technical               acetone                           FID-GC, 1m, 2% PEG-20M                              5
grade                                                     or 2% DEGS-H3PO4
                                                          (total d-phenothrin)

Technical               acetone                           FID-GC, 2m, 2% QF-1
grade                                                     (separation of 
                                                          geometrical isomers)

Technical               acetone                           HPLC, 230 nm, 50cm                
grade                                                     Sumipax OA-2000
                                                          hexane/1,2-dichloro-
                                                          ethane (500/1) 
                                                          (separation of 
                                                          optical isomers)
--------------------------------------------------------------------------------------------------------------------
a   extraction solvent
b   minimum detectable concentration
c   fortification level indicates the concentration of d-phenothrin added to control samples for the measurement of
    recovery
d   1. Baker & Bottomley (1982), 2. Noble et al. (1982), 3. Desmarchelier (1980), 4. Sakaue et al. (1981),
    5. Doi et al. (1985)
3.  SOURCES AND LEVELS OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Industrial Production
 
    Racemic phenothrin was first marketed in 1977 (Hayashi, 1977), but 
is no longer commercially available.  As for d-phenothrin, although 
no production data are publicly available, the annual world-wide 
production level is probably 70-80 tonnes. 

3.2.  Use Patterns

    The main use of d-phenothrin is in aerosol formulations to 
control household and public health insects, alone or in combination 
with other insecticides (e.g., tetramethrin or d-allethrin) or 
synergists (e.g., piperonyl butoxide).  Oil and dust formulations are 
used for the same purpose, as are emulsifiable concentrates.  
d-Phenothrin is also formulated in powders, shampoos, and lotions, 
mixed with a synergist (e.g., piperonyl butoxide), to control human 
lice.  In addition, it is used to protect stored grains. 

3.3.  Residues in Food

    Phenothrin, being photodegradable, has a relatively short residue 
time on plants. 

    Many residue studies (e.g., post-harvest treatment of stored 
grains) have been carried out (FAO/WHO 1980, 1988a). 

    In supervised trials on several crops, emulsifiable formulations 
of racemic phenothrin (0.375-0.50 kg ai/ha) were applied to rice, 
green pepper, and cabbage, 3 to 9 times with 3 to 10 days interval 
(Takimoto et al., 1977).  The resultant residues were 0.005-0.008 
mg/kg in cabbage (3-21 days after treatment), 0.125-1.26 mg/kg in 
green pepper (1-7 days after treatment), and 0.86-2.54 mg/kg and 
0.012-0.25 mg/kg in straw and hulled rice, respectively (7-14 days 
after treatment in both cases). 

    Analyses of residues of racemic phenothrin and d-phenothrin 
used for the protection of stored grains (e.g., wheat, barley, and 
sorghum) have been carried out. The [1R,trans] or [1R,cis] isomer 
of [methylene-14C]-phenothrin was applied at 4 mg/kg to wheat 
grains (11% moisture content) and stored at 15°C or 30°C in the dark.  
Both trans and cis isomers decomposed slowly; 79% and 87%, 
respectively, of the applied radiocarbon remained intact in the grain 
after it had been stored for one year at 30°C. The joint application 
of either  trans-  or  cis-phenothrin with piperonyl butoxide (20 
mg/kg) or piperonyl butoxide plus fenitrothion (4 mg/kg) did not 
significantly affect the residue levels of either isomer over a 
period of 12 months.  The phenothrin isomers and their decomposition 
products were mainly located in the seed coat after storage for one 
year, and the residue levels of both isomers in flour and bran were 
0.77 and 11.4 mg/kg, respectively.  The phenothrin residues in flour 
decreased somewhat during the baking process, leaving 0.57 mg/kg in 
bread (Nambu et al., 1981). 

    After wheat in a silo was treated with approximately 0.55 mg 
d-phenothrin/kg, there was no evidence of residue loss during storage 
for 25 weeks. Residue levels in white flour ranged from 0.15-0.22 
mg/kg (approximately one third of the residues in grain), and in 
white bread from 0.06-0.17 mg/kg.  The decline in phenothrin residues 
during baking was almost all accounted for by dilution (Turnbull & 
Ardley, 1987; Ohnishi et al., 1987). 

3.4.  Residues in the Environment

    No data are available on actual residue levels in air and water. 

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

 Appraisal

    Phenothrin undergoes rapid photodegradation under outdoor 
 conditions. It is transported to a very minor extent from the 
 site of application on plants and in soils. However, very 
 limited movement of phenothrin and its degradation products 
 from soil into bean plants was detected using radiolabelled
 compounds.  Phenothrin remains almost intact on stored grains 
 in the dark for up to 12 months.

    The degradation pathways of phenothrin under environmental 
conditions are summarized in Fig. 2. 

FIGURE 2

4.1.  Transport and Distribution between Media

    The degree of leaching of [1RS, trans]- or [1RS, cis]-phenothrin 
has been studied under laboratory conditions.  Very little movement 
(less than 2%) of  trans- and  cis-phenothrin through soil columns 
occurred when leaching was started either immediately or 14 days 
after treatment (Nambu et al., 1980). 

4.2.  Photodegradationa

    Although d-phenothrin is more resistant to photolysis than 
pyrethrin I, allethrin, and resmethrin (due to a more stable 
alcohol moiety), it still possesses the photo-labile isobutenyl 
group in the molecule and therefore is easily photodecomposed. 

    Ruzo et al. (1982) investigated the photodegradation of 
[1RS, trans]-phenothrin (5)a in oxygenated benzene solution (10-3 
mol/litre) under UV light (360 nm) or in a thin film (0.1-0.3 mg/cm2) 
under sunlight (Fig. 2).  Exposure to sunlight resulted in 30% 
conversion, the major photoproducts being: 

 *  the (1RS) epoxides (21) (22% of the reaction mixture), the 
    alcohol (22) (9%), and the aldehyde (23) (13%) derivatives from 
    oxidation at the (E)-methyl group; 

 *  the caronaldehyde derivative (7) (4%) from ozonolysis;

 *  the hydroperoxide (25) (27%) from hydroperoxidation, including 
    migration of the double bond at the 1'-position of the 
    isobutenyl moiety (Fig. 2). 

Minor products (26) and (27) (3%) resulted from further oxidation 
of the hydroperoxide (25) and from cis/trans isomerization and 
ester cleavage.  Trace amounts of  trans-chrysanthemic acid (20) 
were detected.  3-Phenoxybenzyl alcohol (12) underwent further 
oxidation to form the aldehyde (13) and carboxylic acid (16).  
Unidentified photoproducts accounted for 16.6% of the total.  A 
similar product distribution was obtained in benzene solution. 

4.3.  Degradation in Plants and Soils

    In studies by Nambu et al. (1980), 14C-methylene-labelled 
[1R, trans]-or [1R, cis ]-phenothrin (each 10 mg/kg) disappeared from 
the treated leaves of kidney bean or rice plants with half-lives of 
less than one day under greenhouse conditions.  The residue levels 
in both plants were 0.04-0.28 mg/kg for  trans- phenothrin and 0.10-
0.30 mg/kg for  cis- phenothrin after 30 days, compared with 
approximately 10 mg/kg immediately after treatment.  Both isomers 
primarily underwent ozonolysis at the isobutenyl double bond, 
probably via the photochemical reactions indicated previously 
(Fig. 2).  The resultant ozonides (6) were detected soon after 
treatment but they were rapidly decomposed to the corresponding 
aldehyde (7) and carboxylic acid (8) (3-phenoxy-benzyl-2,2-
dimethyl-3-carboxy-cyclopropanecarboxylate) derivatives.  Cleavage 
of the ester linkage also occurred, together with hydroxylation at 
the 2'-position (10) or 4'-position (9) of the alcohol moiety.  
Conjugation of the acids and alcohols with sugars was also 
observed, and the formation of polar products was more extensive in 
rice than in bean plants. There was little translocation of  trans-  

------------------------------------------------------------------------
a The numbers in brackets following a chemical name refer to the 
  numbers given in Fig. 2.

or  cis-phenothrin or of its degradation products to the untreated 
parts of the plants.  Limited uptake of radiolabelled products into 
bean plants took place from light clay, sandy loam soil, and from 
sand treated with 14C-methylene-labelled  trans- or  cis-phenothrin. 

    The degradation of 14C-labelled [1R, trans]- or [1R, cis]-
phenothrin in two soils was investigated by Nambu et al. (1980).  
Both isomers decomposed rapidly under upland conditions, with 
initial half-lives of 1-2 days, but under flooded conditions the 
degradation was much slower, with initial half-lives of 2-4 weeks 
and 1-2 months for the trans and cis isomers, respectively.  
Analysis of the soil extracts revealed unchanged parent isomers, 
(16), 3-(4'-hydroxyphenoxy)benzoic acid (17), (12), 3-(4'-
hydroxyphenoxy)benzyl alcohol (14), (9), and 3-hydroxy-benzyl-2,2-
dimethyl-3-(2,2-dimethylvinyl)-cyclopropanecarboxylate (11). These 
degradation products were not persistent and underwent further 
degradation in soil, under both upland and flooded conditions, to 
yield large amounts of 14CO2 and unextractably bound residues.  
More 14C carbon dioxide was formed in soils under upland conditions 
than under flooded conditions and more was formed from  trans-
phenothrin than from the cis isomer.  Bound 14C residues were 
associated mainly with the humic acid and fulvic acid fractions of 
soil organic matter.  The fulvic acid fraction contained small 
amounts of the same degradation products as in the soil extracts. 
 
4.4.  Degradation on Stored Foods

    When 14C-[1R, trans ]- or 14C-[1R, cis ]-phenothrin was applied at 
4 mg/kg to wheat grains of 11% moisture content and the crop was 
stored at 15 or 30°C in the dark for 12 months, most of the 
phenothrin remained intact.  Major metabolites were formed by 
hydrolysis of the ester linkage and oxidation of 3-phenoxybenzyl 
alcohol to 3-phenoxybenzoic acid.  The methyl ester of 3-
phenoxybenzoic acid was also produced.  After storage at 30°C for 
12 months, these metabolites amounted to 13.9% in the case of the 
trans isomer and 6.3% in the case of the cis isomer (Nambu et al., 
1981). 

5.  KINETICS AND METABOLISM

 Appraisal

    The pathways by which phenothrin is metabolized in mammals are
 summarized in Fig. 3.

    Comparative metabolism studies have shown that the metabolism 
 of racemic phenothrin is similar to that of [1R,cis,trans]-phenothrin 
 (d-phenothrin).

    No information is available on the in vivo metabolism of the acid 
 moieties of trans([1R,trans])- or cis([1R,cis])-phenothrin.  However, 
 the acid moiety liberated in vivo (chrysanthemic acid) is the same 
 as that of resmethrin and tetramethrin and, therefore, its fate can 
 be predicted from the resmethrin and tetramethrin data. 

FIGURE 3

5.1.  Metabolism in Mammals

 Appraisal

    After rats are treated with radiolabelled phenothrin, either by 
 single or repeated oral exposure, or dermally, the radioactivity is 
 rapidly (and almost totally) excreted into urine and faeces within 
 3 to 7 days.  The major metabolic pathways of both trans- and cis- 
 phenothrin in rats are oxidation at the 4'-position of the alcohol 
 moiety or the isobutenyl group of the acid moiety and cleavage of 

 the ester linkage (see Fig. 3).  Cleavage of the ester bond is more 
 difficult in the cis isomer than in the trans isomer.  Thus, ester-
 form metabolites oxidized in the various positions of the molecule are 
 the major metabolites of the cis isomer and are excreted mostly in the 
 faeces.  However, ester-cleaved metabolites are the major products from
 the trans isomer and are mostly excreted in urine. 

    When [1R, trans ]-phenothrin labelled with 14C at the methylene 
moiety was given as a single oral dose (200 mg/kg body weight) to 
Sprague Dawley male rats, the radiocarbon was rapidly eliminated, 
57% and 43% being recovered within 3 days in urine and faeces, 
respectively (Miyamoto et al., 1974).  There was no detectable 
radiocarbon in the expired air.  Similarly, Sprague Dawley male 
rats given a single oral dose (10 mg/kg body weight) of 14C-
[1R, trans ]-phenothrin, excreted the radiocarbon rapidly in the 
urine (75%) and faeces (21%) (Kaneko et al., 1981). 

    In a study by Isobe et al. (1987), Sprague Dawley male and 
female rats were given a single oral administration of 14C-
[1R, trans ]-phenothrin in corn oil at 4 and 200 mg/kg body weight.  
Within 7 days the radiocarbon was almost completely eliminated in 
the urine and faeces.  The % elimination was as follows: 

-----------------------------------------
Dose          Urine            Faeces    
(mg/kg)  Males  Females    Males  Females
4        38     40         61     60
200      39     25         56     60
-----------------------------------------

    Sprague Dawley male rats eliminated 65% of the dosed radiocarbon 
in the faeces over 3 days after a single oral administration (200 
mg/kg body weight) of 14C-[1R, cis ]-phenothrin (28) (Suzuki et al., 
1976), and 22 and 74% of the dose into urine and faeces, 
respectively, 7 days after a single oral dose of 10 mg/kg body 
weight (Kaneko et al., 1981). 

    When 14C-[1R, cis ]-phenothrin in corn oil was administered once 
orally to Sprague Dawley male and female rats at 4 or 200 mg/kg 
body weight, the radiocarbon was excreted into the urine (11-18%) 
and faeces (81-87%) within 7 days.  Similarly, when Sprague Dawley 
rats were treated repeatedly with 14C-[1R,trans] or 14C-[1R,cis] 
isomers at 4 mg/kg body weight per day for 14 days, the radiocarbon 
was rapidly and almost completely excreted: 75-70% in urine and 24-
29% in faeces for the trans isomer, and 24% in urine and 72-73% in 
faeces for the cis isomer (Isobe et. al., 1987). 

    The tissue residues in rats 7 days after a single oral dose of 
14C-[1R, cis ]- or 14C-[1R, trans ]-phenothrin at 10 mg/kg body 
weight were generally very low although the fat showed somewhat 
higher residue levels (1-2.5 mg/kg) (Kaneko et al., 1981).  
Similarly, high 14C residue levels (up to 23 mg/kg) were found in 
the fat, 7 days after a single oral dose of the [1R,cis] isomer at 
200 mg/kg body weight (Isobe et al., 1987). 

    The major metabolite of the trans isomer, when given as a 
single oral dose of 200 mg/kg to rats, was 3-(4'-hydroxyphenoxy)-
benzoic acid (17) (4'OH-PBacid, 54%).  There were smaller amounts 
of 3-phenoxybenzoic acid (16) (PBacid, 9.5%) and its glycine 
conjugate (Miyamoto et al., 1974). 

    When [1R, trans ]-phenothrin was given to rats at 4, 10, or 200 
mg/kg body weight (oral single dose) or 4 mg/kg body weight 
(repetitive oral dose for 14 days), the sulfate conjugate of 4'-OH-
PBacid was predominant, accounting for 28, 43, 28, and 55%, 
respectively, of the dose.  In addition, PBacid (4, 10, 5, and 6%), 
its glycine conjugate (1,3,2, and 2%) and glucuronide (2,3,1, and 
3%), and free 4'-OH-PBacid (2,11,3, and 3%) were found.  The 
sulfate conjugate of 3-(2'-hydroxyphenoxy)benzoic acid (18) (2'-
OH-PBacid) was also found as a minor metabolite (Kaneko et al., 
1981; Isobe et al., 1987). 

    When rats were given 14C-[1R, trans ]-phenothrin (10 mg/kg body 
weight), the unmetabolized compound and two ester-form metabolites 
were detected in their faeces in small amounts (0.4-1.2%), which 
had hydroxymethyl (29) ( wt-alc- t-phe) or carboxyl group (30)  wt-
acid- t-phe) (see Fig. 2) at the position of the  trans methyl group 
of chrysanthemic acid (Kaneko et al., 1981). 

    When Sprague Dawley rats were administered a single oral dose 
of [1R, trans ]-phenothrin at 4 or 200 mg/kg body weight level or 
given an oral dose of 4 mg/kg body weight per day for 14 days, 
unmetabolized compound was found in the faeces (44-45, 44-60, and 
14-16% of the dose, respectively).  An ester-form metabolite, the 
4'-hydroxy  w(t)-acid derivative of  trans- phenothrin, was also 
detected (0.4-0.6%) (Isobe et al., 1987). 

    When male Sprague Dawley rats were given  cis-phenothrin (200 
mg/kg body weight), three ester-form metabolites, which accounted 
for 14% of the dosed radioactivity, were found in the faeces.  
These were 4'-hydroxy- cis-phenothrin (31) (4-OH- c-phe), an ester-
form derivative with the  trans methyl of the isobutenyl group being 
oxidized to carboxyl group (32) ( wt-acid- c-phe), and a compound 
with the  geminal-dimethyl groups oxidized (2-OH-) in addition to 
both of the above modifications (33) (4'-OH, wt-acid, 2-OH(t)- c-phe) 
(Suzuki et al., 1976). 

    In addition to this, the cis isomer gave rise to nine ester-
form metabolites in the faeces varying in amounts from 2% (4'-OH, 
 wc-alc-c-phe (34)) to 13% (4'-OH,  wt-acid,2-OH(t)- c-phe (33)) of 
the dosed radiocarbon after single oral administration.  These 
ester-form metabolites were transformed by oxidation reactions at 
any of the following positions: 4'-position of the phenoxy group, 
the  trans or  cis methyl of the isobutenyl groups, and the  trans 
methyl of the  geminal-dimethyl group (Kaneko et al., 1981). 

    When Sprague Dawley rats were given a single oral dose of 
[1R, cis ]-phenothrin at 4 or 200 mg/kg body weight level or an oral 
dose of [1R, cis ]-phenothrin at 4 mg/kg body weight per day for 14 
days, ester-form metabolites (1-9% of the dosed radioactivity) were 

found, in addition to unmetabolized compound (17-59% of the dose).  
The urine contained 4'-OH-PBacid as a sulfate conjugate (7-18%) and 
in the free form (0.3-1%), and PBacid as glycine or glucuronide 
conjugates and in the free form (0.3-1%) (Isobe et al., 1987). 

    Following the dermal treatment of male Sprague Dawley rats with 
dust or emulsifiable concentrates (E.C.) of either 14C-[1R, trans ]- 
or 14C-[1R, cis ]-phenothrin at 10 mg/kg body weight, the 14C 
absorption into the body was estimated to be 3-7% of the initial 
dose with dust and 8-17% with the E.C.  After both dust and E.C. 
treatments, the radiocarbon excreta (as a percentage of the initial 
dose) recovered in the urine was 2.6-8.7% for the trans isomer, and 
1.5-4.8% for the cis isomer, and in the faeces was 0.6-2.2% for the 
trans isomer, and 3.0-12.3% for the cis isomer.  Since the same 
metabolites are formed following either oral exposure or dermal 
treatment, it appears that both phenothrin isomers undergo the same 
metabolism once in the systemic circulation, regardless of the 
route of administration (Kaneko et al., 1981; Isobe et al., 1987). 

    Information concerning the comparative metabolism of racemic 
(1RS) phenothrin and its d-isomer (1R) was obtained through a study 
of CD rats and ddY mice given a single oral dose of either 
[1R, trans ]-, [1S, trans ]-, [1RS, trans ]-, [1R, cis ]-, [1S, cis ]-, 
or [1RS, cis ]-phenothrin.  The radiocarbon derived from each isomer 
was almost completely eliminated from the rats and mice within six 
days after dosing.  The trans isomers were mainly eliminated in the 
urine (rat, 85-88%; mice, 65-75%) and the cis isomers mainly in the 
faeces (rat, 57-71%; mice, 54-71%).  The amounts of 14C in the 
urine and faeces of rats and mice treated with the [1R,trans] and 
[1R,cis] isomers did not differ significantly from those 
corresponding to the [1RS,trans] and [1RS,cis] isomers, respectively.  
The 14C tissue residues were very low, except in the fat.  There 
were no striking differences in 14C levels among the three trans 
isomers and the three cis isomers.  The 14C levels of the cis 
isomers in fat (maximum 3.5 mg/kg) were three to seven times higher 
than those of the trans isomers (less than 1 mg/ kg). The major 
urinary and faecal metabolites were remarkably similar in both rats 
and mice. In both rats and mice, there were virtually no 
differences in the metabolic fate of the [1R,trans] and [1RS, 
trans] isomers or of the [1R,cis] and [1RS,cis] isomers (Izumi et 
al., 1984). 

5.2.  Enzymatic Systems for Biotransformation

    In studies by Miyamoto et al.  (1974), [IR, trans ]-phenothrin 
(1 mmol/litre) was incubated with the 8000-g supernatant from a 
liver homogenate of rats, mice, guinea-pigs, rabbits, or dogs at 
37°C for 60 min in the absence of NADPH.  The supernatant from the 
guinea-pig was the most active in degrading [1R, trans ]-phenothrin, 
followed by that of dog, rabbit, rat, and mouse.  The major 
metabolite in all the mammalian species tested was 3-phenoxybenzyl 
alcohol (12) (PBalc). Smaller amounts of PBacid (16) and trace 
amounts of 4'-OH-PBacid (17) were also found.  However, in the 
presence of NADPH, the amounts of PBacid and unidentified ether-
soluble metabolites increased in all species except dog. In 

contrast to [1R, trans ]-phenothrin, [1R, cis ]-phenothrin was hardly 
metabolized at all by the rat liver preparation in the absence of 
NADPH.  NADPH enhanced the degradation rate of the cis isomer, 
leading to the formation of unidentified metabolites, while ester-
cleaved metabolites such as PBacid (16), PBalc (12) and 4'-OH-
PBacid (17) were found in very small amounts.  When [1R, trans ]-, 
[1R, cis ]-, [1S, trans ]-, and [1S, cis ]-phenothrin were incubated 
with rat liver microsomes at 37.5°C for 30-60 min to estimate Km 
and Vmax using a Lineweaver-Burk plot, the values for Km (0.11-0.17 
mmol/litre) were similar for the four isomers, whereas the values 
for Vmax were different; both the trans isomers yielded values for 
Vmax 20-30 times larger than did the cis isomers (Miyamoto et al., 
1974). 

    In studies by Suzuki & Miyamoto (1978), pyrethroid 
carboxyesterase(s) that hydrolyze esters of chrysanthemic acid 
were purified from rat liver microsomes by cholic acid 
solubilization, ammonium sulfate fractionation, heat treatment, and 
DEAE-Sephadex A-50 column chromatography. The 45-fold-purified 
enzyme (38% yield) probably consisted of a single protein with a 
relative molecular mass of approximately 74 000, a Km of 0.21 
mmol/litre for [1R, trans ]-phenothrin, and an optimum pH of 7-9.  
It was susceptible to inhibition by organophosphate and carbamate 
insecticides and insensitive to PCMB ( p-chloromercurybenzoic acid), 
and mercuric and cupric ions.  The enzyme seemed to require neither 
coenzymes nor cofactors and hydrolysed the trans isomers of several 
synthetic pyrethroids (tetramethrin, resmethrin, phenothrin, and 
permethrin) well, at more or less similar rates. On the other hand, 
the cis isomers were hydrolysed at rates 5-10 times lower than 
their trans counterparts.  The purified pyrethroid carboxyesterase 
was apparently identical in nature to malathion carboxyesterase 
and  p-nitrophenyl acetate carboxyesterase. 

6.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    Data on the acute toxicity of racemic and isomeric phenothrin 
for aquatic organisms are summarized in Table 4. 

6.1.  Aquatic Organisms

    Racemic phenothrin yielded 96-h LC50 values of 17-200 µg/litre 
for the fish species tested (Table 4).  The (1S)-optical isomers 
were relatively non-toxic with LC50 values of 10 000 µg/litre, 
whereas the (1R)-optical isomer and racemic phenothrin were of 
similar toxicity with LC50 values between 120 and 200 µg/litre for 
the killifish  (Oryzias latipes) (Miyamoto, 1976). 

    When d-phenothrin was applied to ponds at the rates of 28 or 56 
g/ha to control mosquito larvae, mayfly naiads were most affected 
but no other arthropods (damselfly, dragonfly naiads, ostracods, or 
diving beetle larvae) were seriously affected (Mulla et al., 1980). 

6.2.  Terrestrial Organisms

    The available toxicity data for non-target terrestrial 
organisms are very limited. 

    Phenothrin has low toxicity (acute oral dosage) for bobwhite 
quail with an LD50 >2510 mg/kg body weight (Worthing & Walker, 
1987).  An 8-day feeding study with d-phenothrin on mallard duck 
and bobwhite quail indicated LD50 values of >5620 and >5000 mg/kg 
diet, respectivelya. 







----------------------------------------------------------------------
a Personal communication from J.L. Noles, Ecological Effects 
  Branch, Hazard Evaluation Division, US Environmental Protection 
  Agency, November 1987. 


Table 4.  The acute toxicity of racemic and isomeric phenothrin to non-target aquatic organisms
-----------------------------------------------------------------------------------------------
Species             Size   Parameter   Toxic          Stereo-      Systema  Temper-  Refer-
                                       concentration  isomeric              ature    enceb
                                       (µg/litre)     composition           (°C)
-----------------------------------------------------------------------------------------------
 Fish

Killifish           adult  48-h LC50   200            racemic      S        25       1
 (Oryzias latipes)   adult  48-h LC50   120            (+)-trans    S        25       1
                    adult  48-h LC50   170            (+)-cis      S        25       1
                    adult  48-h LC50   10 000         (-)-trans    S        25       1
                    adult  48-h LC50   10 000         (-)-cis      S        25       1

Rainbow trout              96-h LC50   17             racemic                        2
 (Salmo gairdneri) 

Bluegill                   96-h LC50   18             racemic                        2
 (Lepomis macrochirus)

 Arthropods

 Daphnia pulex              3-h LC50    50 000         racemic      S        25       1
                           3-h LC50    25 000-50 000  (+)-trans    S        25       1
                           3-h LC50    50 000         (+)-cis      S        25       1
                           3-h LC50    50 000         (-)-trans    S        25       1
                           3-h LC50    50 000         (-)-cis      S        25       1
-----------------------------------------------------------------------------------------------
a   s = static
b   1. Miyamoto (1976)   2. Worthing & Walker (1987)
7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    The 1984 Joint FAO/WHO Meeting on Pesticide Residues concluded 
that the toxicological data for racemic phenothrin can be used to 
support that for d-phenothrin, owing to the similarity in 
metabolism and toxicity between the two compounds (FAO/WHO, 
1985b). 

7.1.  Single and Short-Term Exposures

    The acute toxicity in rats and mice is extremely low.  The LD50 	
values were >5000 mg/kg body weight when d-phenothrin was 
administered orally, subcutaneously, dermally, or by 
intraperitoneal injection to male and female Sprague Dawley rats 
(Segawa, 1979a) and ddY mice (Segawa, 1979b) (Table 5). 

Table 5.  The acute toxicity of racemic phenothrin and d-phenothrin
to rats and micea
------------------------------------------------------------------
Compound/Route                      LD50 (mg/kg)              
                             Rat                  Mice           
                       Male       Female     Male       Female          
------------------------------------------------------------------      
Phenothrin (racemic)
   Oral                > 5000     > 5000     > 5000     > 5000      
   Subcutaneous        > 5000     > 5000     > 5000     > 5000      
   Dermal              > 5000     > 5000     > 5000     > 5000      
   Intraperitoneal     > 5000     > 5000     > 5000     > 5000      
   Inhalation          > 1210b    > 1210b    > 1210b    > 1210b     

d-Phenothrin
   Oral                > 10 000   > 10 000   > 10 000   > 10 000    
   Subcutaneous        > 10 000   > 10 000   > 10 000   > 10 000    
   Dermal              > 10 000   > 10 000   > 5000     > 5000      
   Intraperitoneal     > 10 000   > 10 000   > 10 000   > 10 000    
   Inhalation          > 3760b    > 3760b    > 1180b    > 1180b     
------------------------------------------------------------------      
a From:  Segawa (1976; 1979a,b) and Khoda et al. (1977; 1979b; 1980)
b These are values for 4-h LC50 (mg/m3)

    There were no differences between the effects on male and 
female rats in acute toxicity studies carried out by Segawa (1976).  
Signs of poisoning appeared rapidly following the intravenous 
administration of phenothrin.  These included fibrillation, tremor, 
slow respiration, salivation, lacrimation, ataxia, and paralysis.  
These signs, evident within 30 min to one hour following 
administration, diminished rapidly to the point where, after 24 h, 
there were no signs of toxicity. 

    No differences in the oral toxicity between racemic phenothrin 
and d-phenothrin were detected by Segawa (1976; 1979a,b) (Table 5). 

    The intravenous LD50 values for racemic phenothrin in ICR mice 
were 470 and 600 mg/kg for males and females, respectively, while 
those for d-phenothrin were 265 and 315 mg/kg (Hiromori et al., 1984). 

    Following a 4-h acute inhalation exposure (whole body), the 
LC50 values were >1210 mg/m3 for racemic phenothrin (particle size 
5 µm) with both Sprague Dawley rats and ICR mice (Kohda et al., 1979b) 
and >3760 and 1180 mg/m3 for d-phenothrin with Sprague Dawley rats 
and ICR mice, respectively (Kohda et al., 1977; 1979b) (see Table 5). 
At the higher concentration (3760 mg/m3), the mean particle size 
was considered to be 0.72 µm and the cumulative distribution of 
particles having a diameter between 0.46 and 1.09 µm was 88.9%, 
according to a particle-size distribution experiment (Kohda et al., 
1980). 

    In studies by Kohda et al. (1979b), Sprague Dawley rats (15 of 
each sex) were exposed (whole body) by inhalation to racemic 
phenothrin at concentrations of 0, 43, or 220 mg/m3 (4 h per day, 5 
days per week) for 4 weeks.  After this treatment, animals (10/sex 
per group) were sacrificed and the remaining rats were kept for 3 
weeks without treatment.  There were no adverse toxicological 
effects on the animals exposed to the highest dose.  Under the same 
conditions (i.e. 220 mg/m3 for 4 weeks), racemic phenothrin did not 
produce any adverse effects in male or female ICR mice.  Similarly, 
d-phenothrin also produced no adverse toxicological effects in 
Sprague Dawley rats or ICR mice (both male and female) following 
whole body exposure at 210 mg/m3 (particle size 5 µm) for 4 weeks 
(Kohda et al., 1979b). 

    The acute oral and intraperitoneal toxicity of phenothrin 
metabolites in rats and mice are shown in Table 6 and 7 (Kohda et 
al., 1979a; FAO/WHO, 1981). 

Table 6.  The acute oral toxicity of phenothrin 
metabolites
-----------------------------------------------------
Chemical                  No.a      Species   LD50 
                                              (mg/kg)
-----------------------------------------------------
3-Phenoxybenzyl alcohol   12        Rat       1330
3-Phenoxybenzaldehyde     13        Rat       600
-----------------------------------------------------
a   Chemical identification number used in Fig. 2

Table 7.  The acute intraperitoneal toxicity of several phenothrin 
metabolites in mice
----------------------------------------------------------------------
Chemical                                No.a       LD50 (mg/kg)     
                                                 Male      Female
----------------------------------------------------------------------
3-Phenoxybenzyl alcohol                 12       371       424
3-(4'-hydroxyphenoxy)benzyl alcohol     14       750-1000  750-1000
3-(2'-hydroxyphenoxy)benzyl alcohol     15       876       778
3-Phenoxybenzoic acid                   16       154       169
3-(4'-hydroxyphenoxy)benzoic acid       17       783       745
3-(2'-hydroxyphenoxy)benzoic acid       18       859       912
3-Phenoxybenzaldehyde                   13       415       416
----------------------------------------------------------------------
a   Chemical identification number used in Fig. 2

7.2.  Long-Term Exposures and Carcinogenicity

 Appraisal

     There  have  been several  long-term  feeding studies  with racemic 
 phenothrin  or d-phenothrin  (dose levels  ranging from  200 to  10 000 
 mg/kg  diet) in rats and  mice, the length of  exposure ranging from  6 
 months  to  2  years.   A  slight  increase  in  liver  weight  and   a 
 significant difference in some clinical/chemistry parameters from those 
 of  controls were observed  at high doses.   However, the  no-observed-
 effect  level (NOEL) values obtained  in these studies were  high (300-
 1000 mg/kg  diet, corresponding to around 40-160 mg/kg body weight) and 
 no tumorigenicity was observed. Two feeding studies  with  d-phenothrin 
 (doses  of 100-3000 mg/kg diet with exposure period 26 and 52 weeks) in 
 dogs   revealed  similar  results,   the  NOEL  being   300 mg/kg  diet 
 (corresponding   to  around  7-8 mg/kg   body  weight  per   day).   No 
 tumorigenicity  relating to phenothrin  feeding was detected  in  these 
 studies. 

7.2.1.  Rat

    In a study by Murakami et al.  (1981), [1R, cis]-phenothrin
(d-phenothrin) was administered to Sprague Dawley rats (20 of each 
sex per group) at dose levels of 0, 1, 3, or 10 g/kg diet for 6 
months. Ten rats of each sex per group were sacrificed after 3 
months. d-Phenothrin had no significant effect on mortality, 
clinical signs, ophthalmology, urinalysis, or gross and 
histopathological findings. The serum albumin level was elevated 
after 3 months in males fed 10 g/kg and in females fed 3 or 10 
g/kg, and after 6 months in males fed 3 or 10 g/kg.  The albumin-
globulin ratio was raised after 3 months in males fed 3 or 10 g/kg 
and in females fed 10 g/kg, and in both males and females fed 10 
g/kg after 6 months.  Absolute and relative liver weights in both 
males and females fed 3 or 10 g/kg were increased. Based on these 
data, it was concluded that the NOEL for d-phenothrin in this study 
was 1 g/kg diet for both sexes (55.4 mg/kg body weight per day for 
males and 63.3 mg/kg body weight per day for females). 

    In a standard oncogenicity study, Fisher-344 rats (50 of each 
sex per group) were fed d-phenothrin at dose levels of 0, 300, 1000 
or 3000 mg/kg diet for at least 105 weeks in males and at least 118 
weeks in females.  Additional rats (30 of each sex per group) were 
assigned to a chronic toxicity study with a 52-week interim 
sacrifice.  There were no significant effects on clinical signs, 
mortality, food and water consumption, ophthalmology, blood 
biochemistry, haematology, or urinalysis.  However, the body weight 
gain in females fed d-phenothrin at 3000 mg/kg was reduced, and the 
relative liver weight was increased in females fed 3000 mg/kg for 
52 weeks and, at the end of the oncogenicity study, in males fed 
3000 mg/kg.  Microscopic examination revealed that the incidence of 
cystic dilatation of the sinuses of the mesenteric lymph nodes and 
of periacinar hepatocytic hypertrophy was higher in males fed 3000 
mg/kg for at least 105 weeks.  d-Phenothrin did not show any 
oncogenic activity to rats at up to 3000 mg/kg. Although at this 
dose an increase in the incidence of adenomas and carcinomas of the 
preputial gland was seen in males, the 1988 Joint FAO/WHO Meeting 

on Pesticide Residues (FAO/WHO, 1988b) considered it unlikely that 
this finding was of toxicological significance. The NOEL was 1000 
mg/kg diet for both sexes (47 mg/kg body weight per day for males 
and 56 mg/kg body weight per day for females) (Martin et al., 
1987). 

    When Sprague Dawley rats (50 of each sex per group) were fed a 
diet containing racemic phenothrin (0, 200, 600, 2000, and 6000 
mg/kg diet) for 2 years, body weight and food consumption were 
slightly depressed at 6000 mg/kg in both males and females. 
Ophthalmological examinations, haematological studies, urinalyses, 
and clinical chemistry studies were performed at various intervals.  
At the end of the study all animals were sacrificed and examined 
for gross abnormalities, and extensive microscopic examinations 
were conducted on a variety of tissues and organs.  There were no 
abnormal clinical or behavioral problems associated with 
phenothrin administration.  The survival rate of all groups of 
treated rats was similar to that of controls.  Males fed 6000 mg/kg 
showed a significant increase in serum glutamine-pyruvate 
aminotransferase activity.  Ophthalmological examinations revealed 
some abnormalities, all of which appeared to be age related.  
Histopathological examination revealed no significant differences 
between the treated groups and the control group with respect to 
severity of lesions.  No histopathological changes suggestive of 
oncogenicity resulting from phenothrin treatment were found 
(Hiromori et al., 1980). 

7.2.2.  Mouse

    When Swiss White mice (50 of each sex per group) were fed 
racemic phenothrin for 18 months at dose levels of 0, 300, 1000, or 
3000 mg/kg diet, there were no significant effects on mortality, 
clinical signs, haematologic values, clinical chemistry parameters, 
or gross pathological findings. Slight body weight depression 
occurred in males fed 3000 mg/kg, and increased liver weight was 
found at the highest dose level in both males and females.  There 
was a statistically significant difference (compared with the 
controls) in lung amyloidosis in the 1000 and 3000 mg/kg dose 
groups, but no significant increase in tumours attributable to 
phenothrin ingestion (Murakami et al., 1980). 

    In studies by Amyes et al. (1987), B6C3F1 hybrid mice (90 of 
each sex per group) were fed d-phenothrin in the diet at dose 
levels of 0, 300, 1000, or 3000 mg/kg.  Fifty of each sex per group 
were allocated to a standard oncogenicity study lasting 104 weeks. 
The remaining mice were assigned to a chronic toxicity study, where 
10 of each sex per group were sacrificed for interim study after 26 
or 53 weeks and the remaining animals were examined after 78 weeks 
of treatment.  There were no compound-related effects on clinical 
signs, mortality, ophthalmology, blood biochemistry, haematology, 
or urinalysis.  However, body weight gains for males fed d-
phenothrin at 3000 mg/kg were reduced and relative liver weights 
were increased in both sexes fed 3000 mg/kg and in males receiving 
1000 mg/kg.  Microscopic examination revealed that the incidence of 
periacinar hepatocyte hypertrophy with cytoplasmic eosinophilia was 
higher in males fed 3000 mg/kg.  The incidence of liver tumors 

appeared higher in phenothrin-treated female mice than in control 
females, but the difference was not statistically significant. It 
was concluded, therefore, that administration of d-phenothrin to 
mice for 2 years at dietary levels of up to 3000 mg/kg diet did not 
significantly disturb the tumour burden or tumour profile of B6C3F1
hybrid mice.  The NOEL in this study was 300 mg/kg diet for males 
(40 mg/kg body weight per day) and 1000 mg/kg diet for females (164 
mg/kg body weight per day). 

7.2.3.  Dog

    When beagle dogs (six of each sex per group) were fed d-
phenothrin at dose levels of 0, 100, 300, or 1000 mg/kg diet for 26 
weeks, there were no compound-related abnormal findings in 
mortality, clinical signs, body weight, food consumption, 
ophthalmology, gross or microscopic pathology, haematology, or 
urinalysis studies.  However, the alkaline phosphatase activity in 
males fed 300 mg/kg and males and females fed 1000 mg/kg was 
elevated and a slight increase in the mean relative liver weight in 
males fed 1000 mg/kg was noted.  The NOEL in this study was 300 
mg/kg (Pence et al., 1981). 

    In a study by Cox et al. (1987), beagle dogs (four of each sex 
per group) were fed d-phenothrin at dose levels of 0, 100, 300, 
1000, or 3000 mg/kg diet for 52 weeks.  There were no significant 
effects on clinical signs, body weight, food consumption, 
ophthalmology, or urinalysis.  However, decreases in erythrocyte 
count, haemoglobin concentration, haematocrit, and total blood 
protein were noted in both male and female dogs fed 3000 mg/kg, 
whereas mean absolute and relative liver weights increased. 
Compound-related histopathological alterations were noted in the 
adrenal glands and liver.  Focal degeneration of the adrenal cortex 
with cytoplasmic deposition of crystalline material was seen in one 
male dog fed 1000 mg/kg and four dogs fed 3000 mg/kg.  The chemical 
nature or biological significance of this crystalline material was 
not recorded.  Hepatocytes appeared to enlargen slightly in one 
male dog fed 1000 mg/kg and seven dogs fed 3000 mg/kg.  The NOEL in 
this study was 300 mg/kg diet for males and 1000 mg/kg for females 
(8.24 and 26.77 mg/kg body weight per day for males and females, 
respectively). 

7.3.  Mutagenicity

    The results obtained  in vivo and  in vitro test system indicate 
that d-phenothrin does not exhibit any mutagenic properties or 
cause chromosomal or DNA damage. 

    In a DNA-repair test with  Bacillus subtilis (M45 rec- and H17 
wild type strains) using dose levels of up to 5 mg/disk per plate, 
d-phenothrin did not inhibit the growth of any strain at any dose 
level, whereas the positive control, mitomycin C, showed a clear 
effect.  The negative control gave a result similar to that of d-
phenothrin (Kishida & Suzuki, 1981a). 

    A mutagenicity test with  Escherichia coli (WP2  uvr) and 
 Salmonella typhimurium (TA 1535, TA 1537, TA 1538, TA 98, and TA 
100) using d-phenothrin at dose levels of up to 5 mg/plate with and 
without metabolizing enzyme system (S9 mix) yielded negative 
results, whereas a positive control gave a significant number of 
mutants (Kishida & Suzuki, 1981b). 
                                                                       
    In a host-mediated assay using  S. typhimurium G46 (indicator 
bacteria), d-phenothrin in corn oil was given orally (twice with a 
24-h interval) to groups of six male ICR mice at dose levels of 
2500 or 5000 mg/kg body weight.  Soon after the last administration, 
each mouse was injected intraperitoneally with the indicator cells.  
Three hours later, the bacterial mutation frequency in d-
phenothrin-treated mice was no greater than that in the control 
group (Kishida & Suzuki, 1981c). 

    Suzuki et al.  (1981) examined d-phenothrin for its ability to 
induce chromosomal aberrations  in vivo using bone marrow cells.  
ICR mice were treated intrapertioneally with single doses of 2500, 
5000, or 10 000 mg/kg body weight and sacrificed 6, 24, or 48 h 
after treatment.  No chromosomal aberrations as a result of d-
phenothrin treatment were detected. 

    In an  in vitro chromosomal aberration test, Chinese hamster 
ovary cells (CHO-K1) were treated with d-phenothrin (dose levels: 
2 x 10-5 to 2 x 10-4 mol/litre for 24 and 48 h in the absence of S9 
mix; 5 x 10-5 to 5 x 10-4 mol/litre for 6 h in the presence of S9 
mix).  No significant increase in the number of cells with 
chromosomal aberrations was observed (Kogiso et al., 1986). 

    The ability of d-phenothrin to induce sister-chromatid 
exchanges (SCEs) were tested in cultured mouse embryonic cells  in 
 vitro.  At doses of 10-5, 10-4, and 10-3 mol/litre (with and 
without S9 mix), d-phenothrin did not induce any increase in the 
frequency of SCEs (Suzuki & Miyamoto, 1981). 

    In a study of unscheduled DNA synthesis, Hela S3 cells were 
treated with d-phenothrin at dose levels of 0, 0.25, 0.5, 1.0, 2.0, 
or 4.0 mg/ml in the presence of 3H-thymidine (with and without S9 
mix) for 3 h, and the incorporation of 3H-thymidine into DNA was 
measured.  There was no significant increase in the radioactivity 
of DNA from cells treated with d-phenothrin (Foster et al., 1984). 

7.4.  Reproduction, Embryotoxicity, and Teratogenicity

    No teratogenicity or reproductive effects were observed when 
phenothrin was fed to rabbits or mice during the major 
organogenesis period of gestation or to rats in 3-generation 
reproduction studies. 

7.4.1.  Embryotoxicity and teratogenicity

    In studies by Ladd et al.  (1976), pregnant New Zealand White 
rabbits (17 per group) were administered racemic phenothrin orally 
at dose levels of 0, 3, 10, or 30 mg/kg body weight on days 6 to 18 

of gestation.  They were sacrificed on day 29 and the young 
obtained by caesarian section were examined.  At 30 mg/kg, the body 
weight of females decreased during gestation, and there was a 
slight decrease in the number of live young and a slight reduction 
in fetal weight.  Racemic phenothrin had no apparent teratogenic 
effect, as shown by a lack of gross internal or external somatic 
abnormalities and by normal fetal skeletal development following 
prenatal exposure. 

    Pregnant New Zealand White rabbits (15 per group) were orally 
administered d-phenothrin by intubation (0, 10, 100, or 1000 mg/kg 
body weight per day) on days 6 to 18 of gestation, and were 
sacrificed on day 29 or 30.  Following caesarian section, 50% of 
the pups were maintained for 24 h to evaluate survival.  No 
abnormalities were observed among the does (body weight, food 
consumption, clinical observations, and necropsy) or foetuses 
(implantation sites, corpora lutea, resorption sites, weight, 
condition, and viability).  Data on foetal survival and from 
internal and external examinations for abnormalities showed not 
significant effects from administrating d-phenothrin during 
gestation (Rutter, 1974). 

    In studies by Nakamoto et al.  (1973), d-phenothrin was orally 
administered to pregnant ICR mice (17 or 18 per group) at dose 
levels of 0, 30, 300, or 3000 mg/kg body weight on days 7 to 12 of 
gestation (not covering the whole period of organogenesis).  The 
dams were sacrificed on day 18 of gestation and the pups were 
obtained by caesarian section.  Other mice (7 per group) were given 
d-phenothrin at dose levels of 0, 300, or 3000 mg/kg to evaluate 
postnatal effect.  These mice were allowed to deliver naturally and 
the pups were kept for 29 days.  At these levels, d-phenothrin 
showed no adverse effects, as indicated by maternal growth, fetal 
mortality and external and internal examination of fetuses for 
teratogenic or embryotoxic effects. 

7.4.2.  Reproduction studies

    In a standard 3-generation (2 litters per generation) 
reproduction study, groups of rats (8 male and 16 female Charles 
River albino rats per group) were fed racemic phenothrin at dose 
levels of 0, 200, 600, or 2000 mg/kg diet.  Various reproduction 
indices (i.e.  mating index, fecundity index, male fertility index, 
female fertility index, and incidence of parturition) were 
measured.  The adult rats showed no significant mortality or 
complications during the study, and the reproductive parameters 
revealed no significant dose-related adverse effects attributable 
to phenothrin.  Gross and microscopic findings indicated no adverse 
effect resulting from dietary phenothrin.  It was concluded that 
phenothrin had no effect on reproduction (Takatsuka et al., 1980). 

    In a study by Tesh et al.  (1978), d-phenothrin was fed to 
Charles River CD rats (30 of each sex per group) at dose levels of 
0, 300, 1000, or 3000 mg/kg diet throughout two successive 
generations and up to the maturation of a third generation.  At 300 
and 1000 mg/kg, there was no adverse effect upon mortality, somatic 

growth, development, or reproductive performance.  At 3000 mg/kg, 
mortality, body weight, and reproductive performance showed no 
significant response to treatment, and selected F2 animals reared 
to maturity were in all respects comparable with control rats.  
However, F0 and F1 females and selected F2B male and female 
weanlings showed a slight but consistent increase in the relative 
liver weight.  The NOEL in this study was 1000 mg/kg diet. 

7.5.  Neurotoxicity

    Sprague Dawley rats exposed to d-phenothrin by inhalation at 
concentratons of up to 3760 mg/m3 for 4 h showed no toxic signs as 
a result of exposure.  Histopathologically, there were no compound 
related alterations in the sciatic nerve (Kohda et al., 1977). 

    When d-phenothrin was given to Sprague Dawley rats orally for 5 
consecutive days (5 g/kg body weight per day), one out of ten 
female rats died after four doses and signs of poisoning 
(piloerections and urinary incontinence) were noted in several of 
the animals.  However, these signs disappeared rapidly at the end 
of the treatment and there were no other signs of poisoning such as 
leg weakness or ataxia.  All animals were sacrificed 3 days after 
the final dose, and histopathologically examination of the sciatic 
nerve revealed minute changes in axon and myelin, characterized by 
very slight axonal swelling, axonal disintegration, and/or 
demyelination.  Since there were similar changes in the control 
animals, it was suggested that they were not due to the d-
phenothrin.  It was considered that the oral administration of very 
high doses of d-phenothrin does not lead to the neurotoxic effects 
observed with several other pyrethroid esters (Okuno et al., 1978). 

7.6.  Miscellaneous Effects

    No d-phenothrin-attributable pharmacological effects were 
detected in various tests (e.g., spontaneous movement of isolated 
guinea-pig ileum, contraction of the rat phrenic nerve diaphragm 
preparation, cardiopulmonary physiology of anaesthetized cats, 
coordination, and spontaneous movement of mice, and rectal 
temperature of rats) at doses of 100-300 µg/ml  in vitro, 3 mg/kg 
intravenous, or 100-300 mg/kg intraperitoneal.  A tentative arousal 
response was recorded in the electroencephalogram of cats given d-
phenothrin (4 mg/kg) intraperitoneally, as is commonly observed in 
animals given synthetic pyrethroids (Hara et al., 1974). 

7.7.  Mechanisms of Toxicity - Mode of Action

    Some synthetic pyrethroids given intravenously to rats cause 
either tremor (T-syndrome) or choreoathetosis with salivation (CS-
syndrome) (Verschoyl & Aldridge, 1980).  However, d-phenothrin 
(>600 mg/kg body weight) injected intravenously into the lateral 
tail vein caused neither T-syndrome nor CS-syndrome, due to its 
very low acute toxicity.  From a study involving intracerebral 
dosing with [1R, cis]- or [1R, trans]-phenothrin in mice, both 
compounds were classified as Type I pyrethroids based on the 
occurrence of tremors (Lawrence & Casida, 1982) and on 
neurophysiological studies in cockroach cercal sensory nerves 
(Gammon et al., 1981). 
 
8.  EFFECTS ON HUMANS

    Although d-phenothrin has been used for more than 10 years, no 
toxic effects and no cases of poisoning have been reported. 

8.1.  Clinical Studies

    In a study by Hashimoto et al.  (1980), d-phenothrin (talc 
powder formulation with Span 80 as a stabilizer) was applied to the 
head hair and pudenda hair of eight male human volunteers (three 
times at intervals of 3 days) at a dose of 32 mg/man per 
administration (0.44 to 0.67 mg/kg body weight per day).  d-
Phenothrin powder was washed off 1 h after application.  There were 
no significant abnormalities due to d-phenothrin in terms of dermal 
irritation, clinical signs, or blood biochemical and haematological 
parameters.  The blood levels of d-phenothrin were below the 
detection limit of 0.006 mg/kg. 


9.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) has 
discussed and evaluated d-phenothrin at its meetings in 1979, 1980, 
1984, and 1988 (FAO/WHO, 1980, 1981, 1985a, 1988b). 

    Since 1988, an acceptable daily intake (ADI) of 0-0.07 mg/kg 
body weight has been established. 

    In the WHO Recommended Classification of Pesticides by Hazard, 
technical phenothrin is classified as unlikely to present an acute 
hazard in normal use (WHO, 1988). 


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APPENDIX

    On the basis of electrophysiological studies with peripheral 
nerve preparations of frogs ( Xenopus laevis; Rana temporaria, and 
 Rana Escuelenta) it is possible to distinguish between 2 classes of 
pyrethroid insecticides: (Type I and Type II).  A similar 
distinction between these two 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 pronouced 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 organs 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 the "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, 1980).  
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 milliseconds 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, 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-dependant depression of the 
nervous impulse, brought about by a progressive depolarization 
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, persumably 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. 

    The 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 the [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-
butylbicyclophosphorothionate [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,alpha]-
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 benzo-
diazepine 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-
insecticidal 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 depressoin 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 vunerable 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, CONCLUSIONS ET RECOMMANDATIONS

1.  Résumé et évaluation

1.1 Identité, propriétés physiques et chimiques, et méthodes 
d'analyse

    La phénothrine racémique a été synthétisée pour la première 
fois en 1969.  Du point de vue chimique, il s'agit de l'ester de 
l'acide diméthyl-2,2 (diméthyl-2,2 vinyl)-3 cyclopropanecarboxylique 
et de l'alcool phénoxy-3 benzylique (PBalc).  Il se présente sous 
la forme d'un mélange de quatre stéréoisomères : [1R,trans], 
[1R,cis], [1S,trans], [1S,cis].  La d-phénothrine est un mélange 
d'une partie d'isomère [1R,cis] pour quatre parties d'isomère 
[1R,trans], et elle est à l'heure actuelle le seul produit 
technique sur le marché.  C'est l'isomère [1R,trans] qui est 
l'insecticide le plus actif; vient ensuite l'isomère [1R,cis]. 

    La d-phénothrine de qualité technique se présente sous la forme 
d'un liquide jaune pâle à brun jaune et son degré de pureté est de 
92,5 à 94,5%.  Sa densité est de 1,058-1,061 à 25°C et sa tension 
de vapeur de 0,16 mPa à 20°C.  Elle est difficilement soluble dans 
l'eau (2 mg par litre à 25°C) mais soluble dans les solvants 
organiques tels que l'acétone, le xylène et l'hexane. Elle est 
assez stable à l'air mais instable à la lumière, encore que sa 
photodégradation ne soit pas aussi rapide que celle des pyréthrines 
naturelles. Elle est instable en milieu alcalin. 

    Le dosage des résidus peut s'effectuer par chromatographie en 
phase liquide à haute performance avec détecteur ultra-violet, la 
concentration minimale décelable étant de 0,05 mg par kg.  Pour 
l'analyse du produit technique on utilise la chromatographie en 
phase gazeuse avec détection par ionisation de flamme. 

1.2 Production et usage

    La d-phénothrine est utilisée depuis 1977.  On estime que l'on 
utilise chaque année 70 à 80 tonnes de d-phénothrine dans le monde, 
essentiellement pour détruire les insectes incommodants dans les 
habitations, lutter contre les vecteurs de maladies et protéger les 
céréales ensilées; le produit est utilisé seul ou en association 
avec d'autres insecticides ou synergisants.  Il est présenté sous 
forme d'huiles pour aérosols, de poudres ou de concentrés 
émulsionnables. La d-phénothrine est également utilisée pour 
détruire les poux de l'homme, auquel cas elle est présentée sous 
forme de poudre, de shampooing ou de lotion. 

1.3 Exposition humaine

    Les aérosols classiques à usage domestique ne devraient pas 
conduire à des concentrations atmosphériques de d-phénothrine 
supérieures à 0,5 mg/m3.  Dans le blé ensilé, on peut trouver des 
résidus allant jusqu'à 4 mg/kg, mais ces teneurs tombent à 0,8 
mg/kg dans la farine après mouture, et à 0,6 mg/kg après 
panification. 

    Pour détruire les poux, on applique la d-phénothrine sur la 
chevelure, par exemple en trois doses de 32 mg tous les trois 
jours. Il n'existe aucune donnée sur l'exposition professionnelle à 
la d-phénothrine. 

    L'exposition de la population dans son ensemble devrait être 
très faible, mais on manque de données précises sur ce point. 

1.4 Destinée dans l'environnement

    La phénothrine se dégrade facilement, sa demi-vie étant 
inférieure à un jour sur les végétaux et autres surfaces.  La d-
phénothrine ou ses produits de dégradation ne migrent que très peu 
vers les zones non traitées des végétaux.  On a constaté que des 
haricots ne captaient que dans une faible mesure les prouits 
radiomarqués provenant de sols traités par de la phénothrine 
marquée au carbone-14.  Après traitement des sols avec de la 
[1R, trans ]- ou de la [1R, cis]-phénothrine à raison de 1 mg/kg, on 
a constaté que les deux isomères se décomposaient rapidement, la 
demi-vie initiale étant de un à deux jours, mais que, en cas 
d'inondation, la dégradation était considérablement ralentie, la 
demi-vie initiale étant de deux à quatre semaines pour l'isomère 
trans et de un à deux mois pour l'isomère cis.  On a observé que 
les isomères trans ou cis de la phénothrine se déplaçaient 
relativement peu (environ 2%) à travers des colonnes de terre, 
lorsque le lessivage commençait immédiatement ou deux semaines 
après le traitement. 

    En général, la dégradation qui se produit dans l'environnement 
conduit à des produits moins toxiques. 

1.5 Cinétique et métabolisme

    Après avoir reçu une dose unique ou des doses répétées de 
phénothrine radiomarquée par voie orale ou percutanée, des rats ont 
rapidement et presque complètement excrété la fraction marquée dans 
leurs urines et leurs déjections en trois à sept jours. Les 
principales voies métaboliques des isomères cis et trans chez le 
rat consistent en une rupture de la liaison ester et l'oxydation en 
position 4 du reste alcool ou du groupement isobutényle du reste 
acide.  Les métabolites résultant du clivage de l'ester (qui sont 
excrétées essentiellement dans les urines) constituent les 
principaux produits de dégradation de l'isomère trans alors que les 
métabolites restant sous forme d'ester (excrétées essentiellement 
dans les déjections) proviennent pour la plupart de l'isomère cis. 

1.6 Effets sur les êtres vivant dans leur milieu naturel

    La phénothrine a été expérimentée sur quelques groupes 
d'organismes non visés et dans chaque groupe sur quelques espèces 
seulement.  Chez les poissons, la CL50 à 96 heures de la 
phénothrine racémique et des stéréoisomères (1R) va de 17 à 200 
microgrammes par litre.  Une étude, portant sur des invertébrés 
aquatiques, a montré que chez  Daphnia pulex la CL50 à 3 heures 
était de 25 à 50 mg/litre pour tous les isomères et la phénothrine 
racémique. 

    Une seule et unique étude au cours de laquelle de la 
phénothrine a été appliquée à des étangs n'a révélé aucun effet sur 
les arthropodes aquatiques. 

    La toxicité pour les oiseaux est faible, avec une DL50 aiguë 
par voie orale supérieure à 2500 mg/kg de poids corporel chez le 
colin de Virginie et une CL50 par voie alimentaire supérieure à 
5000 mg/kg de nourriture chez ce volatile et chez le colvert. 

    Etant donné que la phénothrine se dégrade rapidement à la 
lumière solaire et qu'on l'utilise principalement pour traiter des 
céréales ensilées, l'exposition environnementale est 
vraisemblablement très faible.  Dans ces conditions, des effets sur 
l'environnement sont tout-à-fait improbables. 

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

    La toxicité aiguë de la d-phénothrine est extrêmement faible, 
la DL50 étant supérieure à 5000 mg/kg de poids corporel chez le rat 
et la souris (par voie orale, sous-cutanée, dermique et 
intrapéritonéale) et la CL50 inhalatoire supérieure à 3760 mg/m3 
chez le rat. Le syndrome d'intoxication se caractérise par une 
hyperexcitabilité, une prostration, des tremblements, de l'ataxie 
et une paralysie. Sur la base de ces symptômes et d'après les 
résultats des études électrophysiologiques sur les nerfs sensoriels 
des cerques de la blatte, la phénothrine est classée parmi les 
pyréthroides du type I. 

    Exposés à de la d-phénothrine par inhalation à des 
concentrations allant jusqu'à 210 mg/m3, quatre heures par jour 
pendant quatre semaines, ou par voie orale cinq jours de suite à 
raison de 5000 mg/kg de poids corporel, des rats n'ont présenté 
aucun effet toxicologique indésirable. 

    Plusieurs études d'alimentation ont été effectuées sur des rats 
et des souris recevant de la d-phénothrine ou de la phénothrine 
racémique à des doses allant de 200 à 10 000 mg par kg de 
nourriture; la période d'exposition allait de six mois à deux ans. 
Ces études ont permis d'établir une dose sans effet observable 
allant de 300 à 1000 mg par kg de nourriture, ce qui correspond à 
peu près à 40-160 mg/kg de poids corporel et par jour. Chez des 
chiens à qui l'on avait administré de la d-phénothrine à des doses 
de 100 à 3000 mg/kg de nourriture avec des périodes d'exposition de 
26 à 52 semaines, deux études ont permis d'obtenir une dose sans 
effet observable de 300 mg par kg de nourriture, soit 7 à 8 mg/kg 
de poids corporel et par jour. 

    Divers systèmes permettant d'étudier  in vivo et  in vitro les 
mutations géniques, les lésions et les réparations de l'ADN ainsi 
que les effets chromosomiques, ont permis de constater que la d-
phénothrine n'avait pas d'effet mutagène. 

    Des études de deux ans ont également montré que la d-
phénothrine n'était pas cancérogène pour le rat ni la souris à des 
doses allant jusqu'à 3000 mg par kg de nourriture.  Aucune 

tératogénicité ni embryotoxicité n'a été observée chez des foetus 
de lapins et de souris dont les mères avaient reçu de la d-
phénotrine à des doses allant jusqu'à 1000 et 3000 mg par kg de 
poids corporel, respectivement. Lors d'une étude de reproduction 
chez le rat, portant sur deux générations, on a établi que la dose 
sans effet observable était de 1000 mg par kg de nourriture. 

    Des rats exposés par inhalation à des doses très élevées de d-
phénothrine (jusqu'à 3760 mg/m3) pendant quatre heures ou, 
quotidiennement, par voie orale, à une dose de 5000 mg par kg de 
poids corporel, cinq jours durant, n'ont présenté aucune 
dégénérescence myélinique ni désagrégation de l'axone au niveau du 
nerf sciatique. 

1.8 Effets sur les êtres humains

    La d-phénothrine est utilisée depuis plus de 10 ans sans que 
l'on ait signalé d'intoxication humaine. 

    Rien n'indique que cette substance puisse avoir des effets 
nocifs sur l'homme pour peu qu'elle soit utilisée conformément aux 
recommandations. 

2.  Conclusions

2.1 Population générale

    L'exposition de la population dans son ensemble à la d-
phénothrine est vraisemblablement très faible et il n'y a 
probablement aucun risque à cet égard si le produit est utilisé 
conformément aux recommandations. 

2.2 Exposition professionnelle

    Si elle est utilisée de manière convenable, moyennant un 
certain nombre de mesures d'hygiène et de sécurité, la d-
phénothrine ne devrait pas présenter de risque pour les personnes 
qui lui sont exposées de par leur profession. 

2.3.  Environnement

    Du fait qu'elle se dégrade rapidement à la lumière solaire et 
qu'elle est principalement utilisée pour traiter les céréales 
ensilées, l'exposition environnementale à la phénothrine est 
vraisemblablement très faible. Dans ces conditions tout effet sur 
l'environnement est extrêmement improbable. 

3.  Recommandations

    Les niveaux d'exposition résultant d'une utilisation conforme 
aux recommandations sont censés être extrêmement faibles, toutefois 
on pourrait envisager de confirmer cette hypothèse en étendant la 
surveillance à la d-phénothrine. 



    See Also:
       Toxicological Abbreviations
       Phenothrin, d- (HSG 32, 1989)
       Phenothrin, d- (PDS)
       Phenothrin, d- (Pesticide residues in food: 1988 evaluations Part II Toxicology)