INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 142
ALPHA - CYPERMETHRIN
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
First draft prepared by Dr E.A.H. van
Heemstra-Lequin and Dr G.T. van Esch,
Netherlands
World Health Orgnization
Geneva, 1992
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WHO Library Cataloguing in Publication Data
Alpha-cypermethrin.
(Environmental health criteria ; 142)
1.Environmental exposure 2.Pyrethrins - adverse effects
3.Pyrethrins - toxicity I.Series
ISBN 92 4 157142 X (NLM Classification: WA 240)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA-CYPERMETHRIN
INTRODUCTION
1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS
1.1. Summary and evaluation
1.1.1. Identity, use, environmental fate and
environmental levels
1.1.2. Kinetics and metabolism
1.1.3. Effects on laboratory mammals and
in vitro test systems
1.1.4. Effects on humans
1.1.5. Effects on other organisms in the
laboratory and field
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, AND ANALYTICAL
METHODS
2.1. Identity
2.1.1. Primary constituent
2.1.2. Technical product
2.2. Physical and chemical properties
2.3. Formulations
2.4. Conversion factors
2.5. Analytical methods
2.5.1. Sampling
2.5.1.1 Air
2.5.1.2 Surface-wipe
2.5.2. Methods for determination
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels and processes
3.2.2. Use
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Air
4.1.2. Water
4.1.3. Soil
4.2. Biotransformation
4.2.1. Biodegradation
4.2.2. Bioaccumulation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Soil
5.2. Food
5.2.1. Crops
5.2.2. Fish
5.2.3. Milk
5.3. Human exposure
6. KINETICS AND METABOLISM
6.1. Absorption, elimination, retention and turnover
6.1.1. Rats
6.1.2. Domestic animals
6.1.3. Humans
6.2. Metabolic transformation
6.3. In vitro metabolic transformation
6.4. Plants
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Oral (technical product)
7.1.2. Oral (formulations)
7.1.3. Dermal
7.1.4. Inhalation
7.1.5. Other routes
7.2. Short-term exposure
7.2.1. Oral
7.2.1.1 Rat
7.2.1.2 Dog
7.3. Skin and eye irritation; sensitization
7.3.1. Skin irritation
7.3.2. Eye irritation
7.3.3. Sensitization
7.4. Long-term and carcinogenicity studies
7.5. Reproduction, embryotoxicity and teratogenicity
7.6. Mutagenicity and related end-points
7.6.1. Mutation
7.6.2. Chromosomal effects
7.6.3. DNA damage
7.6.4. Conclusion
7.7. Special studies
7.7.1. Skin sensation
7.7.2. Neurotoxicity
7.7.3. Immunosuppressive action
7.8. Mechanism of toxicity - mode of action
8. EFFECTS ON HUMANS
8.1. General population exposure
8.2. Occupational exposure
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.1.1. Algae
9.1.2. Bacteria
9.2. Aquatic organisms
9.2.1. Invertebrates
9.2.1.1 Laboratory studies
9.2.1.2 Field studies
9.2.2. Fish
9.2.2.1 Laboratory studies
9.2.2.2 Small scale field or outdoor tank
studies
9.3. Terrestrial organisms
9.3.1. Earthworms
9.3.2. Invertebrates - field studies
9.3.3. Honey-bees
9.3.3.1 Laboratory studies
9.3.3.2 Field studies
9.3.4. Leaf-cutting bees
9.3.5. Birds
10. COMPARISON BETWEEN ALPHA-CYPERMETHRIN AND CYPERMETHRIN
10.1. Use and residue levels
10.2. Environmental impact
10.3. Mammalian toxicity
11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
APPENDIX I
RESUME ET EVALUATION; CONCLUSIONS ET RECOMMANDATIONS
RESUMEN Y EVALUACION; CONCLUSIONES Y RECOMENDACIONES
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA-CYPERMETHRIN
Members
Dr V. Benes, Department of Toxicology and Reference Laboratory,
Institute of Hygiene and Epidemiology, Prague, Czechoslovakia
Dr R. Drew, Key Centre for Toxicology, Department of Applied Biology,
Royal Melbourne Institute for Technology, Melbourne, Australia
(Chairman)
Dr S.K. Kashyap, National Institute of Occupational Health, Meghani
Nagar, Ahmedabad, India
Dr J.I. Kundiev, Research Institute of Labour, Hygiene and
Occupational Diseases, Ul. Saksaganskogo, Kiev, USSR
(Vice-Chairman)
Dr K. Mitsumori, Division of Pathology, Biological Safety Research
Center, National Institute of Hygienic Sciences, Setagaya-ku,
Tokyo, Japan
Dr R.F. Shore, Ecotoxicology and Pollution Section, Institute of
Terrestrial Ecology, Monks Wood Experimental Station, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom
Dr G.J. van Esch, Bilthoven, Netherlands (Joint Rapporteur)
Dr E.A.H. van Heemstra-Lequin, Laren, Netherlands (Joint Rapporteur)
Dr S. Wong, Bureau of Chemical Hazards, Environmental Health
Directorate, Department of National Health and Welfare, Tunney's
Pasture, Ottawa, Ontario, Canada
Observers
Dr W.H. Gross, Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany
Dr J.R. Kielhorn, Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany
Dr C.M. Melber, Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany
Dr D.E. Owen, Shell Internationale Petroleum Maatschappij BV, The
Hague, Netherlands
Secretariat
Dr R.F. Hertel, Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany
Dr K.W. Jager, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland (Secretary)
Mrs C. Partensky, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are kindly requested to communicate any
errors that may have occurred to the Director of the International
Programme on Chemical Safety, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda.
* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Palais des
Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
7985850).
* * *
The proprietary information contained in this monograph cannot
replace documentation for registration purposes, because the latter
has to be closely linked to the source, the manufacturing route, and
the purity/impurities of the substance to be registered. The data
should be used in accordance with paragraphs 82-84 and recommendations
paragraph 90 of the Second FAO Government Consultation (1982).
ENVIRONMENTAL HEALTH CRITERIA FOR ALPHA-CYPERMETHRIN
A WHO Task Group on Environmental Health Criteria for
Alpha-cypermethrin met at the Fraunhofer Institute of Toxicology and
Aerosol Research, Hanover, Germany, from 16 to 20 September 1990, and
was sponsored by the German Ministry of the Environment. Dr R.F.
Hertel welcomed the participants on behalf of the host institute. Dr
K.W. Jager, IPCS, welcomed the participants on behalf of Dr M.
Mercier, Director of the IPCS, and the three IPCS cooperating
organizations (UNEP/ILO/WHO). The Group reviewed and revised the
draft document and made an evaluation of the risks for human health
and the environment from exposure to alpha-cypermethrin
The first draft was prepared by Dr E.A.H. van Heemstra-Lequin and
Dr G.J. van Esch of the Netherlands. Dr van Esch prepared the second
draft, incorporating the comments received following circulation of
the first draft to the IPCS contact points for Environmental Health
Criteria monographs.
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.
The assistance of Shell in making available to the IPCS and the
Task Group its proprietary toxicological information on
alpha-cypermethrin is gratefully acknowledged. This allowed the Task
Group to make its evaluation on the basis of more complete data.
* * *
Partial financial support for the publication of this monograph
was kindly provided by the United States Department of Health and
Human Services through a contract from the National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina,
USA - a WHO Collaborating Centre for Environmental Health Effects.
ABBREVIATIONS
CPA cyclopropane carboxylic acid
EC emulsifiable concentrate
EEC European Economic Community
GC gas chromatography
MRL maximum residue level
MS mass spectrophotometry
NOEL no-observed-effect level
OECD Organisation for Economic Co-operation and Development
OSC oil-enhanced suspension concentrate
PBA phenoxybenzoic acid
SC suspension concentrate
ULV ultra-low volume
WP wettable powder
INTRODUCTION
Cypermethrin (alpha-cyano-3-phenoxybenzyl-3-(2,2-dichloro-vinyl)
-2,2-dimethylcyclopropanecarboxylate) is a racemic mixture of eight
isomers. These eight isomers consist of two groups, those with a cis
orientation across the cyclopropyl ring of the dichlorovinyl and ester
groups and those with a trans orientation.
Alpha-cypermethrin is a mixture of two of the four cis isomers
present to approximately 25% in cypermethrin, i.e. the (1R, cis)S and
the (1S, cis)R isomers. The structure of the eight isomers is
summarized in Fig. 1.
In this monograph the toxicological information specifically
related to alpha-cypermethrin is summarized and compared with the data
on cypermethrin. An evaluation of the full data on cypermethrin, which
is also relevant for alpha-cypermethrin, is given in Environmental
Health Criteria 82: Cypermethrin (WHO, 1989). The summary, evaluation,
conclusions and recommendations of that monograph are added here as
Appendix I.
1. SUMMARY AND EVALUATION; CONCLUSIONS AND RECOMMENDATIONS
1.1 Summary and evaluation
1.1.1 Identity, use, environmental fate and environmental levels
Alpha-cypermethrin contains more than 90% of the insecticidally
most active enantiomer pair of the four cis isomers of cypermethrin as
a racemic mixture.
It is a highly active pyrethroid insecticide, effective against
a wide range of pests encountered in agriculture and animal husbandry.
It is supplied as emulsifiable concentrate, ultra-low-volume
formulation, suspension concentrate and in mixtures with other
insecticides.
The technical product is a crystalline powder with good
solubility in acetone, cyclohexanone and xylene, but its solubility in
water is low. It is stable under acidic and neutral conditions but
hydrolyses at pH 12-13. It decomposes above 220 °C.
No information on levels of alpha-cypermethrin in air is
available.
In water, alpha-cypermethrin is likely to be degraded by
photochemical and biological processes. Surface and sub-surface water
in a pond oversprayed with 15 g/ha active ingredient contained 5% and
19% of the applied dose one day after spraying and 0.1% and 2% of the
applied dose seven days later. About 5% of the applied dose was
present in sediment 16 days after application.
Alpha-cypermethrin is likely to be absorbed strongly onto soil
particles. Residues in soil were below 0.1 mg/kg one year after
treatment with 0.5 kg active ingredient per ha.
The n-octanol/water partition coefficient of alpha-cypermethrin
is 1.4 x 105 (log Pow = 5.16).
The recommended application rates of alpha-cypermethrin are lower
than those of cypermethrin because the former is biologically more
active. As a result, residues on crops are low, and following the use
of recommended application rates the residues in crops are between
0.05 and 1 mg/kg. Residues in marine catfish treated at between 0.001
and 0.05% w/w active ingredient were 0.3-30 mg/kg one week after
storage and 0.22-4.0 mg/kg after 15 weeks of storage.
1.1.2 Kinetics and metabolism
Alpha-cypermethrin administered orally to rats is eliminated, in
the urine, as the sulfate conjugate of 3-(4-hydroxyphenoxy) benzoic
acid and, in the faeces, partly as unchanged compound. Approximately
90% of a single oral dose is eliminated from the body over a 4-day
period, 78% within the first day. Residues in tissues are low except
in fat tissue. The concentration in fat 3 days after a single oral
dose of 2 mg/kg was 0.4 mg/kg. Elimination from the fat is biphasic;
the half-life for the initial phase is 2.5 days and for the second
phase 17-26 days.
Alpha-cypermethrin is metabolized by cleavage of its ester bond.
In the rat, the phenoxybenzyl alcohol portion of the molecule is
hydroxylated and conjugated with sulfate; the cyclopropane carboxylic
acid portion is also conjugated (probably as a glucuronide) prior to
urinary excretion. Studies with liver microsomes from rats, rabbits
and man have demonstrated that esteric hydrolysis and oxidative
pathways can occur in all three species but esteric hydrolysis is the
more prominent pathway for liver preparations from rabbit and man.
In humans, 43% of an oral dose (0.25-0.75 mg) was excreted within
24 h in the urine as free or conjugated cis-cyclopropane carboxylic
acid. The urinary excretion was not increased after five successive
daily doses.
High concentrations (up to 1156 mg/kg) of alpha-cypermethrin were
found in the wool of sheep 14 days after the application of a dip or
pour-on formulation. Low levels were found in subcutaneous fat (up to
0.04 mg/kg). After treating calves along the mid-dorsal line with 10
ml of a 1.6% formulation, no alpha-cypermethrin was found in muscle
and liver. The maximum concentration in perirenal fat over a 14-day
period was 0.26 mg/kg.
After treating lactating cows along the mid-dorsal line with up
to 0.2 g active ingredient, alpha-cypermethrin residues of 0.003 to
0.005 mg/litre were found in the milk from 3 out of 15 treated
animals.
1.1.3 Effects on laboratory mammals and in vitro test systems
Alpha-cypermethrin has moderate to high acute oral toxicity to
rodents. The LD50 values in mice and rats are highly variable and
depend on the concentration of the compound and vehicle. For practical
purposes an LD50 value of 80 mg/kg body weight is considered
representative. However, some reported acute oral LD50 values are
higher. Acute oral exposure results in clinical signs associated with
central nervous system activity.
Single dermal applications of alpha-cypermethrin to mice and rats
at 100 and 500 mg/kg body weight, respectively, did not cause
mortality or signs of intoxication. Similarly, a 4-h inhalation
exposure of rats to an atmospheric concentration of 400 mg/m3 did
not result in mortality or clinical signs.
Technical alpha-cypermethrin has been reported to be minimally
irritating to rabbit skin. Some alpha-cypermethrin formulations cause
severe eye irritation. Technical alpha-cypermethrin is not a skin
sensitizer. In guinea-pigs, alpha-cypermethrin caused stimulation of
sensory nerve-endings in the skin.
Short-term exposure of rats to alpha-cypermethrin at
concentrations up to 200 mg/kg diet per day for 5 weeks or up to 180
mg/kg diet per day for 13 weeks did not cause toxic effects. At higher
dose levels, rats exhibited signs of intoxication associated with
pathology of the nervous system, decreased growth, or increased liver
and kidney weights. No clear haematological, clinical chemistry or
histopathological effects were evident.
In a 13-week oral dog study, the highest dose of 270 mg/kg diet
caused signs of intoxication, but all other parameters examined
(including haematology, clinical chemistry, urinalysis, organ weights,
gross pathology and histopathology) were unaffected. The
no-observed-effect level (NOEL) was 90 mg/kg diet (equivalent to 2.25
mg/kg body weight per day).
An oral study in rats demonstrated that alpha-cypermethrin
induces neurotoxicity due to histopathological alterations of the
tibial and sciatic nerves, axonal degeneration and increased
beta-galactosidase activity.
No data are available on long-term toxicity, reproductive
toxicity, teratogenicity or immunotoxicity.
From the available data on alpha-cypermethrin, it can be
concluded that this compound is non-mutagenic in tests with
Salmonella typhimurium, Escherichia coli and Saccharomyces
cerevisiae, and in vivo and in vitro tests with rat liver cells
for the induction of chromosome aberration and production of DNA
single-strand damage. No increase in chromosomal aberrations was seen
in rat bone marrow cells.
No data are available on the carcinogenicity of alpha-
cypermethrin.
1.1.4 Effects on humans
Exposure of the general population to alpha-cypermethrin is
negligible, provided its use follows good agricultural practice.
Occupational dermal exposure in operators during mixing/loading,
during spraying and washing of the equipment was found to be up to
2.94 mg, 0.61 mg and 0.73 mg, respectively.
In a study of exposure to alpha-cypermethrin during formulation,
exposure levels were assessed by personal and static monitoring of
atmospheric concentrations and measurement of urinary
alpha-cypermethrin metabolites. The group mean personal exposure
levels on the two days while formulating technical concentrates were
2.8 and 4.9 mg/m3, whereas the group mean personal exposure to
technical material on day 3 was 54.1 mg/m3. No metabolites could be
detected in urine (limit of detection, 0.02 mg/litre). During
formulation, skin sensations were reported but these were only mild.
No poisoning incidents have been reported.
1.1.5 Effects on other organisms in the laboratory and field
The 48 and 96-h EC50 (growth) value for the freshwater alga
Selenastrum capricornutum is above 100 µg/litre.
Alpha-cypermethrin is highly toxic to aquatic invertebrates. The
24- and 48-h EC50 (immobilization) values for Daphnia magna are
1.0 and 0.3 µg/litre, respectively, and the 24-h LC50 value for
Gammarus pulex is 0.05 µg/litre. Alpha-cypermethrin is highly toxic
to a number of aquatic arthropod taxa, but is of lower toxicity to
molluscs. The short-term toxicity of the compound can be reduced by
formulation of the product as an oil-enhanced suspension. Although
spray drift may result in toxic effects on aquatic invertebrates, the
rapid loss of alpha-cypermethrin from the water gives potential for
recovery.
Alpha-cypermethrin is highly toxic to fish. The 96-h LC50
values range between 0.7 and 350 µg/litre depending upon the
formulation. Emulsifiable concentrate formulations are much more toxic
than suspension concentrate, wettable powder and micro-encapsulated
formulations. The hazard of alpha-cypermethrin to aquatic
invertebrates and fish lies in its acute toxicity. There is no
evidence for the occurrence of cumulative effects as a result of
long-term exposure.
No data are available concerning the effects of alpha-
cypermethrin on soil microbes. Sewage bacteria were not affected by a
concentration of 3 mg/litre in a closed system.
The toxicity of alpha-cypermethrin to certain Carabid beetles and
neuropteran larvae is relatively low, and there is limited hazard to
pre-adult stages of parasitoid Hymenoptera. Small-plot and large-scale
field studies have demonstrated a low hazard of alpha-cypermethrin to
Carabid and Staphylinid beetles but a relatively high hazard to
Linyphiid spiders. The effects on populations were limited to a single
growing season. Furthermore, alpha-cypermethrin has a low hazard to
Syrphid larvae but has a significant effect on Coccinellids. However,
the rapid dissipation of the residues on foliage gives the potential
for these animals to recolonize rapidly.
Field application of alpha-cypermethrin had no adverse effects on
the relative abundance of entomophages within the arthropod
communities. Its use in small grain cereals would not be associated
with pest "resurgence" or the development of secondary pest
infestations.
In laboratory tests, the toxicity of alpha-cypermethrin to
earthworms is low. No mortality was recorded after 14 days for worms
exposed to up to 100 mg/kg of artificial soil.
In laboratory acute toxicity tests, alpha-cypermethrin was found
to be highly toxic to bees. Oral administration of an emulsifiable
concentrate formulation gave a 24-h LD50 of 0.13 µg/bee, whereas the
corresponding value for topical administration was 0.03 µg/bee
(technical product) or 0.11 µg/bee (EC). The high toxicity of
alpha-cypermethrin to bees did not manifest itself in field trials,
probably as a result of the short-lived repellent effect of
alpha-cypermethrin which causes a decline in bee foraging behaviour
and, thus, in exposure.
No data for the toxicity of alpha-cypermethrin to birds are
available.
1.2 Conclusions
1.2.1 General population
When applied according to good agricultural practice, exposure of
the general population to alpha-cypermethrin is low and is unlikely to
present a hazard.
1.2.2 Occupational exposure
With good work practices, hygiene measures, and safety
precautions, the use of alpha-cypermethrin is unlikely to present a
hazard to those occupationally exposed to it. The occurrence of
"facial sensations" is an indication of exposure. Under these
circumstances work practices should be reviewed.
1.2.3 Environment
With recommended application rates, it is unlikely that
alpha-cypermethrin will attain levels of environmental significance.
It is highly toxic to aquatic arthropods, fish and honey-bees under
laboratory conditions. Significant toxic effects on non-target
invertebrates and fish are only likely to occur in cases of spillage,
overspraying and misuse.
1.3 Recommendations
* Contamination of surface waters with alpha-cypermethrin should be
avoided.
* Alpha-cypermethrin binds strongly to particles. Further
ecotoxicological studies on the effects of alpha-cypermethrin on
sediment-dwelling organisms should be carried out, since this
subject seems to have received little attention.
* The gastrointestinal absorption of alpha-cypermethrin should be
investigated under various conditions.
* The fate of dermally applied alpha-cypermethrin should be
investigated.
* Further information on the long-term toxicity/carcinogenicity and
immunotoxicity of alpha-cypermethrin should be obtained.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity
2.1.1 Primary constituent
Chemical structure: racemic mixture of the two stereoisomers
indicated by boxes in Fig. 1
Empirical formula: C22H19NO3Cl2
Relative molecular
mass: 416.3
Chemical name:
(IUPAC) a racemate comprising (S)-alpha-cyano-3-
phenoxybenzyl (1R,3R)-3-(2,2-dichloro-
vinyl)-2,2-dimethylcyclopropanecarboxy-late
and (R)-alpha-cyano-3-phenoxybenzyl
(1S,3S)-3-(2,2-dichlorovinyl)-2,2-dimethyl-
cyclopropanecarboxylate; a racemate
comprising (S)-alpha-cyano-3-phenoxybenzyl
(1R)- cis-3(2,2-dichloro-vinyl)-2,2-
dimethylcyclopropanecarboxylate and (R)-
alpha-cyano-3-phenoxybenzyl (1S)- cis-3-
(2,2-dichlorovinyl)-2,2-dimethylcyclopro-
panecarboxylate
(Chemical [1alpha(S*),3alpha}-(±)-cyano(3-phenoxy-
Abstracts) phenyl)methyl 3-(2,2-dichloroethenyl)-2,2-
dimethylcyclopropanecarboxylate (9CI)
(From: Worthing & Hance, 1991)
Common name: alpha-cypermethrin (alphamethrin and
alfoxylate are non-official names)
Code numbers: WL 85 871; OMS 3004
CAS registry
number: [67375-30-8] correct stereochemistry;
[52315-07-8] (formerly [69865-74-0],
[86752-99-0], [86753-92-6] cypermethrin (no
stereochemistry stated) were sometimes used
in Chemical Abstracts)
2.1.2 Technical product
Common trade
names: Fastac, Concord, Fendona, Renegade
Purity: technical grade: > 90% pure (m/m)
Impurities: no data.
2.2 Physical and chemical properties
Alpha-cypermethrin is a racemic mixture of the two stereo-isomers
(1:1) indicated by boxes in Fig. 1 and is a crystalline powder. Some
physical and chemical properties of alpha-cypermethrin are given in
Table 1.
Table 1. Physical and chemical properties of alpha-cypermethrin (pure
enantiomeric pair; purity > 99%)
Boiling point 200 °C at 9.3 N/m2
Melting point 80.5 °C
Vapour pressure (20 °C) 170 nPa (1.7 x 107 N/m2)
Density 1.12 g/cm3 at 20 °C
1.28 g/cm3 at 22 °C
Solubility (25 °C) 0.005-0.01 mg/litre water; 620 g/litre
acetone; 515 g/litre cyclohexanone; 7 g/kg
hexane; 351 g/litre xylene
Stability It is stable under acidic or neutral
conditions (pH 3-7) but hydrolyses in
strongly alkaline media (pH 12-13). It
decomposes above 220 °C. Field data indicate
that in practice it is stable to air and
light.
Partition coefficient
n-octanol/water log Pow 5.16 (Pow = 1.4 x 105)
From: Langner (1980); Shell (1983a); Worthing & Hance (1991).
The water solubility of alpha-cypermethrin (98.0%), calculated as
the sum of the cis-1 and the cis-2 isomer (ratio 2.6:97.4)
concentrations, at 20 °C in 0.01 M buffers at pH values of
approximately 4 to 9, ranges from 4.59 to 7.87 µg/litre, as measured
by the OECD and EEC microcolumn techniques. In distilled water alone
the solubility is slightly less, i.e. 2.06 µg/litre. The solubility is
not strongly dependent on pH values within the range of 4 to 9. It is
likely that ionic strength differences account for differences in
solubility between values in pure water and in the buffer solutions
(Baldwin, 1990).
2.3 Formulations
The following formulations exist:
* "Fastac", EC (20-100 g/litre), WP (50 g/kg), SC (15-250
g/litre), ULV (6 to 15 g/litre);
* "Fendona" and "Renegade", EC (50 or 100 g/litre), SC (250
g/litre), WP (50 g/kg).
Combination with other active ingredients also exist, e.g.,
"Azofas" (alpha-cypermethrin and monocrotophos) and combinations of
alpha-cypermethrin with methomyl or Fenobucarb (Worthing & Hance,
1991).
2.4 Conversion factors
1 ppm = 17.02 mg/m3
1 mg/m3 = 0.059 ppm
2.5 Analytical methods
2.5.1 Sampling
2.5.1.1 Air
Samples are collected by drawing a measured volume of air through
a 37-mm diameter silver membrane filter with a glass fibre pre-filter.
They are analysed for total pyrethroid content ( cis- and
trans-cypermethrin isomers) by gas chromatography with electron
capture detection (ECD). The limit of determination is 0.01 µg/filter
(see Table 2) (Armitage, 1984).
2.5.1.2 Surface-wipe
Surface-wipe samples are collected using a filter paper wetted
with diethyl ether. These samples are analysed for total pyrethroid
content ( cis- and trans-cypermethrin isomers) by gas
chromatography with flame ionization detection (FID). The limit of
determination is 0.03 mg/filter (see Table 2) (Armitage, 1984).
2.5.2 Methods for determination
A method for the determination of alpha-cypermethrin in technical
material and formulated products, excluding suspension concentrates,
was described by Shell (1987a). This method is also used to determine
the ratio of the enantiomer pairs cis 1 to cis 2.
The alpha-cypermethrin content is determined by means of
high-performance liquid chromatography (HPLC), using a column packed
with Zorbax SIL, together with ultraviolet detection at 230 nm
(Shell, 1987a).
Methods have been described for the determination of
alpha-cypermethrin in water, soil, crops, and animal tissues and
fluids (see Table 2).
Table 2. Analytical methods for alpha-cypermethrin in air, soil, water and biological mediaa
Sample Extraction Clean-up Detection and Recovery Limit of References
quantification determination
Air 20% ethyl acetate column chromatography gas chromatography with - 0.01 µg/filter Armitage (1984)
in hexane chromosorb W.HP. electron capture detection
Surface 20% ethyl acetate column chromatography gas chromatography with - 30 µg/filter Armitage (1984)
wipe in hexane chromosorb W.HP. flame ionization detection
Soil anhydrous sodium liquid-solid packed column gas 95-100%b 10 µg/kg Shell (1990b)
sulfate with chromatography chromatography, electron capture
acetone/hexane using Florisil detection; confirmation by
capillary GC and packed column
GC-MS
Water solvent partition Florisil disposable capillary gas-liquid 80-100%c 0.01 µg/litre Shell (1990a)
with hexane cartridge chromatography, electron-capture
detection; confirmation by GC-MS
Crops anhydrous sodium partition between packed column gas 90-100%b 10 µg/kg Shell (1989a)
sulfate with hexane and water/ chromatography, electron capture
acetone/hexane acetonitrile; liquid- detection; confirmation by
solid chromatography capillary GC and packed
using Florisil column GC-MS
Animal acetone/hexane partition with gas-liquid chromatography, 80-100%d 10 µg/kg Shell (1988a)
tissues mixture acetonitrile or electron capture detection;
hexane-acetonitrile; confirmation by GC-MS
liquid-solid
chromatography on
Florisil
Milk diethyl ether/ cyano Bond Elut gas-liquid chromatography, 90-100%e 1 µg/litre Shell (1988b)
hexane; Extrelut cartridge electron capture detection;
extraction column confirmation by GC-MS
Table 2 (continued)
Sample Extraction Clean-up Detection and Recovery Limit of References
quantification determination
Blood acetone partition with hexane packed column gas - 10 µg/litre Shell (1986)
(rat) (washed with water); chromatography, electron capture
dried with sodium detection; confirmation by
sulfate; liquid-solid capillary GC and GC-MS
chromatography on
Florisil
a Details of the analytical methods are available from Shell International Chemical Company, London. These methods differentiate
between alpha-cypermethrin and the other isomers.
b Over the concentration range 0.05-0.5 mg/kg
c Over the concentration range 0.05-0.5 µg/litre
d Concentrations 0.1-0.2 mg/kg
e Over the concentration range 0.005-0.02 mg/litre
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Alpha-cypermethrin does not occur in nature.
3.2 Anthropogenic sources
3.2.1 Production levels and processes
Alpha-cypermethrin is manufactured from cis-2,2,dimethyl-3-
(2",2"-dichlorovinyl)-cyclopropane carboxylate ( cis-DVO), 3-phenoxy
benzaldehyde (POAL) and sodium cyanide.
After removal of the solvent, the cis-cypermethrin is
epimerized into alpha-cypermethrin. Solid alpha-cypermethrin crystals
separate and are filtered, washed and dried under vacuum before
drumming-off1.
No data are available on production levels.
3.2.2 Use
Alpha-cypermethrin has been available commercially since late
1983. It is a potent insecticide effective against a wide range of
pests, particularly Lepidoptera and Coleoptera in citrus, cotton,
forestry, fruit, rice, soybeans, tomatoes, vegetables, grapes and
other crops, at a concentration of 5-30 g active ingredient per ha.
Good control of plant-sucking Hemiptera can also be obtained if the
insecticide is applied before populations have become established. It
also controls soil-dwelling Lepidoptera.
Alpha-cypermethrin can be used in most crops for either curative
or preventive treatment. It can replace conventional insecticides in
short-interval spray programmes, or the longer residual performance
may be exploited to reduce the number of sprays per season. Either
option may be chosen since no reports of phytotoxicity have been
received even when sensitive crops have been involved in repeated
applications. It controls ectoparasites ( Boophilus microplus at a
concentration of 50 mg/litre), including strains resistant to
organophosphorus pesticides, as well as sheep lice and Melophagus
ovinus.
1 Manufacturing process of alpha-cypermethrin; Shell International
Chemical Company; letter dated 10 January 1989 (ref. CTMAR/4)
Rapid knockdown and residual control of biting flies in and
around animal housing have been obtained following direct spray
application to animals or structural surfaces. Furthermore,
alpha-cypermethrin controls Blattellidae, Culicidae, flies and other
nuisance or disease-carrying insects, at a level of 10-30 mg/m2,
with good persistence on most surfaces (Fisher et al., 1983; Worthing
& Hance, 1991).
Alpha-cypermethrin is available as an emulsifiable concentrate,
ultra-low-volume formulation and suspension concentrate (flowable
formulations). Mixtures with organophosphorus and carbamate
insecticides have also been developed. Details of formulations are
given in section 2.3.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
Data relevant to alpha-cypermethrin can be found in Environmental
Health Criteria 82: Cypermethrin (WHO, 1989).
4.1.1 Air
No information on the transport of alpha-cypermethrin in air is
available, but its volatility is very low.
4.1.2 Water
Alpha-cypermethrin as an emulsifiable concentrate (EC) was
sprayed from the air (15 g active ingredient/ha) to a field along one
side of which ran a freshwater ditch. The fate and biological effects
of spray drift in the ditch were monitored for 7 weeks after the
application (see sections 9.2.1.2 and 9.2.2.2). Deposition on the
surface of the ditch was around 5 g active ingredient/ha (30% of the
nominal application rate). Alpha-cypermethrin concentrations in the
sub-surface water were 0.6 µg/litre shortly after the application and
decreased to < 0.02 µg/litre within 2 to 4 days. No contamination of
the water was found 200 m beyond either end of the treated field
(Garforth & Woodbridge, 1984).
Two freshwater ponds were treated with an EC formulation of
alpha-cypermethrin in 1987. One pond was oversprayed with 15 g active
ingredient/ha, while the other was treated with the same amount of
alpha-cypermethrin but by direct incorporation into the water. A third
pond served as a control. One day after the treatment, 5% of the
applied substance was found in the surface film of the oversprayed
pond and 19% in the sub-surface water. Residue levels in both
compartments subsequently declined rapidly so that one week later only
0.1 and 2% were still present, respectively. In the pond that received
direct treatment, 37% of the applied alpha-cypermethrin was found in
the sub-surface water one day after treatment. The concentration
subsequently declined more rapidly than in the oversprayed pond so
that one week later only 2% was present. The concentration of alpha-
cypermethrin found in the sediment samples from both ponds 16 days
after treatment indicated that approximately 5% of the
alpha-cypermethrin applied was present at that time. Thereafter the
concentration decreased and was less than 3% in the sediment 33 days
after application. In a bioassay test, the water in both ponds was
found to be acutely toxic to Gammarus pulex for at least 4 days
after application. After a further 29 days, the water was no longer
acutely toxic. The sediment was not toxic to Gammarus pulex
(Pearson, 1990).
4.1.3 Soil
A trial in the United Kingdom (Reculver) investigated the decay
of alpha-cypermethrin in sandy-clay soil treated with a diluted EC
formulation at a dosage rate of 0.5 kg active ingredient per ha.
Samples of soil were taken from the 0-15 cm layer of each plot at
various intervals over a period of one year. Once a year a sample was
also taken from the 15-30 cm layer. The residue immediately after the
application was 0.07 mg/kg soil in the 0-15 cm layer, and within 2
weeks this had declined by 50%. The residues of alpha-cypermethrin in
samples from the 0-15 cm layer and 15-30 cm layer taken 40 weeks and
52 weeks after application were below the limit of determination, i.e.
0.01 mg/kg (Forbes & Knight, 1983).
After one year, a second application to the bare soil was made
and again a diluted EC formulation was applied at a dosage rate of 0.5
kg active ingredient/ha. Samples were taken at various intervals
during this second year. Residues of alpha-cypermethrin in the 0-15 cm
soil layer declined from 0.19 mg/kg immediately after treatment to
0.11 mg/kg after 2.1 weeks and < 0.01 mg/kg after 49 weeks. In
samples from the 15-30 cm layer no residues (< 0.01 mg/kg) were
detectable 23 and 49 weeks after application (Forbes & Burden, 1984).
In the third year of the trial, another application to the same plots
was made with the EC formulation at a dosage rate of 0.5 kg active
ingredient/ha. Residues of alpha-cypermethrin in the 0-15 cm layer
declined from 0.20 mg/kg immediately after treatment to 0.08 mg/kg
after 18 weeks and 0.01 mg/kg after 52 weeks. Residues were not
detectable in the 15-30 cm layer sampled after 32 and 52 weeks. Over
the three years of the trial there was no indication of a build-up of
alpha-cypermethrin residues in the surface soil layer or any evidence
to suggest leaching of the compound into sub-surface soil layers
(Forbes & Wales, 1985a).
A further trial was carried out in the United Kingdom (Coates) to
study the decay of alpha-cypermethrin applied to a peat type soil as
a diluted EC formulation at a dosage rate of 0.5 kg active
ingredient/ha. As in the Reculver study, residues were determined in
the 0-15 cm layer at various intervals and in the 15-30 cm layer 32
weeks after application. At the beginning of the second and third
year, one application was made as at the beginning of the first year.
The residue in the 0-15 cm layer immediately after the first
application was 0.65 mg/kg declining to 0.36 mg/kg within 2 weeks and
to 0.30 mg/kg after 8 weeks. After 16 weeks, the residue was 0.05
mg/kg or less. In the 15-30 cm layer, no residues were found after 32
weeks (Forbes & Mackay, 1983). Immediately after the second
application, the residue in the 0-15 cm layer was 0.65 mg/kg; after
two weeks the level was 0.36 mg/kg and declined to 0.07 mg/kg by 48
weeks after application. No residues were found in the 15-30 cm layer
(Forbes & Wales, 1985b).
In the third year, a residue level of 0.55 mg/kg was found in the
0-15 cm layer immediately after treatment, declining to 0.20 mg/kg
within 8 weeks and to 0.09 mg/kg after 50 weeks. In the 15-30 cm
layer, residues of 0.01 and 0.03 mg/kg were found after 40 and 50
weeks respectively. In this 3-year trial there was no indication of a
build-up of alpha-cypermethrin residues in the surface soil layers, or
any evidence to suggest significant leaching into sub-surface soil
layers (Coveney & Forbes, 1986).
4.2 Biotransformation
4.2.1 Biodegradation
Alpha-cypermethrin has been tested for "ready biodegradability"
in two tests: a) the closed bottle and modified Sturm test, and b)
growth inhibition in a Pseudomonas fluorescens growth test. In these
tests, mineralization of alpha-cypermethrin was not detected. It was
not degraded in these two tests and hence is not considered to be
readily biodegradable (Stone & Watkinson, 1983).
Maloney et al. (1988) studied the microbial transformation of
technical alpha-cypermethrin (96.3% pure) in aerobic batch enrichment
cultures. These microbial enrichments, which contained Pseudomonas
fluorescens (SM-1), Achromobacter sp. and Bacillus cereus, were
able to transform alpha-cypermethrin with a half-life of 7 to 14 days
at a concentration of 50 mg/litre in the presence of 0.05% Tween 80
(v/v). One of the major transformation products was 3-phenoxybenzoic
acid, which was further transformed to 4-hydroxy-3-phenoxybenzoic
acid.
McMinn (1983a) investigated the degradation under aerobic
conditions of alpha-cypermethrin, labelled with 14C in the benzyl
ring, in two types of soil, i.e. sandy clay loam and clay loam. The
soils were treated with 1 mg of the labelled material and gently
agitated to distribute the insecticide. Soils samples were removed for
analysis 2.5, 6, 10, 20 and 42 weeks after treatment. The initial
degradation half-lives were 27 and 13 weeks for sandy clay loam and
clay loam, respectively. However, after 42 weeks the percentage of
applied radioactivity remaining unchanged was 28.9 and 21.6%,
respectively, for the two soils. The formation of total organo-soluble
products after 42 weeks was 32.2 and 24.3% for sandy clay loam and
clay loam, respectively. Total extractable and total non-extractable
radioactivity for sandy clay loam was 32.5 and 18.0% and for clay loam
25.3 and 32.0%, respectively. Metabolites were found in both cases at
levels of 2 to 3%. Unchanged alpha-cypermethrin was present, and the
degradation products had similar chromatographic mobilities to the
previously identified major products of cypermethrin (McMinn, 1983b).
4.2.2 Bioaccumulation
The n-octanol/water partition coefficient of alpha-cypermethrin
is 1.4 x 105 (log Pow = 5.16), compared to a value for
cypermethrin of 2 x 106 (log Pow = 6.3). The actual
bioaccumulation in fish found experimentally for cypermethrin is lower
than might be expected from the partition coefficient. This should
also apply to alpha-cypermethrin, because the pathway and rate of
metabolism are comparable with those of cypermethrin (Shell, 1983b;
WHO, 1989).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
Information relevant to alpha-cypermethrin was given in
Environmental Health Criteria 82: Cypermethrin (WHO, 1989).
5.1.1 Soil
In a study on the deposition of alpha-cypermethrin on the orchard
floor following commercial application to apple trees,
alpha-cypermethrin (100 g EC/litre) was applied at a nominal dose rate
of 26 g/ha using a tractor-driven "Kinkelder" mist-blower. Following
normal practice, spray runs were made between each row of trees and
then around the perimeter of the orchard. One hour after spraying,
pesticide deposits were collected in foil-lined trays positioned on
the orchard floor and analysed. Deposition was found to be variable,
ranging from 10 to 76% of the nominal application rate (Hillaby,
1988).
5.2 Food
5.2.1 Crops
Residue data on cypermethrin have been evaluated by the Joint
FAO/WHO Meeting on Pesticide Residues (FAO/WHO, l980, 1982).
Alpha-cypermethrin application rates to crops range from 5 to 30
g active ingredient/ha. Residue data have been obtained from
supervised trials in many countries. The residue concentrations of
alpha-cypermethrin derived from recommended application rates vary
from 0.05 to 1.0 mg/kg product (Shell, 1984).
A study was carried out to determine whether there was
significant isomerization of alpha-cypermethrin after treatment of
certain crops. Grapes were treated with 10% EC applied at a rate of 18
g active ingredient/ha, and apples and lettuce with 10% EC at 15 g
active ingredient/ha. Samples were taken 3 and 7 days (grapes), 7 days
(apples) and 10 days (lettuce) after treatment. Residues of 0.17 and
0.09 mg/kg were found on grapes, 0.05 mg/kg on apples and 0.17 mg/kg
on lettuce, but none of the samples showed any significant isomer
conversion of alpha-cypermethrin (Bosio, 1982).
In 1983 two trials were carried out in Canada in which
alpha-cypermethrin was applied with a knapsack sprayer to maize
(sweetcorn). Five applications with diluted 10% EC formulations at a
dosage rate of 20 g active ingredient/ha were made, samples were
harvested 7 days after the last application, and the husks, grain and
cobs were analysed separately. Alpha-cypermethrin residues of 0.38
mg/kg were found in the husks, but no residues (limit of
determination, 0.01 mg/kg) were found in the grain or the cobs (Forbes
& Cole, 1986).
5.2.2 Fish
To reduce blow-fly infestations during the curing of marine
catfish, the fish were dipped in EC solutions (15 g/litre) at various
concentrations (0.001-0.05% active ingredient w/v) between the salting
and drying stages of the curing process. Dipping after the salting
stage in a 0.001% solution of the EC proved to be effective. The
levels of residues in treated fish were dependent on the season (wet
and dry season), storage time, concentration of the dip solution and
the size of the fish. In the wet season, the range was from 0.9 to 2.8
mg/kg, whereas in the dry season it was from 0.26 to 30.0 after one
week of storage and 0.22 to 4.0 mg/kg (wet weight of homogenized fish)
after 15 weeks of storage (Forbes, 1985).
5.2.3 Milk
A trial was carried out in 1987 in the United Kingdom where
lactating cows were treated with pour-on formulations of
alpha-cypermethrin. Two formulations were used containing either 10
g/litre or 15 g/litre (see also section 6.1.2). Either 10 ml or 20 ml
of formulation containing 0.1, 0.15 or 0.2 g active ingredient was
applied along the mid-dorsal line of five cows for each treatment.
Milk samples were taken 1, 2, 3, 4, 7, 14 and 21 days after treatment
for the analysis of alpha-cypermethrin. The residues of
alpha-cypermethrin in milk were at a maximum from 2 to 4 days after
treatment. Generally, residues were highest in the 0.2 g group, the
maximum concentration being 0.005 mg/litre (in two samples only). By
day 21 the residues in the milk from all treated cows were < 0.002
mg/litre (the limit of determination) (Sherren, 1988b).
5.3 Human exposure
In a study to quantify the maximum potential dermal exposure of
operators to crop protection products, 13 exposure pads were mounted
on each of three operators and chemicals adhering to gloves were
analysed. The operation involved three distinct stages: mixing product
and loading the tractor; spraying; and washing-up the equipment and
tractor after the exercise. The total dermal exposure for the three
operators was: mixing/loading, 2.45, 0.57 and 2.94 mg/operation;
spraying, 0.38, 0.61 and 0.40 mg/h; and washing-up, 0.12, 0.29 and
0.73 mg/operation (Senior & Lavers, 1990a,b).
6. KINETICS AND METABOLISM
Both cis and trans isomers of cypermethrin are metabolized via
cleavage of the ester bond to phenoxybenzoic acid (PBA) and
cyclopropane carboxylic acid (CPA). The PBA moiety is mainly excreted
as a conjugate. The type of conjugate differs in a number of animal
species. PBA is further metabolized to a hydroxy derivative and
conjugated as a glucuronate or sulfate. The CPA moiety is mainly
excreted as a glucuronate. Consistent with the lipophilic nature of
cypermethrin, the highest tissue concentrations are found in body fat,
skin, liver, kidneys, adrenals and ovaries. The elimination from fat
is approximately 3 to 4 times slower for the cis isomers than for the
trans isomers (WHO, 1989).
6.1 Absorption, elimination, retention and turnover
6.1.1 Rats
Alpha-cypermethrin labelled in the 14C-benzyl moiety has been
studied in Wistar rats at a concentration of approximately 2 mg/kg
body weight in corn oil. The compound, which was given by stomach
tube, was rapidly broken down and the radioactivity was mainly
eliminated in the urine as the sulfate conjugate of
3-(4-hydroxyphenoxy)benzoic acid (40-45% of the dose). Approximately
35% of the dose was eliminated in the faeces, 20% of which was
unchanged alpha-cypermethrin. The proportion of the dose excreted in
the urine and faeces within the first 24 h was approximately 78% and
within 4 days was 90%. Residues in major organs and tissues of rats 4
days after a single oral dose were in general low: liver, 0.03 and
0.05; skin, 0.04 and 0.02; adrenals, 0.03 and 0.06; and kidneys, 0.02
and 0.02 (values are expressed as mg equivalent of
alpha-cypermethrin/kg tissue for females and males, respectively).
However, in body fat, higher residues were found (0.22 and 0.42
mg/kg). The release from skin and fat was biphasic in nature. The
half-life of elimination of radioactivity from fat was approximately
2.5 days for the initial phase and 17-26 days for the slower phase
(the half-life of elimination from fat for cis-cypermethrin was 18.9
days). The half-life values for skin were 2 days for the initial phase
and 40 days for the slower phase. The radioactivity in liver and
kidneys was eliminated apparently by a monophasic process. More than
95% of the residue in fat was present as unchanged alpha-cypermethrin
(Hutson, 1982; Logan, 1983; Hutson & Logan, 1986).
6.1.2 Domestic animals
In a study by Francis & Gill (1991), a formulation containing a
mixture of flufenoxuron and alpha-cypermethrin was applied to groups
of three sheep. The formulation was applied once, either as a dip
diluted at 1:1000 to give a solution of 80 mg flufenoxuron per litre
and 60 mg alpha-cypermethrin/litre or as a pour-on solution applied
directly to the backs of the sheep giving a dose of 0.15 g active
ingredient flufenoxuron and 0.2 g alpha-cypermethrin per sheep. The
sheep were killed at 3, 7 and 14 days after application and samples of
subcutaneous fat, fleece and sheep skin were analysed. The residues of
alpha-cypermethrin in fat ranged from < 0.01 to 0.04 mg/kg and in
skin from 0.02 to 1.4 mg/kg over the three sampling periods, and they
were lower for pour-on formulations than for the dip. Highest tissue
residues were found in wool (sampled from the back); these were (for
the 3, 7 and 14 day sampling periods, respectively) 730, 1020 and 360
mg/kg for dip application and 360, 440 and 360 mg/kg for pour-on
application. Wool sampled from the side of sheep treated with pour-on
formulation were 10 to 30 times lower than wool sampled from the back
region; with the dip solution, however, wool from the side region
contained higher residues than that from the back. Pour-on application
gave lower residues than after a dip.
A trial was carried out during 1987 in the United Kingdom in
which Friesian/Hereford calves (in total 17 female animals) were
treated with an alpha-cypermethrin pour-on formulation. Ten ml of a 16
g/litre formulation was applied to calves along the middorsal line
from shoulder to tail. At 3, 7 and 14 days following treatment,
animals were sacrificed for analysis of tissues, i.e. perirenal and
subcutaneous fat, muscle, kidneys and liver. No residues were detected
in muscle and liver samples at any time (limit of determination, 0.01
mg/kg). In the kidneys a maximum of 0.03 mg/kg was found on day 7 but
by day 14 the residues had decreased to 0.01 mg/kg or less. The fat
tissues contained maximum levels on day 7, i.e. mean concentrations of
0.26 mg/kg (perirenal fat) and 0.08 mg/kg (subcutaneous fat). By day
14 these concentrations had decreased by about two and a half times
(Sherren, 1988a) (see also section 5.2.3).
6.1.3 Humans
Six volunteers (two per dose level) received a single oral dose
of 0.25, 0.5 or 0.75 mg alpha-cypermethrin and, after a period of 2-3
weeks, five successive daily doses of 0.25, 0.5 or 0.75 mg to study
the urinary excretion and bioaccumulation of alpha-cypermethrin. A
parallel study with cypermethrin itself was carried out for comparison
purposes. The metabolism and rate of excretion of a single oral dose
of alpha-cypermethrin were similar to those of cypermethrin itself.
The rate of excretion was dose-related, approximately 43% of the dose
of alpha-cypermethrin being excreted in the urine as free or
conjugated cis-cyclopropane carboxylic acid ( cis-CPA) during the
first 24 h. Urinary excretion did not increase with repeated oral
dosing; an average of 49% of alpha-cypermethrin was excreted in the
urine as free or conjugated cis-CPA within 24 h (van Sittert et al.,
1985; Eadsforth et al., 1988).
6.2 Metabolic transformation
In a study on Wistar rats using alpha-cypermethrin,
14C-labelled in the benzyl moiety, (see section 6.1.1) no evidence
was found for any racemization of the chiral centres of
alpha-cypermethrin in the residues in intestines, faeces or fat. The
major urinary metabolite was the sulfate conjugate of
3-(4-hydroxyphenoxy)benzoic acid, and smaller amounts of
3-phenoxybenzoic acid (II) and 3-(4-hydroxyphenoxy)benzoic acid (III)
were identified. In the faeces, 75% of the radioactivity in the
extract was unchanged alpha-cypermethrin; minor metabolites included
a dihydroxy metabolite (V), 3-(4-hydroxyphenoxy)benzoic acid (III),
3-phenoxybenzoic acid (II) and the 4-hydroxyphenoxy metabolite (IV).
In the adipose tissue, the 14C label was mainly associated with
unchanged alpha-cypermethrin, but a lipophilic metabolite of either
alpha-cypermethrin or 3-phenoxybenzoic acid, probably a mixture of
3-phenoxybenzoyl diacylglycerols, was also present (Hutson, 1982;
Logan, 1983; Hutson & Logan, 1986) (see Fig. 2).
6.3 In vitro metabolic transformation
Creedy & Logan (1984) studied the in vitro metabolism of
cypermethrin and alpha-cypermethrin using liver microsomal
preparations from rats, rabbits and humans. In order to obtain
information on the relative importance of the oxidative and esteric
pathways of degradation of these compounds, incubations were carried
out both in the presence and absence of an NADPH-generating system.
Both cypermethrin and alpha-cypermethrin were broken down via esteric
and oxidative pathways by the liver preparations from the three
species. For rabbit and human liver microsomes, oxidation was a minor
metabolic route compared to esteric hydrolysis in the case of both
compounds. Human liver microsomes were able to carry out the esteric
hydrolysis of alpha-cypermethrin slightly faster than cypermethrin. In
the liver preparations of all three species, cyclopropane carboxylic
acid (mainly produced via the esteric pathway) was the main metabolite
for both compounds (to the extent of approximately 90-99%). Via the
oxidative route, mono-hydroxycypermethrins, dihydroxy-cypermethrin and
small amounts of hydroxycyclopropane carboxylic acid (rat only) were
also produced.
6.4 Plants
The metabolism of cypermethrin in plants is described in WHO
(1989).
The degradation of alpha-cypermethrin and cypermethrin in
cabbages grown to maturity outdoors has been studied. Eighteen days
after transplanting, the cabbages were treated three times with
14C-labelled alpha-cypermethrin or cypermethrin as an EC
formulation. Each treatment consisted of 1.8 mg equivalent with a
spray concentration of 36 g/litre. This treatment was repeated after
11 and 27 days. Each box of cabbages received a total application of
5.4 mg at a dose rate equivalent to 50 g active ingredient/ha. At
harvest (3 months later) the plants were separated into old and new
outer leaves, heart, stalk and roots. No major differences between the
two compounds in distribution of radioactivity throughout the plants
or in the metabolic profile were observed. The highest radioactive
residues were present in the old outer leaves (23% for
alpha-cypermethrin and 27% for cypermethrin), lower levels being found
in new outer leaves, stalk, roots and heart. Very low levels (< 0.05
mg/kg) of both compounds were found in the soil. The major radioactive
residue at harvest was shown to be the pesticide, which was either in
the unchanged form or had undergone cis/trans-isomerization,
presumably photochemically. The profiles of the organosoluble
metabolites were similar, and the major products of alpha-cypermethrin
had chromatographic mobility similar to previously identified products
of cypermethrin metabolism, such as 3-phenoxybenzoic acid and
3-phenoxybenzyl alcohol, partly hydroxylated and/or conjugated. These
compounds were found in minor quantities (McMinn, 1983a; WHO, 1989).
Appraisal
A wide range of studies in mice, rats, dogs, sheep, cows and
humans has shown that cypermethrin is rapidly absorbed, distributed
to a variety of organs and tissues, metabolized and rapidly excreted
from the body (WHO, 1989). There are no major differences in the
absorption, distribution, retention or excretion between the species.
Differences, where they do occur, are related to the rate rather than
the nature of the metabolites formed and the conjugation reactions.
Cypermethrin, both the cis and trans isomers, and
alpha-cypermethrin are primarily metabolized by cleavage of the ester
bond. The metabolites PBA and CPA are mainly excreted as conjugates.
The type of conjugate differs in a number of animal species dosed
with cypermethrin, but humans and rats have the same pathway. Minor
quantities of hydroxylated PBA (conjugated) may also be found. The
terminal half-life of elimination of alpha-cypermethrin from the fat
of rats is 17-26 days, compared to 18.9 days for cis-cypermethrin.
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Single exposure
7.1.1 Oral (technical product)
Alpha-cypermethrin is moderately to highly toxic and 3-4 times
more toxic than cypermethrin.
The clinical signs of toxicity observed in the various acute
toxicity studies on experimental animals with alpha-cypermethrin are
typical for a cyano-containing pyrethroid intoxication. They included
ataxia, abasia, gait abnormalities, choreoathetosis, "tip-toe" walk,
and increased salivation, lacrimation, piloerection, tremor and clonic
convulsions. The majority of the mortalities occurred within the first
3 h and surviving animals recovered within 7 days (Rose, 1982, 1983a).
In the study with alpha-cypermethrin administered in corn-oil
(Rose, 1983a), clonic convulsions, piloerection, salivation and
splayed hind-leg gait were found. The oral LD50 values for
alpha-cypermethrin are summarized in Table 3.
Table 3. Oral LD50 values for technical alpha-cypermethrin
Species Concentration and LD50 in mg/kg body Reference
(strain) vehicle weight (with 95%
confidence limits)
Mouse 5% in corn oil 35 (26-48) Rose (1982)
(CD) 40% in DMSO 762 (514-912) Rose (1982)
50% aqueous suspension 798 (568-1074) Rose (1982)
Rat 5% in corn oil 79 (63-98) Dewar (1981)
(Wistar) 40% in DMSO approximately 4000 Rose (1982)
50% aqueous suspension > 5000 Rose (1982)
Rat 10% in corn oil 40-80 Rose (1983a)
(Wistar) 20% in corn oil 368 (282-487) Rose (1983a)
Woollen et al. (1991) noted a higher degree of absorption of
cypermethrin when it was applied in corn oil. This could be the
explanation for the higher toxicity of alpha-cypermethrin administered
in corn oil.
7.1.2 Oral (formulations)
Formulations of alpha-cypermethrin have moderate acute oral
toxicity (Table 4). The clinical signs observed after oral
administration to rats are characteristic of cyano-containing
pyrethroid intoxication (see section 7.1.1.). The majority of the
mortalities occurred within 3 days of dosing. The degree of acute oral
toxicity of formulations containing mixtures with other active
ingredients depended on the toxicity of the latter ingredients.
7.1.3 Dermal
Alpha-cypermethrin has low dermal toxicity. No deaths or signs of
intoxication were observed in rats (Dewar, 1981; Shell, 1983a) and
mice (Rose, 1982; Shell, 1983a) receiving a single 24-h dermal
exposure of 500 mg/kg body weight (25% in DMSO) and 100 mg/kg body
weight (5% in corn oil), respectively.
The dermal LD50 values in rats of formulations of
alpha-cypermethrin and of alpha-cypermethrin mixed with another active
ingredient are summarized in Table 4. In all cases, the maximum dose
that could be applied was tested.
With the pour-on formulations, no clinical signs were observed.
Blood around the nose and eyes was the only sign seen in the case of
SC formulations. Clinical signs observed after the application of EC
or ULV formulations of alpha-cypermethrin included increased
lacrimation, chromodacryorrhoea and unkempt appearance, aggressiveness
and diarrhoea. The Fastac/BPMC formulation caused the same signs of
intoxication and also oedema at the application site. With the
Fastac/methomyl formulation, fasciculation, lethargy, salivation,
piloerection, hunched back, chromodacryorrhoea and cyanosis were
observed. Animals treated with Fastac/Azodrin formulation showed the
above-mentioned symptoms, and some additionally showed ataxia, abasia,
hypothermia, eye pallor and prostration/coma.
7.1.4 Inhalation
Groups of five male and five female albino Fischer-344 rats were
exposed for 4 h to a dust atmosphere containing 30% (m/m)
alpha-cypermethrin on silica powder at an average concentration of 1.3
g/m3 (equivalent to 0.4 g active ingredient/m3). The mass media
diameter of the dust particles was 4.2 µm (geometric standard
deviation 6.4). The animals were observed for 14 days after the
exposure but there were no signs of intoxication. Macroscopic
examination of the lungs did not reveal any effects. Thus, the acute
LC50 was > 1.3 g 30% silica powder dust/m3 or > 0.4 g active
ingredient/m3 (Blair, 1984).
Table 4. Oral and dermal LD50 values for formulated alpha-cypermethrin in rats (Fischer-344)
Formulationa LD50 in mg total formulation per kg Reference
body weight (with 95% confidence limits)
Oral Dermal
100 g/litre EC 101 (82-119) > 1800 Rose (1984d)
100 g/litre EC 136 (98-186) > 1800 Rose (1984e)
100 g/litre EC 174 (125-327) > 2000 Price (1985a)
30 g/litre EC 229 (178-292) > 2000 Rose (1984f)
30 g/litre EC 673 (597-753) > 2000 Rose (1985)
15 g/litre pour-on > 2000 > 2000 Price (1988)
10 g/litre pour-on > 2000 > 2000 Price (1988)
100 g/litre SC 1804 (1507-2168) > 2000 Price (1985b)
60 g/litre SC > 5000 > 2000 Gardner (1991)
15 g/litre SC > 5000 > 2000 Price (1986)
15 g/litre ULV 5838 (5130-6665) > 2000 Rose (1984c)
Mixtures with other active ingredients
Fastac/methomyl EC 58-97 (males) > 1900 Rose (1984h)
15/120 g/litre 73 (51-89) (females) > 1900
Fastac/BPMCb EC 310 (215-462) > 2000 Price (1987)
10/400 g/litre
Fastac/Azodrin EC 25 (18-34) > 2000 Gardner (1989)
20/400 g/litre
a EC = emulsifiable concentrate; SC = suspension concentrate; ULV = ultra-low volume
b BPMC = 2 sec-butylphenyl methylcarbamate (fenobucarb)
7.1.5 Other routes
The acute intraperitoneal LD50 for rats of a 10% solution of
alpha-cypermethrin in corn oil was 3.39 (3.03-3.83) ml/kg body weight,
or 339 mg active ingredient per kg body weight. The surviving animals
showed characteristic pyrethroid signs of intoxication, e.g., ataxia,
abasia, choreoathetosis, gait abnormalities, "tip-toe" walk and
salivation (Rose, 1984a).
7.2 Short-term exposure
7.2.1 Oral
7.2.1.1 Rat
Groups of Wistar rats (10 of each sex at each dose level and 20
of each sex as controls) were fed 0, 25, 100, 200, 400 or 800 mg
alpha-cypermethrin/kg diet (equivalent to 0, 1.25, 5, 10, 20 or 40
mg/kg body weight) for 5 weeks. At 400 and 800 mg/kg diet, signs of
intoxication, such as abnormal gait and hypersensitivity were
observed, and food intake and body weight were decreased in both sexes
compared with the control group. Changes in blood chemistry, e.g.,
decreases in protein and increases in urea levels, were observed in
both sexes of rats fed 800 mg/kg diet and in males fed 400 mg/kg. The
weights of livers and kidneys of both sexes of rats fed 800 mg/kg diet
and livers of male rats fed 400 mg/kg were increased. No
histopathological changes were observed except in the case of one
severely intoxicated male animal fed 800 mg/kg diet, which showed
sparse axonal degeneration in the sciatic nerve. No effects were seen
in the animals fed 200 mg/kg diet for five weeks (Pickering, 1982).
In a 13-week study, Wistar rats (30 males and 30 females per test
group, and a control group consisting of 60 males and 60 females),
which were initially 5 weeks old, were fed 0, 20, 60, 180 or 540 mg
alpha-cypermethrin/kg diet (equivalent to 0, 1, 3, 9 or 27 mg/kg body
weight). After six weeks of feeding, one third of the animals were
killed for interim haematological, clinical chemical and gross
post-mortem examination. The remaining animals were killed after 13
weeks. Signs of intoxication, such as abnormal gait with splayed hind
limbs, were found in 3 out of 20 males fed 540 mg/kg diet. Several
instances of transient skin sores and fur loss were observed
particularly in the rats fed 540 mg/kg. There was decreased growth,
which correlated with decreased food intake, in both sexes fed 540
mg/kg from the first week onwards. No clear effects on the
haematological and clinical chemical parameters were found. Organ
weights were comparable with those of the control animals. No
histopathological abnormalities were found except sparse axonal
degeneration in the sciatic nerve, without clinical signs of toxicity,
in two males fed 540 mg/kg. No axonopathy was observed in the three
animals with abnormal gait. There were marginal effects (decreased
growth during week one and from week 10 onwards) in the males fed 180
mg/kg diet. No effects were found in the 60-mg/kg group (Clark, 1982).
7.2.1.2 Dog
Beagle dogs (one male and one female) were fed alpha-cypermethrin
in the diet at the following concentrations: 200 mg/kg diet for 7
days, 400 mg/kg diet for 2 days, and 300 mg/kg diet for 7 days. With
200 mg/kg no signs of intoxication were observed, whereas dosing with
300 mg/kg or more caused weight loss, ataxia, subdued behaviour, head
nodding, food regurgitation, inflammation of gums and tongue, body
tremors and diminished response to stimuli. Haematological, clinical
chemical and gross pathological examination showed no effects
(Greenough & Goburdhun, 1984).
In a further study, Beagle dogs (one male and one female)
received 300 mg/kg diet for 3 days (male dog) or 4 days (female dog)
and 250 mg/kg diet for 7 days. Both animals showed the above-mentioned
signs of intoxication, the only difference being that when it was
being fed the 250-mg/kg diet the female animal showed these signs more
frequently than the male animal. There were no effects on haematology,
clinical chemical parameters, urinalysis, faecal occult blood test or
gross pathology (Greenough & Goburdhun, 1984).
In a study by Greenough et al. (1984), 36 pure bred Beagle dogs
(18 males and 18 females) received a diet containing
alpha-cypermethrin at 0, 30, 90 or 270 mg/kg diet for 13 weeks. The
group dosed at the highest concentration comprised six males and six
females while the other groups consisted of four males and four
females. All animals fed 270 mg/kg diet exhibited signs of
intoxication, such as whole body tremors, head nodding, "lip-licking",
subduedness, ataxia, agitation and a high-stepping gait. These signs
increased in both intensity and duration as the study progressed. Food
consumption, body weight gain, organ weights, ophthalmoscopy,
haematological and clinical chemical parameters, urinalysis, gross
pathology and microscopy of 18 organs and tissues of all test groups
showed no dose-related effects. In this study, the no-observed-effect
level was considered to be 90 mg/kg diet (equivalent to 2.25 mg/kg
body weight).
7.3 Skin and eye irritation; sensitization
7.3.1 Skin irritation
Undiluted technical alpha-cypermethrin was minimally irritating
when applied as a single occluded dose for 24 h to intact and abraded
rabbit skin (Dewar, 1981).
New Zealand white rabbits were used to study the primary skin
irritation of a number of alpha-cypermethrin formulations. The test
duration was 4 h, the observation period was 7-21 days, and the
formulations tested were 30 and 100 g/litre EC, 15 g/litre ULV, 10 and
15 g/litre pour-on formulation, 15 and 100 g/litre SC, and
Fastac/methomyl (15/120) EC. The EC formulations caused mild to
moderate skin irritation. Superficial necrosis was observed in one or
two animals treated with 100 g/litre EC, but there was no permanent
in-depth skin damage. The effects persisted for up to 7 days. The EC
formulations and the 100 g/litre SC formulation were classified as
mildly irritating. All other formulations tested were either
non-irritating or only slightly irritating (Rose, 1984c,d,e,f,h, 1985;
Price, 1985a,b, 1986, 1988).
7.3.2 Eye irritation
Undiluted formulations were tested for their eye irritancy
potential in groups of six rabbits using the Draize test. All the EC
formulations tested (30 or 100 g/litre) caused severe eye irritation,
including corneal opacity and damage to the iris (Rose, 1984d,e,f,
1985).
When an EC formulation (100 g/litre) and its components, both in
the undiluted form and at typical in-use dilutions (1 in 400 and 1 in
1333 aqueous dilution), were tested for eye irritancy potential, the
undiluted formulation was severely irritating, with or without
irrigation, while the undiluted blank formulations were mildly to
severely irritating. The diluted test formulations, with or without
alpha-cypermethrin or with emulsifier, were non-irritating. It was
concluded that the eye irritation resulted from the combined
formulation ingredients (especially the emulsifier) and that
alpha-cypermethrin per se gave only slight irritation, if any
(Dewar, 1981; Rose, 1984b). In-use dilutions (0.0075%) of another 100
g/litre EC formulation and its blank formulation were non-irritating
(Rose, 1984g).
Two pour-on formulations (10 and 15 g/litre) caused moderate and
slight conjunctival inflammation, respectively. The 10 g/litre
formulation was considered to be an eye irritant (Price, 1988). Two SC
formulations (15 and 100 g/litre) were mildly irritating, causing
slight conjunctival redness and chemosis (Price, 1985b, 1986). A 15
g/litre ULV formulation was mildly irritating to rabbit eyes and there
was a moderate initial pain response (Rose, 1984c). An EC formulation
containing Fastac/methomyl (15:120 g/litre) was a severe eye irritant.
The vascularization of the cornea and iritis were considered to be
irreversible (Rose, 1984h).
7.3.3 Sensitization
Technical alpha-cypermethrin was tested in the guinea-pig
maximization test of Magnusson and Kligman using groups of 10 male and
10 female guinea-pigs and a control group of 55 animals of each sex.
The following concentrations were used: intradermal injection, 0.05%
(v/v) in corn oil; topical application and challenge, 50% (m/m) in
vaseline. On the basis of the negative results it was concluded that
alpha-cypermethrin is not a skin sensitizer in guinea-pigs (Dewar,
1981).
An EC formulation (100 g/litre) and its corresponding blank were
tested, as a 50% solution in corn oil, in the Buehler guinea-pig
sensitization test. The topical challenge was carried out with a 30%
solution in corn oil. None of the animals showed positive responses at
24 or 48 h after the challenge (Rose, 1984g).
7.4 Long-term and carcinogenicity studies
No long-term or carcinogenicity studies have been conducted with
alpha-cypermethrin.
7.5 Reproduction, embryotoxicity and teratogenicity
Alpha-cypermethrin has not been tested for reproductive effects
or teratogenicity.
From the available reproduction and teratogenicity studies with
cypermethrin it is clear that no influence on reproduction performance
occurs at a level of 100 mg/kg diet, nor are there any teratogenic
effects even with dose levels high enough to cause maternal toxicity
(WHO, 1989). Furthermore, the no-observed-effect level of cypermethrin
for reproduction and teratogenicity is comparable with the
no-observed-effect levels based on other parameters of toxicity. In
consequence, there is no reason to believe that alpha-cypermethrin,
consisting of two cis isomers also present in cypermethrin, would
behave differently.
7.6 Mutagenicity and related end points
7.6.1 Mutation
The results of the various mutagenicity studies with
alpha-cypermethrin are summarized in Table 5.
Alpha-cypermethrin (in DMSO) at concentrations of 31.25, 62.5,
125, 250, 500, 1000, 2000 or 4000 µg/ml did not increase reverse gene
mutation (at the arg 4-17, trp 5-48 or hom 3-10 markers) in log- or
stationary-phase cultures or forward mutation (to cyclo-heximide
-resistance) in log-phase cultures of Saccharomyces cerevisiae XV
185-14C, either in the presence or absence of rat-liver S9 fraction.
Concentrations of 10 and 50 µg/ml 4-nitroquinoline- N-oxide and 1250
and 5000 µg/ml cyclophosphamide were used as positive controls
(Brooks, 1984).
Alpha-cypermethrin (in DMSO) at concentrations of 31.25, 62.5,
125, 250, 500, 1000, 2000 or 4000 µg/plate, both with and without
microsomal activation, did not increase reverse mutation rates in
Salmonella typhimurium TA98, TA100, TA1535, TA1537 and TA1538 or in
Escherichia coli WP2 and WP2 uvr A. Mitotic gene conversion was not
induced in liquid suspension cultures of log-phase cells of
Saccharomyces cerevisiae JD 1, dosed with solutions of
alpha-cypermethrin at concentrations of 10, 100, 500, 1000 or 5000
µg/ml, both in the presence or absence of a rat liver S9 fraction.
These studies were carried out in comparison with four positive
control compounds (Brooks, 1982).
7.6.2 Chromosomal effects
In a study by Clare & Wiggins (1984), groups of five male and
five female Wistar rats were administered a single oral dose of 2, 4
or 8 mg alpha-cypermethrin in 5% corn oil/kg body weight and killed 24
h after dosing. The control group received corn oil alone.
Cyclophosphamide was used as a positive control. Alpha-cypermethrin
caused no increase in the incidence of chromatid or chromosome
aberrations or polyploidy in bone marrow cells.
Alpha-cypermethrin in aqueous carboxymethylcellulose at
concentrations of up to 40 µg/ml did not increase the frequency of
chromatid gaps, chromatid breaks or total chromatid aberrations in rat
liver (RL4) cell cultures (Brooks, 1982).
7.6.3 DNA damage
Alpha-cypermethrin in DMSO (20%) was administered to Wistar rats
as a single oral dose of 40 mg/kg body weight. The exposure time was
6 h. Alpha-cypermethrin failed to produce any detectable DNA
single-strand damage using alkaline elution profiles of liver DNA.
Methylmethane sulfonate was used as a positive control and DMSO as the
solvent control (Wooder, 1982).
7.6.4 Conclusion
From the available data on alpha-cypermethrin, it can be
concluded that this compound is non-mutagenic in tests with
Salmonella typhimurium, Saccharomyces cerevisiae, and in vivo and
in vitro tests with rat liver cells for the induction of chromosome
aberration and production of DNA single-strand damage.
Table 5. Mutagenicity tests on microorganisms
Organism/strain Dose Type of test Metabolic Result Reference
activation
Salmonella typhimurium up to 4000 µg/plate plate with or negative Brooks (1982)
TA98, TA100, TA1535, without
TA1537, TA1538
Escherichia coli up to 4000 µg/plate plate with or negative Brooks (1982)
WP2, WP2 uvrA without
Saccharomyces cerevisiae up to 5000 µg/ml liquid suspension with or negative Brooks (1982)
JDI culture without
Saccharomyces cerevisiae up to 4000 µg/ml liquid suspension with or negative Brooks (1984)
XV 185-14C culture without
Rat liver cells (RL4) up to 40 µg/ml negative Brooks (1982)
(chromatid gaps, breaks or
aberrations)
Rat liver DNA one oral dose of negative Wooder (1982)
(DNA single strand damage) 40 mg/kg body weight
Rat bone marrow one oral dose of negative Clare & Wiggins
chromosome study up to 8 mg/kg body (1984)
weight
7.7 Special studies
7.7.1 Skin sensation
It is known that exposure to certain types of pyrethroids can
result in a transient skin sensation in humans (Le Quesne et al.,
1980).
Guinea-pigs received 0.1 ml of a 0.01, 0.1 or 1.0% solution of
alpha-cypermethrin in ethanol or a 1, 10 or 20% solution of
alpha-cypermethrin (w/v) in corn oil on the skin. Sensory stimulation
was quantified by counting the number of times each animal turned to
lick or bite its treated flank in preference to the non-treated flank.
Skin stimulation was observed during a 2-h period at all dose levels
except the lowest. In the groups of guinea-pigs treated with 10% and
20%, some animals exhibited an exaggerated hopping movement and a
repeated head shaking activity at the time of maximum skin stimulation
(40-60 min after treatment). This behaviour was not seen with the 1%
solution or more dilute ones (Hend, 1983).
7.7.2 Neurotoxicity
Large oral doses of alpha-cypermethrin and other synthetic
pyrethroids (WHO, 1989) have been shown to produce minor
histopathological lesions in the sciatic nerve of rats, described as
sparse axonopathy in peripheral nerves.
Rose (1983b) conducted a two-phase study. In the first phase, the
time-course for development and recovery from pyrethroid-induced nerve
lesions was investigated by measuring biochemical correlates of
neuropathological change (the enzymes beta-glucuronidase and
beta-galactosidase) in groups of Wistar rats (five of each sex per
group) at periods of 2-12 weeks after the start of dosing. The daily
doses of alpha-cypermethrin (96.6%), administered by stomach tube,
were 37.5 mg/kg body weight for the first 11 doses and 25.0 mg/kg body
weight for the subsequent 9 doses over a 4-week period (5 times/week).
DMSO was used as the solvent for 10 doses and then arachis oil. In
all, 21% of the animals died and more than 80% of the treated animals
showed clinical signs of intoxication. Maximum enzyme activities in
the sciatic posterior tibial nerves were found 5 weeks after the start
of the experiment and had returned to control values by 12 weeks. In
the trigeminal nerve and trigeminal ganglia, a slight but not
significant increase in enzyme activities was found.
In the second phase of the study, 10 male and 10 female Wistar
rats were given 20 oral doses of alpha-cypermethrin in DMSO (0, 10, 20
or 40 mg/kg body weight per day) over a period of 4 weeks (5
times/week). Only two animals died, one given 10 mg/kg and one given
20 mg/kg. In the 40-mg/kg group, 75% of the animals developed clinical
signs, whereas in the 20-mg/kg group only 25% of the animals showed
these clinical effects. In the 10-mg/kg group, the animals showed no
differences from the controls. No clear influence of
alpha-cypermethrin on growth was found. Five weeks after the initial
dose, which corresponded to the period of maximal enzyme changes,
biochemical changes (increases of up to 60%) indicative of a mild
axonal degeneration were found in both the distal and proximal
sections of the sciatic posterior tibial nerve in animals administered
40 mg/kg body weight. In the 20-mg/kg group, only a small (up to 20%)
increase in beta-galactosidase activity was found in the proximal
sections of the sciatic posterior nerve. The same trends were found in
the trigeminal nerve and ganglia. No changes were found in the
10-mg/kg group (Rose, 1983b).
7.7.3 Immunosuppressive action
No data on the immunosuppressive action of alpha-cypermethrin are
available.
7.8 Mechanism of toxicity - mode of action
The mechanism of toxicity and mode of action of cypermethrin (and
other pyrethroids) are extensively described in section 8.8 of the
Environmental Health Criteria 82: Cypermethrin (WHO, 1989). Recently
Vijverberg & van den Bercken (1990) and Aldridge (1990) summarized
current knowledge of the neurotoxicity and mode of action of the
different pyrethroids (see also Appendix 1).
Pyrethroids induce toxic signs that are characteristic of a
strong excitatory action on the nervous system. Toxic doses generally
cause hypersensitivity to sensory stimuli, and a number of compounds
may induce tingling sensations in the skin. Two distinct toxic
syndromes have been described in mammals. The T-syndrome is induced by
pyrethrins and non-cyano pyrethroids, and the CS-syndrome, induced by
cyano-pyrethroids such as cypermethrin and alpha-cypermethrin, is
characterized by choreoathetosis and salivation.
The available data 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 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 (for instance cypermethrin and alpha-cypermethrin) 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 (with no alpha-cyano
group) and the two insecticides cypermethrin and alpha-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 between the symptoms of poisoning
by alpha-cyano pyrethroids and those of the classical pyrethroids is
not necessarily due to an exclusive central site of action. It may be
related to the long-lasting repetitive activity in sense organs and
possibly in other parts of the nervous system, which, in a more
advance state of poisoning, may be accompanied by a
frequency-dependent depression of the nervous impulse.
Pyrethroids also cause pronounced repetitive activity and a
prolongation of the transient increase in sodium permeability of the
nerve membrane in insects and other invertebrates. Available
information indicates that the sodium channel in the nerve membrane is
also the most important target site of pyrethroids in the invertebrate
nervous system.
Because of the universal character of the processes underlying
nerve excitability, the action of pyrethroids should not be considered
to be 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 most vulnerable to the action of pyrethroids, the ultimate
lesion that causes death will depend on the animal species,
environmental conditions, and on the chemical structure and physical
characteristics of the pyrethroid molecule.
8. EFFECTS ON HUMANS
8.1 General population exposure
No data concerning the exposure of the general population to
alpha-cypermethrin are available.
8.2 Occupational exposure
A study of alpha-cypermethrin exposures was carried out during
formulation using both technical concentrate and technical material at
Durban, South Africa. The oil-damped solid, crystalline, dry technical
concentrate contained a minimum of 90% (m/m) alpha-cypermethrin.
Exposures were assessed by personal and static monitoring of
atmospheric alpha-cypermethrin concentrations, urinary
alpha-cypermethrin metabolite concentrations and by medical
examination. Four individuals were exposed during 3 days of operation.
The group mean personal exposures for the two days whilst formulating
technical concentrate were 2.8 and 4.9 µg/m3 and the group mean
personal exposure to technical material on day 3 was 54.1 µg/m3.
Urinary alpha-cypermethrin metabolites could not be identified (limit
of detection, 0.02 mg/litre). Formulation was successfully completed,
only minor skin sensations being reported by two of the
non-operational personnel, possibly resulting from particles of
alpha-cypermethrin settling directly on the skin, face and neck. Dust
concentrations were up to 30 times greater during handling the
technical material compared with oil-damped technical concentrate, and
local exhaust dust extraction reduced dust emission by a factor of up
to 17 (Western, 1984).
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
Appraisal
The acute toxicity of alpha-cypermethrin to Daphnia magna and
Gammarus pulex is similar to that of cypermethrin. However, in a
reproduction study with Daphnia magna, alpha-cypermethrin seemed to
be slightly more toxic than cypermethrin. Comparison of the results
of a reproduction study in Daphnia magna with the results of acute
tests shows that the hazard of alpha-cypermethrin lies in its acute
toxicity. There is no significant potential for cumulative effects
occurring as a result of long-term exposure to lower concentrations.
Alpha-cypermethrin is highly toxic to a number of aquatic
arthropod taxa but of low toxicity to molluscs. The short-term
toxicity of the compound can be reduced by formulating the product as
an OSC. Contamination through spray drift from commercial
applications will generally be low, and so the effects on susceptible
taxa will be limited. The rapid loss of alpha-cypermethrin from the
water gives the potential for complete recovery of affected
populations.
Laboratory studies show that values for the acute toxicity and
the toxicity to the early-life stages of fish are similar for
alpha-cypermethrin and cypermethrin. A comparison of the results from
both alpha-cypermethrin studies reveals that the hazard of the
compound results from its acute toxicity, and there is no significant
potential for additional effects occurring as a result of long-term
exposure to lower concentrations. Laboratory and field studies have
shown that the toxicity of alpha-cypermethrin to fish is greatly
influenced by the formulation, particulate formulations showing
significantly less toxicity than emulsifiable concentrates.
Field studies demonstrate that the high toxicity of
alpha-cypermethrin to fish observed in laboratory studies is not
realized under field conditions. Contamination of water bodies by
inadvertent overspraying or spray drift does not present a hazard to
fish.
9.1 Microorganisms
9.1.1 Algae
The acute toxicity of alpha-cypermethrin to a single-celled green
alga, Selenastrum capricornutum, at 24 °C has been determined. The
pesticide was dispersed using acetone, and the 2- to 4-day EC50 for
growth was above 100 µg/litre (Stephenson, 1982).
9.1.2 Bacteria
The effects of cypermethrin on microbial activity in the soil
have been investigated in a series of studies. Cypermethrin was
applied to sandy loam at concentrations of 2.5 and 250 mg/kg. No
effects on the rates of carbon dioxide evolution or oxygen uptake were
observed at the lower rate, but significant inhibition of carbon
dioxide evolution and a decrease in oxygen uptake were observed at the
higher rate of application. There were no effects at either
concentration on nitrogen fixation, ammonification, nitrification or
glucose utilization (WHO, 1989).
Sewage bacteria were unaffected by the presence of
alpha-cypermethrin (3 mg/litre) in a closed system test, while the
growth of Pseudomonas fluorescens was unaffected at 100 mg/litre
(Stone & Watkinson, 1983).
9.2 Aquatic organisms
9.2.1 Invertebrates
9.2.1.1 Laboratory studies
Acute toxicity studies with Daphnia magna (aged < 24 h) showed
that at 20 °C technical alpha-cypermethrin, dispersed in acetone under
static conditions (daily renewal), has effects at concentrations below
1 µg/litre. The 24-h and 48-h EC50 values (immobilization) were 1.1
and 0.3 µg/litre, respectively (Stephenson, 1982).
Water samples taken from field enclosures 24 h after treatment
with an EC formulation were analysed for alpha-cypermethrin and
bioassayed with Gammarus pulex. The 24-h LC50 value for this
organism was 0.05 µg/litre (Garforth, 1982a; Shires, 1982).
The effect of technical alpha-cypermethrin on survival, growth
and reproduction of Daphnia magna was studied over a period of 21
days by Garforth (1982b). The test solution was renewed daily and the
temperature ranged between 18.5 and 20.2 °C. The results are
summarized in Table 6.
Table 6. Effects of alpha-cypermethrin on the reproductive cycle of
Daphnia magnaa
Effect Nominal concentration (µg/litre)
LOEL NOEL
Survival of parent generation 0.3 0.1
Growth of parent generation 0.1 0.03
Production of young 0.1 0.03
a From: Garforth (1982b)
LOEL = Lowest-observed-effect level; NOEL = No-observed-effect
level
9.2.1.2 Field studies
Garforth (1982a) studied the effects of alpha-cypermethrin on a
range of aquatic invertebrates in metal enclosures, each containing
about 1 m3 water, placed in an outdoor experimental pond. A diluted
EC formulation was sprayed onto the water surface at concentrations of
1, 3, 10, 30 and 100 g active ingredient/ha, and samples were taken up
to 7 days after application. The concentration of alpha-cypermethrin
was around 50% of the nominal level 24 h after application and
decreased to 10 to 20% of the nominal level 7 days after application.
The lowest concentration was toxic to Asellidae. Thirteen families
of aquatic arthropods were tested; most were killed at 1 g/ha except
one species of Coenagriidae, which tolerated about 3 g/ha. Three
families of molluscs were tested and were found to be unaffected at
100 g/ha.
Studies to investigate the relative toxicity of two formulations
of alpha-cypermethrin (a 100-g/litre EC and a 100-g/litre oil-enhanced
suspension concentrate (OSC) with and without anti-evaporant agents)
to aquatic invertebrates have been carried out. Water samples were
taken from field enclosures treated with a range of doses (0.1-5 g/ha
for the EC and 0.1-10 g/ha for the two OSC formulations) and
bioassayed with Gammarus pulex. The 24-h LD50 values (in g
alpha-cypermethrin/ha equivalents) of water samples taken 24 h after
application were 0.9 for the EC, 6.3 for the OSC without
anti-evaporant, and 2.8 for the OSC plus anti-evaporant formulation.
Thus, one day after treatment, both OSC formulations were less toxic
to Gammarus pulex than the EC formulation. However, the EC
formulation lost its toxicity more rapidly than either of the OSC
formulations (see also section 4.1.2). The effects on other aquatic
invertebrate communities could not be accurately assessed, since the
results for macro-arthropods and zooplankton were inconclusive.
Coenagriidae, Chironomidae and zooplankton seemed to be relatively
tolerant. The residues in water and sediment, 22 days after treatment
with the EC at 2 g alpha-cypermethrin/ha or with both OSC formulations
at 5 g/ha, were < 0.004 µg/litre and < 0.01 mg/kg, respectively, for
all three formulations (Inglesfield, 1985b).
The hazard to aquatic invertebrates resulting from spray drift
from the aerial application of an EC (15 g alpha-cypermethrin/ha) has
been investigated by Garforth & Woodbridge (1984). Details of the
study are described in section 9.2.2.2. The sub-surface water
concentration was 0.6 µg alpha-cypermethrin/litre shortly after
application and decreased to < 0.02 µg/litre within 2 to 4 days. The
contamination initially caused a significant reduction in the
abundance of several groups of aquatic arthropods, including beetles,
chironomids, corixids, mites and zooplankton. However, within 4 to 7
weeks the affected fauna had completely recovered.
In a study by Pearson (1990), two freshwater ponds were treated
with alpha-cypermethrin as an emulsifiable concentrate in 1987. One
pond was oversprayed at 15 g active ingredient/ha, while the other was
treated with the same amount of alpha-cypermethrin but by direct
incorporation into the water (see section 4.1.2). Indigenous
populations of zooplankton nauplii and of copepods ( Cyclops spp.)
were significantly reduced in both ponds by the treatment but
recovered within 26-45 days. Other zooplankton were not plentiful but
appeared to be less severely affected in the oversprayed pond than in
the pond treated by incorporation. Populations of phantom midge larvae
( Chaoborus spp) were killed by both treatments. However, within 47
days after treatment, populations of young larvae had developed in the
oversprayed pond to almost pre-treatment numbers, and to a lesser
extent in the pond with direct incorporation.
9.2.2 Fish
9.2.2.1 Laboratory studies
The available acute 96-h LC50 values for two fish species are
summarized in Table 7.
The effects of the type of formulation on the acute toxicity to
fish are summarized in Table 8. Suspension concentrate, wettable
powder and micro-encapsulated formulations were 10 to 70 times less
acutely toxic to rainbow trout than the EC formulation (Shires,
1983b).
Table 7. Acute toxicity of technical alpha-cypermethrin in fish
Species Mean weight Vehicle Test system Temperature 96-h LC50 Reference
(g) (°C) (µg/litre) (95%
confidence limits)
Rainbow trout 3.3 dispersed via static water; 15 2.8 Stephenson (1982)
(Oncorhynchus mykiss) acetone 12 h renewal of (2.1-3.5)
test solutions
Fathead minnow 0.76 adsorbed onto continuous 23-25 0.93 Stephenson (1983)
(Pimephales promelas) pumice flow-through (0.78-1.2)
Table 8. Effect of type of formulation on the toxicity of alpha-cypermethrin to fish in laboratory studies
Species Weight Tempera- Formulation 96-h LC50 Reference
(g) ture (°C) (µg/litre)
Rainbow trout 0.8-2.5 15 100 g/litre EC 5.6 Shires (1983b)
(Oncorhynchus 250 g/litre SC 350
mykiss) 100 g/kg WP 120
50 g/kg WP 220
50 g/kg ME > 100
50 g/kg CD 65
Rainbow trout 0.11-0.25 15 15 g/litre OSC 10a Pearson (1986)
(Oncorhynchus 15 g/litre OSC 71
mykiss) 100 g/litre OSC 16a
100 g/litre OSC 56
Common carp 3.5-4 24-30 100 g/litre OSC 11 Stephenson
(Cyprinus carpio) 15 g/litre EC 0.8 (1986)
50 g/kg WP 60
Puntius 0.3-0.5 24-30 100 g/litre OSC 3.2 Stephenson
gonionotus 15 g/litre EC 0.7 (1986)
50 g/kg WP 22
a Denotes daily renewal of test solutions. All other tests were carried out without renewal of the test solutions.
EC = emulsifiable concentrate; SC = suspension concentrate; OSC = oil-enhanced suspension concentrate; WP= wettable powder;
ME = micro-encapsulated;
CD = ß-cyclodextrin.
The toxicity of alpha-cypermethrin to the early-life stages of
fish has been studied in a 34-day continuous-flow embryo-larval test
with the fathead minnow (Pimephales promelas). Eggs less than 24 h
old were exposed to nominal concentrations of 0.03 to 1.0 µg/litre.
Pre-hatch, post-hatch and overall mortality and final body weight were
recorded. On the basis of the most sensitive parameter (overall
survival) and measured exposure concentrations, the lowest
concentration of alpha-cypermethrin producing an adverse effect was
0.09 µg/litre and the highest concentration producing no effect (NOEL)
was 0.03 µg/litre (Stephenson, 1983).
9.2.2.2 Small scale field or outdoor tank studies
The acute effect of formulation on the toxicity of
alpha-cypermethrin to fish under field conditions was investigated in
studies using stainless steel enclosures placed in an experimental
pond. In the first study (Shires, 1983b), the rainbow trout (13-32 g)
was the test species and the results are summarized in Table 9. The EC
formulation was at least 30 times more toxic than any of the other
formulations. The number of fish used