PESTICIDE RESIDUES IN FOOD - 1979
Sponsored jointly by FAO and WHO
EVALUATIONS 1979
Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
and the
WHO Expert Group on Pesticide Residues
Geneva, 3-12 December 1979
PERMETHRIN
IDENTITY
Common Name: Permethrin has been approved by ANSI and BSI and
proposed to ISO.
Chemical Names: 3-phenoxybenzyl (±) cis, trans 3-(2,2-dichlorovinyl)
2,2-dimethylcyclopropane-1-carboxylate (IUPAC)
4-(phenoxyphenyl) methyl (±) cis, trans
3-(2,2-dichloro-ethenyl-2,2-
dimethylcyclopropanecarboxylate (CAS)
Synonyms: Code numbers: PP 557, R86557, NIA 33297, FMC 33297,
NRDC 143, S 3151, WL 43479, SBP-1513
Trade names: ADION, AMBUSH, ECTIBAN, KAFIL, MATADAN, PERTHRINE,
POUNCE, TALCORD
Structural Formula:
Molecular Formula: C21H20Cl2O3
Molecular weight: 391.30
Composition of Technical Product
Technical grade permethrin contains four stereoisomers deriving from
chirality of the cyclopropane ring at the C-1 and C-3 positions. The
nomenclature standards mentioned above (ISO, ANSI, BSI) do not
prescribe the ratio of isomers in "permethrin". Glenn and Sharpf
(1977) have shown that the ratio of cis to trans isomers varies with
the method of synthesis. It is desirable to produce different
cis/trans ratios for certain insecticidal applications (e.g., lower
cis/trans ratios for animal health products). It is therefore
important to note the isomer ratios in products used in the supervised
trials and metabolism studies. Cis permethrin is more insecticidally
potent than the trans isomer. The isomers also differ significantly
in rates of photolysis and hydrolysis, in biotransformations and in
bioaccumulation. It should be noted therefore that the conclusions
and recommendations of this meeting are based entirely on agricultural
and horticultural uses of technical grade permethrin containing
cis/trans isomers in approximately a 40/60 ratio. Furthermore, in
this monograph the term permethrin relates only to this mixture.
The our major manufacturers of permethrin jointly submitted
information to the meeting (Manufacturers, 1979) which indicate that
the technical grade products of any of the four manufacturers also
meet the following general specifications:
i) Not less than 89% permethrin (typically 91-93%);
(ii) State: yellowish brown to brownish oily liquid;
(iii) Specific gravity: 1.214;
(iv) Easily soluble in hexane, benzene, chloroform, ethanol and
acetone. Solubility in water <1 ppm;
(v) Each impurity present at <2%.
The meeting examined manufacturers' statements of impurities which
reflected the somewhat different processes of manufacture used.
Formulations commercially available
1.25 to 50% emulsifiable concentrates
25% wettable powders
2 to 5% fogging formulations
5% ULV formulations
Stability
Permethrin is moderately stable in the environment. Elliott et al.
(1973) reported it to be 10-100 times more stable than earlier
synthetic -pyrethroids. The increased resistance to photolysis is
attributable to substitution of the dichlorovinyl moiety for the
isobutenyl group of chrysanthemic acid found in natural pyrethrins and
other synthetic pyrethroids.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, Distribution and Excretion
Rats
Permethrin is rapidly absorbed, distributed and excreted in mammalian
species following oral administration. Approximately 80% of the
administered permethrin was found in urine and faeces within 48 hours
(Mills and Mullane, 1976). Following oral administration of
individual isomers, differences were noted with respect to the
excretion patterns, the trans-isomer was excreted more rapidly than
the cis-isomer. 14CO2 observed following administration of
methylene-labelled permethrin suggested degradation of the
cyclopropane carboxycyclic acid moiety.
Within 48 hours following a single dose (6.5 mg/kg), administered as a
corn oil solution orally to rats, greater than 80% was eliminated in
urine and faeces. Within 7 days, from 92 to 100% of the radioactivity
was eliminated in urine and faeces (Mills and Mullane 1976).
Male rats were administered permethrin orally at a dose of 10 mg/kg.
Following administration, the uptake into blood was rapid with a peak
level observed at 1.5 to 10 hours after dosing. There were
differences noted in the absorption of radioactive material relating
to the position of the 14C-isomer (uptake of the 14C-acid was slower
than that noted with the 14C-alcohol permethrin) suggesting ester
degradation prior to absorption. The half-life in blood following a
single acute oral administration was approximately 7 hours (Bratt et
al., 1977).
Whole body autoradiography studies confirmed the rapid absorption,
distribution and excretion pattern noted following acute oral
administration. Studies at 1, 24 and 96 hours after administration
showed a rapid passage through the major tissues and organs prior to
being excreted (Bratt, et al., 1977). The half-life of permethrin in
adipose tissue following oral administration daily for 12 days was
calculated to be 18 days reflecting the slower elimination from
adipose tissue than from blood (Bratt, et al., 1977).
Groups of female rats (15 rats/group) were administered permethrin in
corn oil solution, orally at a dose rate of 0.9-1.5 mg/kg, daily for
three weeks. Residue levels did not exceed 1 ppm in adipose tissue.
Permethrin levels in adipose tissue were retained with a half-life of
approximately two weeks. Low levels of residues in liver and kidney
were completely removed (below the level of detection) within 7 days
and no residues were noted in brain tissue.
A group of 60 female rats were administered permethrin orally at a
dose of 1 mg/kg daily for 11 weeks after which dosing was terminated.
The animals were maintained for 7 further weeks for tissue
distribution studies. Distribution to adipose tissue reached a
plateau level within three weeks and did not exceed 2 ppm. At the
conclusion of the study, the level of radioactivity declined slowly,
disappearing entirely within 7 weeks. The half-life of adipose tissue
residues again approximated two weeks. Qualitative analysis of
residues in adipose tissue suggested a change in the cis/trans-isomer
ratio (increased cis and decreased trans) reflective of the more
readily metabolized trans-isomer.
Mice
Groups of 10 male and 10 female mice were fed permethrin in the diet
for 4 weeks at dosage levels of 0, 20, 500 and 4000 ppm to compare
residue concentrations in adipose tissue with data obtained from
animals fed similar concentrations for 80 weeks. Residue levels were
consistently higher in female than males. The residue levels in
peritoneal adipose tissue were essentially the same as those seen in
animals fed for over 80 weeks. There was a rapid build-up to
equilibrium levels in mice within 4 weeks of dietary exposure (Hogan
and Rinehart, 1977).
Dogs
Adult beagle dogs were orally administered 6.2-6.5 mg/kg dissolved in
corn oil in gelatin capsule. Within 48 hours approximately 85% was
excreted in urine and faeces. At the conclusion of the 7-day trial,
permethrin had cleared from the body although it was excreted at a
slower rate in the dog than had been observed in the rat. Residues at
7 days were noted in a variety of tissues and organs including fat
which contained the highest residue (0.5-0.8 ppm) (Mills and Slade,
1977).
Further studies on the distribution and retention in tissues of dogs
were performed. Following subacute administration (1 mg/kg, oral) for
10 days, the residues were examined in adipose tissue. Permethrin was
noted after the first dose in adipose tissue. At the termination of
the dosing, residues did not exceed 6 ppm. There was a significant
modification in the ratio of the cis:trans isomers (cis predominated),
again reflecting a difference in the rate of metabolism of the two
isomers. At the conclusion of the study, approximately 1 ppm residues
were noted in liver and kidney with substantially less in muscle
tissue (the level in muscle tissue barely exceeded the limit of
detection of the analytical procedure) (Bratt and Slade, 1977).
Cows
Groups of lactating cows were administered permethrin orally or
dermally. Milk, blood and excretory products were analyzed for 7 or
14 days after which the animals were sacrificed for tissue analysis.
Permethrin was rapidly absorbed by both routes of administration.
Residue levels in the milk of both orally- and dermally- administered
cows increased for 24 to 48 hours following administration, although
following dermal administration, residues in milk were exceedingly
low. Within 7 days all residues had disappeared (Bewick and Leahey,
1976). In the animals dosed orally, 40% of the excreted radioactivity
was found in the urine with 60% found in the faeces. Residue levels
were again characterized in adipose tissue as permethrin.
Lactating cows were administered permethrin in ethanol orally at a
dose of 1 mg/kg for three consecutive days. Permethrin had no adverse
effect on the cows, and at the conclusion of a 12-days trial the
animals were sacrificed and tissues and organs examined for the
presence of residues. Permethrin was rapidly absorbed and excreted
with the majority of residue, from 90 to 100% of the administered
dose, recovered predominantly in urine and faeces. Milk and milk fat
analyses were performed and small quantities of residues of both cis-
and trans-permethrin (cis isomer predominated) were observed
(substantially in the lipid fraction). In general there was a more
rapid elimination of trans-permethrin and its metabolites than of
cis-permethrin (and its metabolites).
In general, the permethrin isomers, although fat soluble, are readily
metabolized and excreted by cows and goats (Gaughan, et al., 1978a;
Hunt and Gilbert, 1977). In cows permethrin appears in small
quantities in milk fat and adipose tissue. Following multiple
administration (3 days), complete recovery of permethrin was observed
within 12 to 13 days in cows.
Hens
Permethrin is absorbed, distributed, metabolized and excreted in hens,
the rates of which are substantially faster in avian species than in
mammalian species (Gaughan et al., 1978b). Permethrin, administered
to laying hens for three consecutive daily doses of 10 mg/kg, was
rapidly absorbed, distributed and largely eliminated from the body
within one day after the final dose. Approximately 90% of the
administered dose was recovered in excreta with small residues noted
in eggs (predominantly yolk) and in adipose tissue. The residue
observed in hen was predominantly the cis-isomer.
Goats
Goats were administered orally at a dosage rate of 20 mg/kg/day for 7
consecutive days. Low levels of residues were observed in the milk.
The residue level appeared to plateau within 4-5 days of the initial
treatment. A sample of milk, containing approximately 0.026 ppm in
the whole milk, was analyzed for residues in milk fat. Fifty percent
of the total residues was extracted with milk fat and was found to be
unchanged permethrin although the cis:trans ratio changed from
approximately 4:6 to 2:1 (Leahy, et al., 1977). At the conclusion of
the study, low levels of residues were noted in various organs (i.e.,
kidney, liver and muscle) with extremely low levels in adipose tissue.
Metabolism
Rats and Mice
The sites of metabolic attack on permethrin include: ester cleavage
(which appears to be more rapid or complete for the trans- than for
the cis-isomer), hydroxylation of the gem-dimethyl group of the
cyclopropanecarboxylic acid, hydroxylation of the 4'-position of the
3-phenoxybenzoic acid and subsequent conjugation of both the phenolic
and carboxylic acid substituents. Following oral administration to
rats, the metabolic pathway for both cis- and trans-permethrin was
reported by Elliott, et al., (1976), and Gaughan, et al., (1977). In
addition, the degradation observed in vitro by the action of
subcellular oxidative enzymes of rat, mouse and insects was described
by Shono et al., (1979).
Oxidative and hydrolytic mechanisms play a major role in the
metabolism of permethrin. A schematic of the metabolic profile can be
seen in Figure 1. In vitro preparations have been observed to
hydrolyse trans-permethrin to a greater extent than the corresponding
cis-isomer. The preferred site of hydroxylation on the alcohol moiety
is the 4'-position with secondary sites occurring in the 6- and
2'-positions. Aryl hydroxylation occurs at the 4'- and 6-position
with isolated mouse microsomal preparations but only at the
4'-position with similar preparations from the rat. Hydroxylation at
the 2'-position was observed with cis-permethrin only with mouse
preparations. In vitro studies have defined the sites of
hydroxylation on both the acid and alcohol portions of permethrin.
With the carboxylic acid moiety, mammalian microsomal preparations
hydroxylate one of the gem-dimethyl groups which is further oxidized
to the corresponding aldehyde and carboxylic acid. In both in
vitro and in vivo studies, agreement has been found on the
greater extent of hydrolysis of trans- than of cis-permethrin and on
the major sites of hydroxylation of each of the pyrethroid isomers.
In vitro, several metabolites have been reported (i.e., the
aldehyde and acid of the gem-dimethyl permethrin and corresponding
carboxylic acids). Some stereo specificity has been encountered with
mouse and rat microsomal in vitro preparations. The preferred
methyl group for hydroxylation is the 1R-versus the 1S-permethrin
isomer (Soderlund and Casida, 1977). In general, it has been
recognized that the lower toxicity of the trans-isomer relative to the
cis-isomer of permethrin is associated and, consistent with its
greater ease of biodegradation both in vivo and in vitro.
Adult male rats were orally administered permethrin as a solution in
corn oil at a dosage rate of 10 and 100 mg/kg. Within 24 hours,
approximately half of the administered dose was excreted in urine and
faeces. Analysis of the urine and faeces was performed in an effort
to see if the rat produced the cyclopropane dicarboxylic acid
metabolite observed as the plant metabolite. Low levels of this
product were observed in both urine and faeces. At least two of the
four possible diastereoisomers were also detected in this experiment
(Bewick and Leahey, 1978).
Cows
Individual isomers of cis- and trans-permethrin were orally
administered to lactating cows for three consecutive days at a dose
rate of approximately 1 mg/kg body weight. Residues noted in milk
consisted almost entirely of unmetabolized cis-permethrin. Trace
levels of hydroxylated permethrin were also noted as milk residues.
Major excretory metabolites included: hydroxylated permethrin (on the
gem-dimethyl group), 3-phenoxybenzyl alcohol and a glutamic acid
conjugate of 3-phenoxybenzoic acid. As noted with milk, most of the
residues in adipose tissue were unmetabolized permethrin. In
comparison with the metabolic profile observed in rats, cows excrete a
larger proportion of ester metabolites, including their glucuronides,
and are unique in utilizing glutamic acid for conjugation of the
acidic metabolites. Quantitatively, cows carry out more extensive
hydroxylation on the gem-dimethyl moiety and less on the benzoyl
moieties reacting in a greater concentration of
4'-hydroxyphenoxybenzoic acid-(sulfate) metabolite in rats rather than
cows. Qualitatively, similar results to those noted with cows have
been observed with goats (Hunt and Gilbert, 1977).
Hens
The metabolic fate in hens was investigated following oral
administration of a dose of 10 mg/kg/day for three consecutive days.
The overall metabolic pathway was similar to that noted with mammalian
species. Permethrin was extensively hydrolyzed and oxidized with the
trans-isomer more extensively degraded. In egg yolk, permethrin and
trans-hydroxymethyl cis-permethrin were detected as residues.
Extensive detoxication via hydrolytic, oxidative and conjugative
reactions, is probably responsible for the relative insensitivity of
avian species (Gaughan et al., 1978b).
Plants
The metabolic fate in plants has been investigated both in the field
and under greenhouse conditions (Gaughan and Casida, 1978). The
metabolic products from plants were identical with permethrin
metabolites observed in mammals with the exception of glucose as the
primary conjugating moiety. The major metabolites were those products
of ester cleavage (which occurs in plants as well as mammals more
rapidly with the trans- than the cis-isomer) and conjugation of the
liberated acid and alcohol fragments. Minor oxidative pathways of
both the acid and alcohol fragments have been identified.
Inert Substrates
Photolytic decomposition in various solvents under artificial light or
on soil exposed to direct sunlight resulted in a variety of
decomposition products. Significant reactions included isomerization
of the cyclopropane ring and ester cleavage. Additionally, reductive
dechlorination and degradation of the isobutenyl moiety has been
reported. On soil, permethrin degrades slowly with relatively little
isomerization of the cyclopropane ring. Photoproducts that retain the
ester linkage were present in small quantities. A variety of
photodecomposition products have been observed which do not appear to
be mammalian metabolites (Holmstead, et al., 1978).
Effects on Enzymes and Other Biochemical Parameters
Permethrin was administered orally to adult male rats (the dose level
used was not specified) for 4, 8 or 12 days in an attempt to evaluate
the effect on liver metabolizing enzymes. No effects were noted at 4
days, but at 8 and 12 days cytochrome P-450 and cytochrome c
reductase activity was significantly increased. In comparison with
known inducing compounds such as phenobarbital and 3-methyl
cholanthrene, permethrin is a weak inducer. It was suggested that
cytochrome P-450 (and not P-448) was induced (Carlson, 1976).
TOXICOLOGICAL STUDIES
Special Studies for Neurotoxicity
Rat
Groups of rats (6 male and 6 female rats per group) were fed
permethrin in the diet at dosage levels of 0 and 6000 ppm for up to 14
days. Severe clinical signs of poisoning were evident in all the
treated animals. Only one male survived the 14-day trial. Sections
of the sciatic nerve from 2 females and 3 males were examined
histologically. Fragmented and swollen axone were observed in 4 of
the 5 animals indicating that permethrin, at a dose level sufficient
to produce severe clinical signs of poisoning or death, induces
sciatic nerve damage characterized as axonal swelling and myelin
degeneration (Hend and Butterworth, 1977).
In a short-term study designed to determine the relationship of high
level administration on the sciatic nerve, groups of rats (10 male
rats/group) were fed permethrin in the diet at dosage levels of 0,
2500, 3000, 3750, 4500, 5000 and 7500 ppm for 14 days. Clinical signs
of acute poisoning and death occurred at 5000 ppm and above. At all
dose levels, there were clinical signs of poisoning characterized by
slight to moderate tremors. Food consumption and growth was reduced
at all levels. At the two lowest dosage levels clinical signs of
poisoning disappeared within the first week whereas, at the higher
dose levels, signs of poisoning were noted throughout the study.
Histological examinations were performed using light and electron
microscopy. Rats receiving 2500 ppm and above in the diet showed no
ultrastructural changes in the sciatic nerve. Disruption of the
myeline sheath was observed in both test and control animals although
it was somewhat prevalent in the test animals. The Schwann cells of
permethrin-treated animals were vacuaolated with the vacuoles derived
mainly from dilated endoplasmic reticulum with some mitochondrial
swelling. Intercellular vacuolation was also observed, but was
believed to be early autolytic changes in the nerve and not related to
permethrin toxicity. Hypertrophy of the Schwann cells was not
observed at dose levels below 3000 ppm (Glaister et al., 1977).
Hen
Groups of hens were administered permethrin orally (as a 40% W/V
solution in DMSO) at a daily dose level of 1 gm/kg daily for 5 days.
After 3 weeks, the dosing regimen was repeated and the animals were
maintained for three weeks. A positive control group was administered
TOCP orally and a negative control group received no treatment. There
were no deaths and no signs of neurological disturbance in any of the
animals treated with permethrin. All TOCP-treated hens displayed
clinical and histological evidence of neurotoxicity. Delayed
neurotoxic potential normally associated with certain organophosphates
was not evident (Milner and Butterworth, 1977).
A group of 15 adult hens was administered permethrin orally at a dose
of 15 ml/hen (specific gravity was 1.2 suggesting a dose of 18 grams
or 9 grams per kilogram body weight). The birds were redosed on day
21 and observed for a further 21 days before sacrifice and
histological examination. A negative (water) and a positive (TOCP,
500 mg/kg) control group were included in this trial. All of the
animals treated with TOCP showed signs of delayed neurotoxicity
ranging from slight muscular incoordination to paralysis. There were
no signs of ataxia observed in any of the permethrin or negative
control groups. Histological examination revealed no degenerative
changes as a result of administering permethrin while degenerative
changes were noted with the positive control (Ross, et al., 1977).
Special Studies on Reproduction
Rat
Groups of rats (10 male and 20 female per group) were fed permethrin
in the diet at dosage levels of 0, 20 and 100 ppm and subjected to a
standard 3-generation, 2-litter per generation reproduction study. A
third litter of the F3 was produced because of poor pregnancy rates
in both test and control animals. There were no effects noted with
respect to mortality, mating, pregnancy and fertility with the
exception of the F2 mating index which was reduced in controls and
all treatment groups. Survival and growth of pups were not affected.
Hematological evaluations of F2 adults between the second and third
mating showed no unusual effects. Ophthalomogic examination was also
normal. There was no indication that dietary levels of up to and
including 100 ppm would adversely affect reproduction in the rat over
a course of 3 generations (Schroeder and Rinehart, 1977).
Groups of rats (12 male and 24 female rats per group) were fed
permethrin in the diet at dosage levels of O, 500, 1000 and 2500 ppm
for 12 weeks. At 12 weeks the animals were mated to initiate a
standard 3-generation (2 litters per generation) reproduction study.
In each generation, the first litter was grossly examined at weaning
and discarded. Representatives from the second litter were chosen as
parents of the next generation. The second litter of the F3
generation was examined histologically and a third F3 litter was
produced and examined for teratogenic effects. Clinical signs of
acute poisoning (tremors, etc.) were noted at 2500 ppm, predominantly
in the females. Tremors were noted sporadically at the lower dose
levels. There were no effects attributable to permethrin with respect
to male or female fertility, gestation viability of pups, sex ratio,
litter size or on lactation. Standard indices, calculated for this
study, were normal and on gross examination no adverse effects were
noted. Clinical signs of poisoning were observed in pups of the 2500
ppm dose group but this did not result in mortality. Ten male and
female weanlings of the F3 second litter were examined
histologically. A centrilobular hypertrophy and cytoplasmic
eosinophilia were observed in all dose groups and was dose dependent
with respect to incidence and severity. The third litter of the F3
generation, sacrificed on day 21 of gestation for teratologic
examination, showed no specific effects with respect to pre- or
post-implantation loss, litter size, weight or sex ratio of
individuals. The number of corpora lutea, implantations and viable
fetuses were increased at 2500 ppm. As a consequence of this large
litter size, individual fetal weights were slightly reduced. Soft
tissue analysis and skeletal examinations of the foetuses revealed no
unusual teratogenic effects. Based on the standard reproduction
study, permethrin had no effect on any reproductive parameter (Rodge
et al., 1977).
Special Studies for Teratogenicity
Mice
Groups of mice (from 27 to 32 mice per group) were administered from
day 7 through day 12 of pregnancy at dosage levels of 0, 15, 50 and
150 mg/kg body weight. On day 18, 2/3 of the animals were sacrificed
and examined for implantation and resorption sites. Viable young were
examined for somatic and skeletal abnormalities. The remaining
pregnant animals were allowed to deliver and to wean the pups. After
3 weeks of lactation, animals were examined for behavioural
abnormalities and for differentiation and growth. At 6 weeks of age,
all animals were sacrificed and subjected to internal and external
examination.
There were no effects noted with respect to maternal toxicity over the
course of the study. Growth and differentiation of pregnant females
were not affected by permethrin. Neither the number of implantation
sites nor the litter size was adversely affected. The size of
individual pups and the incidence of gross external, internal and
skeletal abnormalities were not significantly different than the
control values.
Permethrin did not appear to affect those animals allowed to bear and
wean young at dosage levels up to and including 150 mg/kg. Growth of
young animals did not appear to differ from control values, and 3
weeks after weaning the surviving animals did not show any differences
with respect to growth and major organ changes. There was no
teratogenicity associated with permethrin in this mouse bioassay
(Khoda, et al., 1976b).
Rats
Groups of pregnant rats (20 rats per group) were administered
permethrin at dose levels of 0, 22.5, 71.0 and 225 mg/kg orally from
day 6 to day 16 of gestation. On day 20 animals were sacrificed and
examinations made of corpora lutea and foetuses from each animal.
Somatic and skeletal examinations were performed on the foetuses.
Preliminary dose range finding studies suggested that at levels of
approximately 338 mg/kg an acute maternal toxic response would be
noted. The high dose level of 225 mg/kg used in this teratology study
did not produce an adverse toxicological response. There were no
abortions or maternal deaths. There were no significant differences
in pregnancy frequency, corpora lutea or the total number of
implantations. Placental and fetal weights were similar to the
controls and skeletal and structural abnormalities were not observed.
Based upon the standard teratological bioassay with rats, permethrin
did not show any teratologic potential (McGregor and Wickramaratne,
1976b).
Groups of rats (from 29 to 34 pregnant rats per group) were
administered at dosage rates of O, 10, 20 or 50 mg/kg body weight from
day 9 through 14 of pregnancy. On day 20, approximately 2/3 of the
pregnant females were sacrificed and the remainder allowed to deliver
and wean pups. After lactation, the pups were examined for behaviour
and for growth and differentiation. All pups were sacrificed at 6
weeks of age and examined grossly for signs of internal or external
malformation.
Pregnant females, treated with the high dosage level, showed toxic
signs of poisoning (ataxia, tremor and a slight reduction in body
weight). There was no overt mortality, although foetal lose at the
high dose level was slightly increased. A slightly higher incidence
of non-ossified sternebra was noted at the high dosage level. The
number of implantation sites and the litter size were not affected and
growth and differentiation were similarly unaffected. Internal and
external examinations showed that, with the exception of the slight
skeletal variation noted at the high dose level, there were no
permethrin-associated changes.
In those animals allowed to bear and wean pups, there were no notable
differences from control values with respect to gestation,
implantation sites, delivery and numbers of live young. Growth and
differentiation of the offspring did not appear to be affected by the
administration. There were no abnormalities noted with respect to
gross pathology. Weights of major tissues and organs at the
conclusion of the study were normal. In this rat bioassay, permethrin
did not show a teratogenic effect (Khoda, et al., 1976a).
Special Studies on Mutagenicity
Permethrin was bioassayed for mutagenic activity using the
Salmonella reverse mutation test (Ames Assay). At concentrations up
to 2500 µg per plate, in the presence or absence of a rat liver
activation system, there were no significant increases in mutations in
the TA 1535, TA 1538, TA 98 and TA 100 strains (Longstaff, 1976;
Newell and Skinner, 1976). In addition to the standard "Ames" assay,
permethrin was examined and found to be negative in E. coli WP2, a
test for base pair substitution mutations (Newell and Skinner, 1976).
Permethrin did not increase the number of revertant colonies of S.
typhymurium (TA1535, TA1537, TA1538, TA98 and TA100) in the presence
or absence of a mouse liver subcellular activation preparation
obtained from 6 strains of PCB-treated mice. Permethrin was negative
when tested at dose levels up to 1 mg/plate (Suzuki, 1977).
Groups of 8 male rats were administered by a single intraperitoneal
injection or by 5 daily intraperitoneal injections at dose levels of
0, 600, 3000 and 6000 mg/kg body weight in a cytogenetic investigation
on the mutagenic effects of permethrin on bone marrow cells. Animals
were sacrificed 24 hours after the single administration and 6 hours
after the last multiple administration. Positive controls of
trimethyl phosphate and Mitomycin C were employed. There were no
differences in any of the groups treated with permethrin with either
the single or the multiple administration. The two positive controls
showed significant increases in chromosomal damage in rat bone marrow
cells (Anderson and Richardson, 1976).
Permethrin was bioassayed for mutagenic activity using E. coli and
the Salmonella typhimurium (Ames) assay. At concentrations up to
5000 µg permethrin/plate, in the presence or absence of a rat liver
activation system, there were no significant increases in mutations in
the standard Salmonella strains and in the E. coli W2 (Shirasu,
et al., 1979). A host-mediated assay in mice, using the G46 strain of
S. typhmurium as an indicator, was also negative at dosage levels
of 200 mg/kg body-weight (Shirasu, et al., 1979).
Mice - Dominant Lethal Study
Groups of male mice (15 mice per group) were administered permethrin
in a corn oil solution, orally for 5 consecutive days, at dose levels
of 0, 15, 48 and 150 mg/kg. A positive control group received a daily
oral dose of 100 mg/kg ethylmethanesulfonate for five days. Each male
mouse was mated to 2 virgin females for a one-week period after which
the females were changed and the males mated with a second group of
virgin females. The process was repeated until the treated male mice
had been mated at weekly intervals for eight weeks in a standard
dominant lethal study. Female mice were killed 12 days after
fertilization and uteri were examined for implantation, early death
and late death. There was no effect on pregnancy as a result of
permethrin treatment. Implantations were different in week 3 and 7
only with the low dose group. There were no consistent dose-related
effects. There were no effects on early or late death and, in
contrast to data reported with ethylmethanesulfonates there were no
dominant lethal effects as a result of administration of permethrin to
male mice (McGregor, et al., 1976a).
Special Pharmacological Studies
The pharmacological action of permethrin on isolated ileum,
nictitating membrane, blood pressure, respiration and heart rate were
investigated in rabbit, guinea pig or cat. Permethrin reduced the
incidence and amplitude of contraction of isolated rabbit ileum but
induced no changes in a similar preparation from the guinea pig.
Permethrin affected blood pressure and respiration following
intraperitoneal administration of dosages of 4 mg/kg and above. The
hypotensive effect was not affected by pre-treatment with atropine or
propanolol. Permethrin was shown to produce slight contraction of
nictitating membranes. An increase in rabbit ECG was observed at dose
levels above 4 mg/kg. The increased rate was not accompanied by
changes in the wave pattern (Nomura and Segawa, 1979).
Changes were noted in the EEG tracings at high dose levels; doses
which were lethal to rabbits. Spike waves and an increased amplitude
of slow waves were induced at 100 mg/kg body weight. At doses of 30
mg/kg, no changes in rabbit EEG were observed. Permethrin did not
induce changes in ECG at levels below those which were lethal.
There was no change in hexobarbital-induced sleeping time in mice
administered permethrin at dose levels ranging up to 2000 mg/kg body
weight (Takahashi, et al., 1979).
Acute Toxicity of Varying Cis:Trans-Permethrin Ratios to Female Rats
LD50
Cis:Trans Ratio (mg/kg) Reference
80:20 396 Jaggers & Parkinson, 1979
57:43 333
50:50 748
40:60 630
20:80 2800
Acute Toxicity
Species Sex Route Solvent LD50 Reference
mg/kg
Rat M oral water 2949 Parkinson, 1978
F oral water >4000 Parkinson et al, 1976
M oral DMSO 1500 Clark, 1978
F oral DMSO 1000 Clark, 1978
M oral corn oil 500 Jaggers & Parkinson,
1979
M oral corn oil 430 Khoda, et al, 1979
F oral corn oil 470 Khoda, et al, 1979
M&F oral corn oil 1200 Braun & Killeen, 1975
M&F oral none 6-8,900 Braun & Killeen, 1975
M dermal water >5176 Parkinson, 1978
F dermal none >4000 Parkinson et al, 1976
M dermal none >2500 Khoda, et al, 1979a
F dermal none >2500 Khoda et al, 1979a
M&F dermal xylene >750 Clark, 1978
M sc corn oil 7800 Khoda, et al, 1979a
F sc corn oil 6600 Khoda, et al, 1979a
M ip water >3200 Parkinson et al, 1976
F ip water >3200 Parkinson et al, 1976
Mouse F oral water >4000 Parkinson et al, 1976
M&F oral DMSO 250-500 Clark, et al, 1978
M oral corn oil 650 Khoda, et al, 1979a
F oral corn oil 540 Khoda, et al, 1979a
M sc corn oil >10000 Khoda, et al, 1979a
F sc corn oil approx.
10000 Khoda, et al, 1979a
M dermal none >2500 Khoda, et al, 1979a
F dermal none >2500 Khoda, et al, 1979a
Rabbit F oral water >4000 Parkinson et al, 1976
Guinea M oral water >4000 Parkinson et al, 1976
pig
Hen oral >1500 Milner & Butterworth,
1977
Rabbit F dermal none >2000 Parkinson et al, 1976
These data are reflective of the greater toxicity of cis-permethrin as
compared to trans-permethrin.
Acute Oral Toxicity of Several Metabolites of Permethrin
LD50
Chemical Species (mg/kg)
3-phenoxybenzyl alcohol rat 1330
3-(2,2-dichlorovinyl) rat 980
2,2-dimethyl cyclo-
propanecarboxylic acid
3-phenoxybenzaldehyde rat 3600
Signs of poisoning
Following oral administration of permethrin, signs of poisoning became
apparent within two hours of dosing and persisted for up to three
days. The most notable signs of poisoning include tremors,
hyperactivity, urination and defecation, salivation, ataxia,
lacrimation and generally excessive hyperactivity (Parkinson, et al.,
1978).
Acute Intraperitoneal Toxicity of Several Permethrin Metabolites in
Mice
LD50 (mg/kg)
Compound Male Female
3-Phenoxybenzyl alcohol 371 424
3-4'-Hydroxyphenoxy) benzyl
alcohol 750-1000 750-1000
3-(2'-Hydroxyphenoxy) benzyl
alcohol 876 778
3-Phenoxybenzoic acid 154 169
3-(4'-Hydroxyphenoxy)
benzoic acid 783 745
3-(2'-Hydroxyphenoxy)
benzoic acid 859 912
3-Phenoxybenzaldehyde 415 416
All compounds were dissolved in corn oil, except 3-Phenoxybenzoic
acid, which was dissolved in DMS0 (Khoda, et al., 1979b).
Skin sensitization studies with permethrin dissolved in dimethyl
formamide administered to guinea pigs for three consecutive days
followed four days later by a challenge dose resulted in minimum
levels of erythema suggesting that permethrin is not a strong skin
sensitizer. Installation undiluted to the eyes of female rabbits only
caused minimal pain, redness, chemosis of the conjunctiva and slight
discharge. (Parkinson, et al., 1976).
SHORT-TERM STUDIES
Mice
Groups of mice (20 male and 20 female mice/group) were fed at dietary
dosage levels of 0, 200, 400, 1000, 2000 and 4000 ppm for 28 days.
One additional group was fed a dietary level of 80 ppm for two weeks
which was increased for 10,000 ppm for the final two weeks of the
study.
There was no mortality over the course of the study. Growth was
unaffected at all dosage levels with the exception of weight loss at
the initiation of the 10,000 ppm dietary group. Food utilization of
both males and females receiving 10,000 ppm was poor. There were no
effects noted at 4000 ppm and below. Gross and microscopic
examination of tissues and organs was performed at the conclusion of
the study on the control and the highest dose groups. Liver weight
and liver to body weight ratios were increased at 2000 ppm and above.
Increased weight and body weight ratios were also observed in several
tissues of males receiving 10,000 ppm (kidney, heart and spleen).
Gross tissue changes were observed in females at 2000 and 10,000 ppm
which were not dose-related nor accompanied by histological
abnormalities. On histological examination, regenerating tubules in
the renal cortex and changes in the centrilobular hepatocytes
(characterized by an increased eosinophilia) were observed in all the
treated animals (Clapp, et al., 1977b).
Rat
Groups of rats (16 male and 16 female rats per group) were fed in the
diet at concentrations of 0, 375, 750, 1500 and 300O ppm for six
months. Permethrin was dissolved in corn oil and mixed with the diet,
resulting in a final dietary corn oil concentration of 2%. There was
no mortality recorded over the course of the study. Signs of
hypersensitivity and tremors were observed at 3000 ppm during the
early stages of the study. Growth, as evidenced by body weight
changes, was unaffected. Food and water consumption were normal.
Urinalyses, haematologic values and clinical biochemistry parameters
showed no changes related to the presence in the diet. At the
conclusion of the study, data, based on gross and microscopic
examinations of tissues and organs, suggested that there was a slight
increase in liver weight and liver to body weight ratio at 3000 ppm.
There were no significant histological findings attributable to the
presence in the diet. A slight hypertrophy of liver parenchymal cells
was observed occasionally, accompanied by slight fatty changes. There
were no suggestions of cirrhosis and the gross changes were not
accompanied by clinical chemistry abnormalities. A no-effect level in
the study was noted at 1500 ppm (equivalent to 93 mg/kg/day for males
and 110 mg/kg/day for females) (Kadota, et al., 1975).
A short-term study was designed to evaluate the reversibility of
hepatic changes observed in the rat following short-term high level
dietary administration. Groups of rats (48 female rats/group) were
fed in the diet at dosage levels of 0 and 2500 ppm for 28 days. At
the conclusion of the feeding trial, animals were sacrificed or
maintained on control diets and sacrificed periodically at 1, 4 and 8
weeks after the termination of permethrin feeding. Over the course of
this trial, growth and food consumption were examined. Biochemical
analyses of plasma alanine transaminase activity and liver microsomal
enzyme activity were examined. In addition, gross and microscopic
examinations were performed on the liver. An examination of the
smooth endoplasmic reticulum (SER) was made with the aid of an
electron microscope. Pericentral hepatocytes were photographed and
the SER was quantitatively analyzed.
There was no mortality over the course of the study. Food consumption
and food utilization during the treatment period were reduced, and
permethrin-fed animals weighed less than control animals during the
treatment period. But they gained weight rapidly, and at the
conclusion of the study there were no differences in body weight. At
the conclusion of four weeks of feeding, significantly higher absolute
and relative liver weights were observed as a result of permethrin
administration. During the 8-week recovery period, the absolute liver
weight, although not significantly different than the control, was
slightly higher. In contrast, liver to body weight ratios for the
treatment group over the recovery period were significantly higher
than control values. There were no effects over the course of the
study on plasma alanine transaminase. Liver microsomal oxidative
enzyme activity was significantly higher than control values at the
conclusion of the study and for one week after permethrin dosing
ended. Normal values were recorded at 4 weeks but the data at the
8-week interval were again higher than control values. Quantitation
of the smooth endoplasmic reticulum in rat liver cells showed
significant increases as a result of permethrin. Within 4 weeks of
the end of the feeding interval, there were no significant differences
in the treated and control animals (Bradbrook, et al., 1977).
Groups of rats (6 male and 6 female rats per group) were fed in the
diet at dosage levels of 0, 30, 100, 300, 1000 and 3000 ppm for five
weeks. Clinical signs of acute toxicity were evident at 3000 ppm
although there was no mortality observed. Growth was decreased in
both males and females at 3000 ppm. Relative liver weight was
increased in both males (1000 ppm and above) and females (3000 ppm).
There were no effects noted on other tissues and organs. Slight
effects were noted at 3000 ppm in certain clinical chemistry
parameters while no effects were noted on hematological parameters.
Examination of tissues and organs of the two highest dose groups did
not show unusual effects as a result of the diet (Butterworth and
Hends, 1976).
Groups of rats (8 male and 8 female rats/group) were administered
permethrin in the diet at levels of 0, 20, 100 and 1000 ppm for 26
weeks in a study designed to evaluate liver hypertrophy. There was no
mortality, and growth and food consumption were normal. While the
mean liver weight was increased at all dosage levels, a significant
increase of liver weight was noted only at 1000 ppm. The increase in
weight at the highest dose level was also associated with an increase
in the smooth endoplasmic reticulum and in biochemical parameters
evaluating subcellular oxidative mechanisms in the liver. At 100 ppm,
there were slight non-significant increases in biochemical activity,
and at 20 ppm no effects were observed on any of the parameters
measured (Hart, et al., 1977c).
Groups of young rats (8 males and 8 females/group) were fed at dosage
levels in the diet of 0, 200, 500, 1000, 2500, 5000 and 10,000 ppm for
four weeks. All animals fed 10,000 ppm died within three days.
Mortality was evident at 5000 ppm, and hypersensitivity at 2500 ppm
and other non-specific signs of poisoning were observed at dosage
levels of 1000 ppm. At 1000 ppm, the acute clinical signs of
poisoning which appeared on the first day of the study decreased
rapidly and after the first day of the study, there were no signs of
poisoning. Food consumption and growth was reduced at 5000 ppm.
There were no effects on hematological parameters, clinical chemistry
and urinalysis with the exception of a reduction in urinary protein
excretion in males fed 5000 ppm. On gross and microscopic examination
of tissues and organs, the liver weight and liver to body weight
ratios were increased in males at 2500 ppm and above and in females at
1000 ppm and above. The study was designed as a preliminary dose
range-finding study for long-term dietary administration (Clapp, et
al., 1977a).
Groups of rats (10 male and 10 females per group) were fed in the diet
at dosage levels of 0, 20, 100 and 500 ppm for 90 days. There was no
mortality over the course of the study although tremors were noted in
some animals at the two highest dose levels primarily during the first
week of treatment. Hematology, clinical chemistry, urinalyses and
ophthalmological examinations failed to show any effects attributable
to the presence of permethrin. Growth and food consumption were
normal with all animals. At the conclusion of the study, gross
examination of tissues and organs showed significant increases in
absolute and relative liver weight at the two highest dose levels
which were consistent with data from microscopic examination of the
liver showing a compound-related centrilobular hepacyte hypertrophy in
both males and females. There were no significant effects noted at
the 100 ppm dosage level although slight indications of the hepatic
effects were reported in a few of the male animals. There were no
changes in other tissues or organs attributable to permethrin (Killeen
and Rapp, 1976b).
Dog
Groups of beagle dogs (4 male and 4 female dogs per group) were fed
permethrin by gelatin capsule daily for three months at dosage levels
of 0, 5, 50 and 500 mg/kg body weight/day. There was no mortality
observed over the course of the study. Clinical signs of poisoning
were noted in both males and females at the highest dose group at
various times. Growth and food consumption as well as clinical
chemistry, hematology, and urinalysis parameters were unaffected by
the administration of permethrin. At the conclusion of the study,
gross and microscopic examination of tissue and organ increases were
noted in liver weight and liver to body weight ratios of animals
administered 50 mg/kg and above. Histological examination did not
reveal changes associated with or attributable to the permethrin
(Killeen and Rapp, 1976a).
Groups of dogs (4 male and 4 female beagle dogs/group) were
administered permethrin orally in gelatin capsule once a day, 7 days a
week for 13 weeks at dose levels of 0, 10, 100 and 2000 mg/kg body
weight. The animals were weighed weekly and the dosage was adjusted
on the basis of body weight. Ophthalmological examination and
laboratory investigations were performed prior to initiation and at 4
and 12 weeks of dosing. At the conclusion of the study, gross and
microscopic examination of tissues and organs was performed.
There was no mortality over the course of the study although clinical
signs of poisoning were evident soon after administration of 2000
mg/kg. Females administered the high dose gained weight at a slower
rate than controls, although the reduction in weight was predominantly
as a result of reduced weight gain in 1 of 4 females rather than in
the whole group. There were no effects noted in any of the
hematology, clinical chemistry or urinalysis parameters. At the
conclusion of the study, gross and microscopic analyses revealed no
significant effects on tissues and organs at any dose level. Gross
examination of liver suggested a slight increase in liver weight at
2000 mg/kg/day which was not accompanied by histopathological changes
(Edwards et al., 1976).
Cow
Groups of 3 lactating cows were fed in the diet at dosage levels of 0,
0.2, 1.0, 10 and 50 ppm for 28 days. Animals were milked daily and
sacrificed at the conclusion of the study for tissue residue analysis
and gross and microscopic examination of tissues and organs.
There was no mortality and adverse effects were not noted during the
course of the trial. There were no effects on growth or on milk
production. Milk residues of permethrin were observed within 3 days
at the two highest dietary levels. There were no milk residues seen
with dosage levels of 1 ppm or below. The level of milk residue
appeared to plateau rapidly and did not increase with time (but rather
may have decreased). Analysis of individual cis- and trans-isomers
showed the ratio of permethrin isomers in milk appeared to change over
the course of the study with the cis-isomer predominating. Tissue
residues did not occur at a dietary dosage level of 1 ppm and below,
while at the dietary levels of 10 ppm and 50 ppm there were residues,
predominantly in fat. Low levels of residue were also present in
muscle and kidney at the highest dose level. Permethrin appeared not
to accumulate but to plateau rapidly in the fat. There were no
histopathological observations on tissues or organs which could be
related to the presence of permethrin in the diet (Edwards and
Iswaran, 1977).
LONG-TERM STUDIES
Mice
Groups of mice (70 male and 70 female mice per group were fed in the
diet at dosage levels of 0, 250, 1000 and 2500 ppm for 2 years. [The
permethrin used over the course of the study varied in isomer ratio
(cis 35-45:trans 65-55).] SPF-Alderley Park strain of albino mouse
was used for the study. Growth, food consumption, general behaviour
and interim sacrifices with gross and microscopic pathological
examination were examined over the course of the study.
There was a slightly higher rate of mortality at 2500 ppm, but the
differences were not statistically significant. Behaviour of the
treated animals did not differ from controls. Growth was slightly
decreased at the two highest dose levels at various intervals over the
course of the study. At an interim sacrifice and at the conclusion of
the study, gross examination of tissues and calculations of relative
tissue weights showed a significant dose-dependent increase in liver
to body weight ratio at the two highest dose levels in females and at
the highest dose levels of males. Hepatic aminopyrine N-demethylase
activity was also substantially increased at the highest dose level,
although the data for this parameter do not appear to follow a
consistent pattern and was measured only at 26 and 52 weeks. In
males, kidney weight, while decreased at all dose levels at the
conclusion of the study, was not decreased in a dose-dependent
pattern. Differences in kidney weight were not evident at the 26 and
52 week interim sacrifice. Gross and microscopic examination of
tissues and organs (and specific examination for hepatic neoplasia)
did not reveal any significant carcinogenic effects as a result of
dietary permethrin. Many of the non-tumor abnormalities observed were
those associated with aging mice, characterized as an increased
eosinophilia of the centrilobular hepatocytes. This effect was more
evident in the two higher dose levels. In males, a decrease in
vacuolation of the proximal tubular epithelium of the kidney was noted
at all dietary levels. There were no notable effects on the sciatic
nerve. A high incidence of lung adenomas was observed with all
animals in the study, but statistical analysis did not suggest that
this event was related to permethrin. Electron microscopic
examination of the subcellular components of liver suggested a
proliferation of the smooth endoplasmic reticulum in animals fed 2500
ppm. This was also observed to a lesser degree at 1000 ppm and was
absent at the lowest level of permethrin (Hart, et al., 1977a; 1977b).
Groups of mice (75 male and 75 female CD-1 strain mice per group) were
fed in the diet for 104 weeks. Alterations were made in the dietary
dosage levels during the course of the study. From weeks 1 to 19, the
dosage levels were 0, 20, 100 and 500 ppm. At week 19, the 500 ppm
was increased to 5000 ppm and maintained for 2 weeks before being
returned to 500 ppm. At week 21, the 100 ppm groups was increased to
4000 ppm where it was maintained for the remainder of the study.
There was no overt mortality or changes in behaviour of the mice
exposed to permethrin. However, there appeared to be a dose-dependent
increase in mortality at the latter part of the experiment which was
evident at the 4000 ppm dose level. Growth was decreased in males at
4000 ppm. With the exception of blood glucose which was reduced at
4000 ppm, there were no effects on hematology or clinical chemistry
parameters. Gross and microscopic examinations of tissues and organs,
during the course of the study and at its conclusion, showed some
slight changes in gross organ weights. In both males and females at
500 ppm and above, the liver weight was increased. Heart weight was
increased at 4000 ppm. Neoplastic changes were observed in some
animals of all groups which was not associated with dietary levels.
While there was no direct effect with respect to hepatic neoplasms
(either malignant or benign), it was noted that hepatocellular
hypertrophy, pleomorphism and degeneration occurred in mice receiving
permethrin in the diet with somewhat greater frequency and with some
indication of a relationship to the dose level. However, there were
no oncogenic effects on mice (Hogan and Rinehart, 1977; Rapp, 1978).
Rat
Groups of rats (60 male and 60 female rats per group) were fed in the
diet at concentrations of 0, 500, 1000 and 2500 ppm for two years. A
group of 12 animals of each sex was sacrificed at 1 year. Acute signs
of poisoning (tremors and hypersensitivity) were noted during the
first 2 weeks of the study at the highest dose level. There was no
mortality attributable to the presence in the diet and growth was
unaffected. While there were no substantial differences in mortality,
males, fed 1000 ppm and above died somewhat earlier (by week 76) than
did those at lower levels. This early mortality was not noted in
females. There were no significant differences in growth or food
consumption over the course of the study in either males or females.
Hematological examination, performed at varying intervals during the
course of the study, showed no significant differences from control
values. There were no substantial effects on ophthalmological,
urological and clinical chemistry parameters. Liver aminopyrine
N-demethylase activity was increased at all dose levels in both males
and females. Bone marrow smears showed no unusual effects.
Gross and microscopic examination of tissues and organs was performed
at 1 and 2-year intervals. Histological examinations of tissues and
organs and an examination of all animals dying with neoplastic changes
were also performed. Liver weights were increased in males and
females at the 2500 ppm dose level at 1 year. After 2 years, liver
weights and liver to body weight ratios were increased in males at all
doses and in females at 1000 ppm (the female gross liver weight was
significantly increased at 1000 ppm but not at 2500 ppm although the
liver to body weight ratio was significantly increased at both levels
of feeding). In all cases, at 104 weeks liver size was increased.
Kidney weights were also increased predominantly in males at all dose
levels.
Hepatocyte vacuolation was seen at 1 year in males at the highest dose
level only and in females at all dose groups. Examination of the
smooth endoplasmic reticulum showed significant increases in both
males and females at 52 weeks at all dietary feeding levels. At the
conclusion of the study, significant endoplasmic reticulum increases
were noted only at the highest dose levels although non-significant
increases were noted at all dose levels in both males and females.
Examination of the sciatic nerve showed no effect attributable to the
permethrin. There was no oncogenic effect noted at levels up to and
including 2500 ppm in the diet (Richards et al., 1977).
Groups of rats (60 male and 60 female rats per group) were
administered permethrin in the diet at dosage levels of 0, 20, 100 and
500 ppm for 2 years. There was no mortality or adverse effects on
growth, food consumption or behaviour attributable to the presence of
permethrin in the diet. Hematology, clinical chemistry and urinalyses
were performed at either 6 months of 1 year and at the conclusion of
the study. There were no effects on a wide variety of parameters
examined. Differences in laboratory tests were not dose-related and
were not attributable to the presence in the diet. Ophthalmological
examination did not indicate abnormalities. Gross pathology
examinations were not performed at the conclusion of the study
although an evaluation was made of organ weights and organ to body
weight ratios in a variety of tissues. At the 1-year interval, a few
male and female animals were sacrificed from the 100 ppm group (no
controls or other groups were examined at this point). In males, at
the conclusion of the study, there was a slight increase in mean gross
liver weight at all dosage levels. There were no statistically
significant increases in mean values and in liver to body weight
ratios. In females, slight increases in liver size were noted at the
two higher dose levels. However, the liver to body weight ratios were
not increased. Ovarian weight was significantly higher than control
values, but the comparative ovary to body weight ratio was not. Blood
glucose levels were increased at 500 ppm in both males and females at
24 months and in females at 18 months.
The potential for a carcinogenic effect was evaluated in these animals
using standard histological examinations and a further exhaustive
histopathological regimen using a step-sectioned histology technique,
multiple slides, and exhaustive pathological examination. Two
independent evaluations concluded that there was no oncogenic
potential for permethrin. While there was a dose-dependent increase
in gross liver weight in both males and females, these values were
small and not statistically significant. A no-effect level in this
study was estimated to be 100 ppm (Braun and Rinehart, 1977; Billups,
1978a; 1978b).
COMMENTS
Permethrin has a low acute toxicity in a variety of mammalian species.
It is rapidly absorbed, distributed to a variety of tissues and
organs, metabolized and excreted. The metabolic fate has been
thoroughly investigated. Metabolism in mammals and plants involves
predominantly ester cleavage with or without oxidative hydroxylation,
and is similar in all species studied. However, because of the
chemical complexity in part due to the isomeric nature of the
molecule, the variety of metabolic products is large. In addition,
photooxidation mechanisms have produced unusual metabolic products
(i.e. a decarboxylated molecule). Cis-permethrin has been shown to be
more stable than the trans-isomer and is reflected by the cis-isomer
which predominates as a residue in adipose tissue and milk fat.
Following acute poisoning at high dosage levels, permethrin has been
shown to produce a clinically reversible peripheral neuropathy in
rodents (see Report Section 3.3). Histologically, the clinical signs
were described in the sciatic nerve as axon degeneration accompanied
by myelin fragmentation. The neuropathy has not been demonstrated at
dosage levels below those at which acute clinical signs of poisoning
were observed. No data were available to assess the susceptibility of
man to the peripheral neuropathy.
Long-term studies in both rats and mice have shown no oncogenic
potential, a finding which coincides with short-term mutagenicity,
teratogenicity, and reproduction bioassays. In short-term and
long-term studies, permethrin was noted to have an effect on the liver
described as an increased liver weight and liver to body weight ratio.
This increase, which may be an adaptive response, was accompanied by
centrilobular hepatocyte hypertrophy and an increase in the
subcellular smooth endoplasmic reticulum. The no-effect level was
based on the response noted at dosage levels above 100 ppm.
There were no observations in man reported. As permethrin production
and use is expected to be associated with occupational exposure, the
monitoring and study of heavily exposed populations is recommended for
future evaluation. Because of the lipophilic nature of the molecule,
studies on the potential for bioaccumulation are necessary.
TOXICOLOGICAL EVALUATION
Level Causing no Toxicological Effect
Rat: 100 ppm in the diet equivalent to 5.0 mg/kg body weight.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0-0.03 mg/kg body weight.
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
Permethrin has developed rapidly in worldwide agricultural usage even
though it was commercially introduced only recently. It is a stomach
and contact insecticide with adulticidal, ovicidal and larvicidal
activity against a wide range of insects. The compound shows no
systemic or fumigant activity, and has very limited value in soil
treatments because of rapid degradation in soil and lack of systemic
action. The principal agricultural and horticultural uses are in
repeated spray programmes.
Permethrin also has potential for animal health applications.
However, these uses have been excluded from consideration by the 1979
Meeting, because available information was incomplete. Similarly,
although the chemical is also used on certain primary animal feed
crops the meeting postponed the consideration of residues on such feed
crops until the total picture becomes clear on residues in foods of
animal origin, both from direct treatment of animals and from
ingestion in their feeds.
The evaluation of post-harvest uses of permethrin was also deferred
until more information becomes available.
Although worldwide usage is already heavy, many national
authorizations for its use are probationary, experimental, for
emergency uses or limited by special provisions in national statutes.
Many governments also are in the process of evaluating proposals for
official national MRLs and/or registrations. Under these
circumstances, the Meeting was unable to ascertain what were the
authorized national use patterns (good agricultural practices) at this
time.
Table 1 contains a summary of the patterns which have been described
by the manufacturers as effective use in various countries or
geographic areas.
Table 1. Summary of Use Patterns for Permethrin on Various Crops
Application Pre-Harvest
Crop Countries rates Withholding
(g ai/ha) Interval
A. FIELD CROPS
Cotton USA 110-220 14 days
Africa 75-200 Non-specified
Rest of World, 75-200 Up to 7 days
incl. Central/
South America
and Caribbean
Soya Brazil 30-100 60 days
USA 55-110 21 days
110-220 60 days
Maize Australia up to Typically
Canada 330 1 day
Germany
South Africa
USA
Oil Seed Rape Western Europe 50-100 (Generally 7
weeks or more)
Sorghum Brazil 50 45 days
B. FOLIAR AND ROOT VEGETABLES
Beans Worldwide 110-220 -
(Phaseolus
vulgaris)
Cruciferae Worldwide up to 110 up to 7 days
(Broccoli
B. Sprouts
Cabbage
Cauliflower
Kale
Kohlrabi
Turnips)
Celery USA 110-220 3 days
Leeks Netherlands 50 ppm ai -
in spray
Table 1. Continued...
Application Pre-Harvest
Crop Countries rates Withholding
(g ai/ha) Interval
Lettuce Worldwide 55-220 up to 21 days
Peas Western Europe 50 None specified
Spinach Western Europe 30 up to 7 days
Spring onions UK 40 ppm ai in Non specified
spray
Carrots UK 100 None specified
Japanese Japan 100 ppm ai
radish in spray
Potatoes Worldwide 55-220 Non specified
C. TREES AND SOFT FRUITS
Apples, pears,
plums, cherries,
peaches Worldwide 40-90 Up to 14 days
Citrus (Mediterranean 50 None specified
climate)
Raspberries, UK 40-62.5 Up to 3 days
Strawberries Canada
Currants Western Europe 40-50 None specified
Grapes Western Europe 40-100 Up to 14 days
North America
Kiwi fruit New Zealand 25 14 days
D. FRUITING VEGETABLES
Tomatoes, Worldwide 40-220 Up to 15 days
Peppers,
Eggplants
Table 1. Continued...
Application Pre-Harvest
Crop Countries rates Withholding
(g ai/ha) Interval
Greenhouse Canada 50-125 ppm Up to 7 days
Tomatoes, Japan ai in spray
peppers, Western Europe or 150-220
cucumbers, g ai/ha as
gherkins a fog
Melons, Central 100 None specified
squash America
E. ON OTHER CROPS
Coffee Brazil 50-7530 days
Hops Western Europe 300 ppm ai (up to 3 weeks)
in spray
Mushrooms Netherlands 100 (up to 3 days)
Tea Far East 40 ppm ai Non specified
in spray
RESIDUES RESULTING FROM SUPERVISED TRIALS
General Observations
Data on the findings from supervised trials were reviewed in the form
of country reports from six members of the Codex Committee on
Pesticide Residues and from the principal manufacturers of permethrin.
These submissions included reports of raw data and a consolidated
summary prepared jointly on behalf of the basic manufacturers
(Manufacturers, 1979). These reports relate to trials in 16 countries
on over 40 crops and they refer to the analysis of over 3,500
individual samples. The reports were referred to and considered by
the meeting as a basis for reaching conclusions and making
recommendations. Because of the volume of these reports however, it
has not been found possible to reproduce them all in this monograph.
In place of fully comprehensive publication therefore, the Tables
included in this monograph have been selected as typical of findings
on particular situations (e.g. specific crop, formulation, method of
application, dose rate, waiting period or other situation). The
complete set of original data has been retained within FAO and WHO
should a need to refer to it arise.
Following the above-mentioned course, Table 2 contains a summary of
typical findings of residues following field trials with a number of
crops. In assembling the data, gas-liquid methods of analysis were
used as described under "Methods of Residue Analysis" in this
monograph. Because the residues on plants have been shown to consist
almost wholly of permethrin, with only very small proportions of DCVA
and other known metabolites (see Table 5), the figures also relate
only to the parent compound unless otherwise stated. Tables 3 and 4
illustrate the distribution and effects of repeated applications on
given crops.
Residue Findings for Particular Crops
Cotton, oilseeds and other field crops
In cotton where levels in the seeds are influenced by the degree of
protection by the ball during late season spraying, residues were
generally below 0.1 mg/kg. Samples analyzed were the ginned
(undelinted) seed. The highest value reported at effective use rates
is 0.27 mg/kg. At effective use rates, maximum residues reported were
0.05 mg/kg in soybeans, 0.07 mg/kg in sweet corn kernels, 0.08 mg/kg
in peas and less than 0.01 mg/kg in peeled coffee beans. Sprays are
normally applied to oil seed rape seven weeks or more before harvest.
Residues in the oil seeds were non-detectable (less than 0.01 mg/kg).
Root and tuber vegetables
Residue in potatoes were consistently non-detectable (below either
0.01 mg/kg or 0.05 mg/kg). In carrots, Japanese radish and sugar
beets, the highest residues found were 0.04 mg/kg, 0.04 mg/kg and 0.02
mg/kg respectively (Table 2).
Sweet Corn
Analyses of sweet corn were performed separately on kernels, cob and
husks. Surprisingly, residues on the cob (0.01 to 0.12 mg/kg) were
somewhat higher than on kernels. It is possible that residues were
mechanically transferred from the husks (residues up to 29 mg/kg)
during the process of separating the fractions for analysis. In any
event, this is of little significance since the MRLs for the vegetable
sweet corn are usually expressed in terms of mg/kg in or on "kernel
plus cobs".
Leafy Vegetables
In crops such as cabbage, celery and lettuce, residues are present
primarily in the outer leaves. The extent to which wrapper leaves are
stripped before these crops are marketed makes an important
contribution to the variations in residue levels seen on these crops.
Residues in lettuce during the first few days after spraying at
effective use rates were generally in the range of 1-5 mg/kg, although
values at high as 17 mg/kg were recorded. In cabbages, corresponding
values were generally around 1 mg/kg, with a highest value of 2.7
mg/kg. Residues up to 1.9 mg/kg and 5.7 mg/kg were found in untrimmed
celery and in spring onions during the first 3-4 days after spraying
at effective use rates.
Residues reported in some other leafy vegetables were generally
smaller than those in cabbages. For example, the maximum values
recorded at effective use rates were: broccoli, 1.4 mg/kg; Brussels
sprouts, 1.0 mg/kg; kale, 1.1 mg/kg; and spinach 1.3 mg/kg. However
it was noted that the data on spinach and kale were derived from a
single field trial and further trials on these crops were considered
to be desirable.
In cauliflower curds and in leeks, levels were usually at or below 0.1
mg/kg, with highest values of 0.31-0.32 mg/kg. The highest value
reported in kohlrabi was 0.04 mg/kg.
Legume Vegetables
Predictably, residues in Phaseolus beans, which are generally eaten in
the pod, are higher than those in soybeans or peas, where the seeds
are protected from the spray. Mean residues of 0.1-0.2 mg/kg in
Phaseolus compare with less than 0.1 mg/kg in soybeans and in peas.
Pome fruits, stone fruits, citrus, berries and other fruits
Considerable residue data are available on apples, on which the rate
of residue decline tends to be smaller than on various vegetables. At
effective use rates, residues were below 2 mg/kg. Similar patterns
were seen on pears, peaches and cherries, although levels on plums
were 0.1 mg/kg or less. In oranges, melons and kiwifruits, residues
were found almost exclusively in the peel; in edible flesh levels were
not found to exceed 0.03 mg/kg. As the data for citrus were confined
to a single study with oranges in Spain, the results from supervised
trials with other citrus fruits in other countries were considered to
be desirable.
Berries and small fruits
At effective use rates, residues on currants were generally below 1.0
mg/kg, with a highest value of 1.3 mg/kg. They were also consistently
below 1.0 mg/kg on berries and on grapes, at effective use rates.
Fruiting vegetables
Residue levels in cucumbers were generally below 0.1 mg/kg with
occasionally higher values (up to 0.28 mg/kg). In gherkins and
squashes levels were less than, or equal to, 0.02 mg/kg and 0.01 mg/kg
respectively. Permethrin residues in peppers and tomatoes were
generally higher than those found in cucurbitae, although they were
still below 1 mg/kg at effective use rates. An exception was tomatoes
in the USA where the need for higher use rates has yielded residues up
to 1.6 mg/kg. Residues in eggplants of up to 0.05 mg/kg were
reported.
Tea, hops, mushrooms
Conventional spray and ULV applications resulted in residues in dried
tea in the range of 1-21 mg/kg. A programme of sprays yielded
residues in hops of up to 7.6 mg/kg during the ten days after last
spraying and effective spray rates for control of pests in mushrooms
resulted in residues consistently below 0.05 mg/kg.
General Comments on Residue Findings
Site of residue on the plant
As might be expected for a non-systemic and fairly stable compound,
the amounts of residue found on different parts of crops were largely
dependent in their direct exposure at the time of application. This
is particularly marked with leafy vegetables such as lettuce and
cabbage where residue levels in wrapper leaves usually were very many
times (e.g. 10 to 100) those on central heads as trimmed for
commercial distribution. Similarly, residues on fruits such as
melons, citrus and kiwi fruits have been almost confined to the peel
or similar outer protective surfaces. This is illustrated in Table 3
which contains typical findings from the examination of samples of
cabbage, lettuce, oranges, melons and kiwi fruit.
Repeated applications
The rate of decline in residue levels is fairly slow, half-life
periods ranging from about 1 to 3 weeks depending on the crop.
However, there is no obvious build-up of residues following repeated
applications within the rates and frequencies that are needed to
obtain good insect control. Any such effect is small compared with
inter-site variations. This is illustrated in Table 4 which records
the residues found following the treatment of various crops by
different numbers of applications.
Effect of formulation employed
Ground and aerial applications yielded similar residue levels in a
wide range of vegetables and field crops (Fujie, 1977a, b, 1978a;
Ussary, 1976a, 1977a, b, c, d, e, f, g, i, j; 1978a, b, c, d, f, g, h,
1979a). As examples, there were no striking differences in residue
levels following the application of various emulsifiable concentrate
formulations or between residues in fruits such as apples and pears
following the use of emulsifiable concentrates and wettable powders
(e.g. Ussary, 1977k). Similarly, there were no major differences in
residue levels in greenhouse cucurbitae and solanaceae following spray
and fogging applications at effective rates under similar conditions.
Table 2. Residues of Permethrin following Supervised Trials with Various Crops
(A selection typical of the numerous reports available)
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
A. FIELD CROP
Cottonseeds USA 25 to 40% 110 3 to 16 0 0.07 0.03 (3)
(1975/77) 14-16 0.03 0.03 (2)
53-56 0.27 0.07 (12)
450 0 0.14 0.08 (2)
16 0.06 (1)
55-76 0.08 0.03 (7)
Other Supervised trials in Australia, Mexico and Argentina had similar findings
Soybeans USA 25 to 40% 100 to 165 1 to 3 20-65 0.04 0.02 (51)
(1975/78) 220 to 275 " 14-65 0.05 0.02 (8)
450 " 41-85 0.01 <0.01 (5)
In Brazil the results were similar.
Sweet corn USA 25% 110 8 0-4 <0.01 <0.01 (6)
(1976-78) 210-220 7-16 0-4 0.07 0.02 (13)
280-450 6-13 0-4 0.12 0.03 (11)
Also results from Australia and Canada.
Oilseed Rape Sweden and UK residues not greater than 0.01
Sugarbeet FRG 25% 30 1 0-70 <0.01 (16)
(roots) UK 400 1 8 0.02 (1)
B. LEGUME VEGETABLES
Beans Netherlands
(Phaseolus (1978) 25% 125 1 3 0.29 0.14 (6)
vulgaris) UK 200 200 1 0-3 0.31 0.22 (3)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Kidney, runner
snap) USA results similar
Peas UK 25% 100 4-35 0.04 0.01 (13)
(1976,1978) 1.25% 1 and 200 0-3 0.02 0.01 (3)
Also S. Africa and the Netherlands.
C. LEAFY VEGETABLES
Broccoli USA 25% 100 2-10 1 1.4 0.47 (23)
(1975/78) 40% 6-7 0.3 0.15 (15)
440 2 0 1.8 (1)
1 1.5 (1)
7 0.48 (1)
South Africa and U.K. similar.
Brussels USA 25% 105-140 2-13 0-1 1.0 0.25 (18)
sprouts (1975-77) 7-8 0.56 0.23 (13)
40% 210 2-4 0 0.26 0.21 (2)
7 0.17 (1)
Results also from Canada, Netherlands and U.K.
Cabbage Germany F.R, 25% 38 2 0 1.6 1.3 (3)
(1976) 7 0.87 0.42 (3)
U.K. 25% 140 1 0 2.5 1.8 (2)
(1975/76) 19 0.39 0.25 (2)
Additional results available from Germany and U.K., Australia, Canada and U.S.A.
Chinese Japan 20% 300-400 3 7 1.8 0.90 (8)
Cabbage 15-16 0.45 0.32 (8)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Cauliflower U.S.A. 35% 105-110 2-13 0-2 0.32 0.08 (24)
(1975/77) 4O% 7 0.10 0.04 (15)
210-220 2-8 1-2 0.07 0.04 (4)
7 <0.01 <0.01 (3)
Results also from Canada, Germany and U.K.
Kale Germany F.R. 25% 22.5 2 0 1.1 0.85 (3)
(1977) 7 0.64 0.59 (3)
14 0.43 0.32 (3)
Kohlrabi Germany F.R. 25% 38 2 0-21 0.04 0.02 (14)
(1976)
Similar findings from the Netherlands.
Lettuce Netherlands 2% 50-75 1 0 4.1 4.1 (3)
(1977)
(Indoor)
U.S.A. 25% 105-140 2-10 0-1 5.7 0.71 (18)
(1975/79) 40% 7 1.2 0.24 (15)
(outdoor)
U.K. 1.25% 200-240 1 0-3 5.4 3.6 (5)
(1978)
(outdoor)
Other results from Netherlands, U K. and U.S.A.: also from Germany (F.R.)
Spinach Germany F.R. 25% 30 3 0 1.3 1.1 (3)
4 0.55 0.52 (3)
10 0.18 0.13 (3)
D. ROOT AND TUBER VEGETABLES
Carrots U.K. 1.25% 100 1 0-3 0.04 0.04 (5)
(1978) 200 1 0-3 0.12 0.08 (4)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Japanese Japan 20% 150-200 2-4 30-45 0.04 0.02 (10)
radish (roots)
0.140.06(10)
Potatoes Reports from Australia, Canada, Germany, Netherlands, U.K. and U.S.A.
all find no residues above limit of determination.
E. BULB AND STEM VEGETABLES
Celery U.S.A. 25% 220 8-21 0 3.3 3.0 (4)
(1977) 7 1.4 1.2 (4)
(untrimmed)
0 0.68 0.47 (4)
7 0.28 0.25 (4)
(trimmed before analysis)
450 8-21 0 8.9 5.6 (4)
7 2.3 1.2 (4)
(untrimmed)
0 1.3 0.88 (4)
7 0.53 0.51 (4)
Leek Netherlands 25% 1-2 6-7 0.31 0.12 (8)
(1973)
Onion(spring) U.K. 1.25% 400 1 0-3 0.830 50(3
(1978) 10% 1 0-4 5.73:5 (8}
F. FRUITING VEGETABLES
Cucumbers Canada 50% 1 1 0.28 0.17 (3)
(1977) 4 0.06 0.05 (3)
(Indoors)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Cucumbers Japan 20% 2-3 1 0.17 0.09 (4)
(cont'd) 3 0.06 0.03 (4)
Other figures from Canada and Japan, also from Germany, Netherlands,
Mexico, U.K and U.S.A.
Eggplants U.S.A. 25% 220 5 3-7 0.05 0.03 (2)
(1978)
Gherkins Netherlands 25% 125 1 3-7 0.02 0.02 (4)
(Indoors)
(1978)
Melons Mexico Edible flesh
(outdoors) 50 100-200 1-3 0.02 0.02 (4)
(1978) Skin
0.69 0.32 (4)
Peppers U.K. 25% 125 2 0 0.67 0.59 (3)
(Indoors) 1 0.65 0.52 (3)
(1978)
Results similar from Denmark and Canada.
Squash Mexico 50% 100 to 1-7 0.01 <0.01 (6)
(outdoors) 200
(1978)
Tomatoes U.S.A. 25% 105-135 1-13 0 1.3 0.32 (57)
(outdoors) 40% 7 0.51 0.14 (24)
(1975/80) 420 2-8 0.45 0.29 (4)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Tomatoes U.K. 25 350 3 1 0.90 0.77 (2)
(cont'd) (Indoors)
(1976) 7 1.1 0.59 (2)
Additional indoor and outdoor data also available from Australia, Canada, Denmark, Germany,
Netherlands, Japan, S. Africa, Spain, U.K. and U.S.A. These include residues following
treatments with sprays and with fog.
G. POME FRUITS, STONE FRUITS, CITRUS
Apples Australia 10% 125 1-5 0-1 1.1 0.81 (3)
(1975/77) 50% 21 0.59 0.45 (3)
250 1-5 0-3 2.0 1.4 (3)
21 1.2 1.0 (2)
U.S.A. 25% 75-80 1-14 1 1.9 1.0 (5)
(1976/78) 14-16 0.89 0.42(3)
In addition to other findings fron Australia and U.S.A., results of supervised trials
on apples were available also from Canada, France, Germany, Netherlands, South Africa and U.K.
Pears Canada 25% 62.5 1-6 0-1 1.9 0.77 (18)
(1976/78) 21 0.35 0.20 (2)
Australia 10% 125-150 4-6 0 1.7 1.2 (2)
50% 14 1.3 0.81 (2)
Other and similar figures are available from Australia, Canada, France,
Germany, Netherlands, South Africa, U.K. and U.S.A.
Peaches Australia 10% 125-150 4-6 0 1.7 1.2 (2)
(1976/77) 50% 14 1.3 0.81 (2)
Germany 25% 75 2 0 0.83 0.57 (3)
(1977) 14 0.27 0.18 (3)
Further figures available from Canada and others from Australia and Germany.
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
Cherries Germany 25% 75 2 1 1.2 0.90 (3)
(1977) 14 0.56 0.35 (3)
flesh peel
Oranges Spain 25% 100 3 0 0.01 <0.01 (3)
(1976) 0.41 0.33 (3)
7 0.01 <0.01 (3)
0.57 0.34 (3)
H. SMALL FRUITS AND BERRIES
Blackcurrants U.K. 1.25% 40 1 0-3 1.3 0.91 (5)
(1978)
Redcurrants Netherlands 25% 50 1 7 0.81 0.56 (4)
(1977)
Grapes Germany 25% 150 3-4 0 1.1 0.58 (6)
(1975/76) 14 0.95 0.42 (6)
Similar results from Australia, Canada, France, South Africa and U.S.A.
Raspberries U.K. 1.25% 40 1 0-3 0.80 0.50 (5)
(1978)
Canada 25% WP 62.5 3 8 0.23 (1)
(1975)
Strawberries U.K. 1.25% 40 1 0-3 0.56 0.29 (5)
(1978) " 80 1 11 0.49 0.36 (5)
Also figures received from Canada
Kiwi fruit New Zealand 50% 25 3-7 7 0.50 0.30 (3)
(1979) 14 0.56 0.34 (3)
Table 2. Continued...
Country Formulation Appl. Number Interval Residue Measurements
Crop (year) strength rate of last appln. Highest Mean
(E.C.) (g.ai/ha) Applns. and harvest (No.of results)
I. COFFEE, MUSHROOMS
Coffee (beans) Brazil 50% 100 1 1 )Peeled or
(1978) 3 )washed berries
15 )<0.01(1)
200 1 0.03 (1)
3 0.02 (1)
Tea Indonesia
(dried) (1978) 2% 10 2-4 1 5.2 (1)
6 3.3 2.1 (3)
100 2-4 1 21 (1)
6 8.1 6.7(3)
5% ULV 40 2-4 1 6.3(1)
6 1.7 2.9(3)
Hops Germany (F.R.) 25% 150-500 5 0 7.4 ( 6.0 (3) Fresh
( weight
(1977) 7 4.9 ( 3.8 (3) basis)
25% 7 36 (18 (3) (Dry
10 22 (16 (3) basis)
Mushrooms Germany F.R 25% 200 2 1-3 0.04 0.02 (6)
(1977)
Table 3. Residues in Outer Coverings and in Edible Parts of Certain Crops
(The figures quoted are typical of numerous data held by FAO)
Rate of Interval between Permethrin Residues (mg/kg) In
Crop Country appl. last Application Wrapper Trimmed
(g ai/ha) and Harvest (days) Leaves Heads
Cabbage U.S.A. 200 1 5.9 0.10
3 4.8 0.17
7 2.9 0.05
110 0 5.2 0.14
1 8.4 0.24
3 7.4 0.15
55 0 0.67 <0.01
1 0.56 <0.01
3 0.58 <0.01
7 0.53 <0.01
Lettuce U.S.A. 200 1 day 47 0.71
3 days 9.2 0.50
7 days 9.6 0.34
14 days 6.3 0.35
220 0 days 6.2 0.39
1 day 5.4 0.38
3 days 4.9 0.24
7 days 4.6 0.36
110 0 days 2.5 <0.01
1 day 2.7 <0.01
3 days 2.3 <0.01
7 days 1.2 <0.01
In Peel Edible flesh
Orange Spain 50 7 0.34 <0.01
Melon Mexico 100-200 1-3 0.32 0.02
Kiwi fruit New Zealand 50 0 1.7 <0.03
(Ussary 1977 d,e,i,j; 1978 f,j; 1979 h.; Swaine and Sapiets, 1979 a,b; Cheong, 1977, 1979)
Table 4. Correlation of Residues with Number of Applications
(Figures extracted from a larger Table of USA Data)
Rate of Interval between No. of Permethrin
appl. last application Appl.s Residues
Crop (g ai/ha) and harvest (mg/kg)
Broccoli 70-110 0-1 days 2 0.28(4)
6-8 0.37(3)
9-10 0.20(8)
2-4 days 2 0.18(3)
6-8 0.30(3)
9-10 0.22(4)
6-7 days 2 0.12(2)
6-8 0.18 1)
9-10 0.15(4)
Brussels 105-140 0-1 days 2 0.08(2)
sprouts 3-4 0.24(2)
5-7 0.06(4)
0-13 0.38(3)
3-8 days 2 0.13(2)
3-4 0.22(2)
5-7 0.09(4)
9-13 0.30(3)
14 days 2 0.08(1)
5-7 0.06(1)
Cabbage 105-140 0-1 days 3-4 0.07(7)
5-6 0.12(7)
7-9 0.06(10)
10-11 0.13(5)
200-220 0-1 days 3-4 0.44(3)
5-6 0.21(6)
10 0.15(2)
3 days 3-4 0.49(2)
5-6 0.20(3)
10 1.1(1)
7-8 days 3-4 0.40(2)
5-6 0.10(3)
7-9 0.04(1)
Cauliflower 200-220 0 days 2-3 0.06(2)
8-9 <0.01(1)
1-2 days 2-3 0.05(3)
8-9 <0.01(1)
Table 4. Continued...
Rate of Interval between No. of Permethrin
appl. last application Appl.s Residues
Crop (g ai/ha) and harvest (mg/kg)
Celery 220 0-1 days 8-9 0.37(4)
(trimmed) 16-21 0.40(4)
3 days 8-9 0.28(2)
16-21 0.30(2)
220 7 days 8-9 0.26(2)
16-21 0.23(2)
Celery 220 0-1 days 8-9 3.0(4)
(untrimmed) 16-21 3.1(4)
3 days 8-9 1.5(2)
16-21 1.9(2)
7 days 8-9 1.0(2)
16-21 1.4(2)
Lettuce 200-275 0-1 days 2 0.43(3)
3-4 0.64(3)
6-10 0.30(10)
3-4 days 2 0.21(2)
3-4 0.28(3)
6-10 0.26(5)
7 days 2 0.05(2)
3-4 0.21(3)
6-10 0.24(6)
13-14 days 2 0.01(2)
3-4 0.25(3)
6-8 0.10(2)
Tomatoes 105-130 0-1 days 1-3 0.09(4)
4-6 0.10(5)
2-5 days 1-3 0.04(4)
4-6 0.08(6)
7 days 1-3 0.04(4)
4-6 0.06(4)
7-10 0.13(2)
Figures in parentheses are numbers of results upon which the means are
based (Ussary, 1976 c; 1977 c,d,f,g,h,i,l; 1978 c-i).
Table 5. Residues of Permethrin, 3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane
carboxylic Acid (DCVA), and 3-Phenoxybenzyl Alcohol (3-PBA) in Some Crops
Grown in the USA
(Typical examples extracted from a larger table)
Rate of Interval Residues of Stated Compounds
Crop appl. No. of last appl. (mg/kg means figures)
(g ai/ha) appl.s and
Harvest Permethrin DCVA 3-PBA
Alfalfa 220-440 1 3 11 0.66 0.51
7 6.1 1.1 0.55
14-21 1.6 0.67 0.45
Broccoli 220-440 2-8 0-2 0.70 <0.10 <0.05
6-7 0.25 <0.10 <0.05
Celery 220-440 17-21 0-1 3.4 0.28 0.21
(untrimmed) 3 1.9 0.18 0.21
7 1.4 0.25
Lettuce 220-440 3-11 0-1 14 1.0 0.42
(wrapper leaves) 3 4.8 0.93 0.46
7 5.1 0.84 0.32
Lettuce 220-440 3-11 0-1 0.27 0.04 0.04
(heads) 3 0.26 0.03 0.05
7 0.25 0.05 0.03
Tomatoes 105-130 2-12 0-1 0.38 0.01 0.03
7-8 0.17 0.02 0.02
210-440 2-12 0-1 0.40 <0.10 <0.05
7-8 0.12 <0.10 <0.05
FIGURE 2a;V079PR16.BMP
FATE OF RESIDUES
IN ANIMALS
a) Cows and Goats
Permethrin is extensively metabolized and rapidly excreted by cows and
goats. Overall patterns of excretion and metabolism are similar to
those seen in the rat and dog (see "Biochemical aspects" section).
Residues in fat and secreted in milk decline on cessation of dosing
(Bewick and Leahey, 1976; Edwards and Iswaren, 1977; Gaughan et al,
1976; 1978a; Hunt and Gilbert, 1977; Leahey et al, 1977).
When cis-and trans-isomers of 14C-labelled permethrin (carbonyl and
methylene labelled) were administered orally to lactating Jersey cows
for three consecutive days at approximately 1 mg/kg body weight,
radioactivity was largely eliminated from the body in faeces and in
urine within 12 or 13 days after the initial treatment. Total
14C-permethrin equivalents in milk were consistently below 0.3 mg/kg
and declined on cessation of exposure. Residues in fat were present
at low levels. Residues in meat and milk were higher when
cis-permethrin rather than trans-permethrin was administered and
consisted almost entirely of unmetabolized permethrin. Total
14C-permethrin equivalent in blood reached a transient peak shortly
after each dose and dropped to trace levels within 2-4 days after the
last dose (Gaughan et al., 1976, 1978a).
In another study cows received a single oral dose of 40:60
cis:trans 14C-labelled permethrin (either cyclopropane or
methylene labelled) at 2.5 mg/kg body weight, equivalent to
approximately 80 mg/kg in the diet. Levels of radioactivity in milk
reached a maximum of 0.13 mg permethrin equivalents/kg after 1-2 days.
These declined to less than 0.02 mg/kg after seven days. Levels of
radioactivity in the fat were 0.12-0.18 mg permethrin equivalents/kg
after seven days and 0.05-0.08 mg/kg after fourteen days, indicating
that the small residues in fat are also not maintained on cessation of
dosing (Bewick and Leahey, 1976).
Leahey et al (1977a) dosed goats orally with 40:60 cis:trans
14C-labelled permethrin (cyclopropane or methylene labelled) at a
rate equivalent to approximately 10 mg/kg in the diet for seven days.
Total radioactive residues in the milk reached a plateau of 0.02-0.03
mg permethrin equivalents/kg after five days. 30-50% of this
radioactivity was associated with the butterfat fraction of the milk
in which total radioactive residues were 0.13-0.27 mg permethrin
equivalents/kg.
Where "alcohol" labelled permethrin was used, approximately 70% of the
14C in kidney tissue was 3-phenoxybenzoic acid (IV) plus
3-(4'-hydroxyphenoxy)benzoic acid (V) (Figure 2). Approximately 30%
of the 14C in the liver was due to 3-phenoxybenzyl alcohol (III) plus
3-(4'-hydroxyphenoxy) benzyl alcohol. A further 15% was due to
3-phenoxybenzoic acid (IV) Plus 3-(4'-hydroxyphenoxy) benzoic acid
(V). Where "acid" labelled permethrin was used, approximately 10-15%
of the label in liver and kidney was due to the cis and trans
3-(2,2-dichlorovinyl) cyclopropane carboxylic acids (I and II)
(principally the trans isomer) (Leahey et al., 1977a).
In another study goats were dosed orally with either the cis- or
trans-isomers of 14C-labelled permethrin (carbonyl or methylene
labelled) at a rate equivalent to approximately 6 mg/kg in the diet
for ten days. Total radioactive residues in the milk reached a
plateau after three days of 0.02-0.05 and <0.01-0.01 mg permethrin
equivalents/kg respectively for the cis- and trans-isomers. The
goats were sacrificed 24 hours after receiving the final dose, when
levels of radiocarbon in meat tissues were measured. Total
radioactivity in the fat of animals receiving the cis isomer was ten
times higher than in those receiving the more readily hydrolysed
trans-isomer (Hunt and Gilbert, 1977).
Groups of three barren, Friesian cows, yielding 9-13 litres of milk
per day were maintained on diets containing non-radiolabelled
permethrin at approximately 0.2, 1.0, 10 and 50 mg/kg. The permethrin
was absorbed on grass nuts. After 28-31 days two cows in each group
were sacrificed. The third was returned to control diet for seven
days before sacrifice. Samples of milk and of meat tissues were
analysed for permethrin residues by the gas chromatographic method
reviewed under "Methods of Residue Analysis" below. At the 0.2 and
1.0 mg/kg dietary inclusion rates, permethrin residues in milk were
less than 0.01 mg/kg. Residues in kidney, liver muscle and
subcutaneous fat were also less than 0.01 mg/kg and in peritoneal fat
less than 0.05 mg/kg. The higher dietary levels of 10 and 50 mg/kg
resulted in low residues in milk of 0.01-0.06 mg/kg (mean 0.02 mg/kg)
and 0.03-0.2 mg/kg (mean 0.1 mg/kg) respectively. These levels are
approximately 0.2% of the corresponding dietary levels. Residues did
not accumulate over the period of the study and they declined rapidly
on returning the animals to control diet, to below 0.01 mg/kg within
seven days. Permethrin residues in muscle, liver and kidney were
below 0.1 mg/kg. Residues in peritoneal fat were again higher than in
subcutaneous fat (Edwards and Iswaren, 1977).
b) Hens
Hens were dosed orally with 40:60 cis-trans 14C permethrin
(cyclopropane or methylene labelled) for ten days at a rate equivalent
to approximately 10 mg/kg in the diet or separately with cis- and
trans-isomers (carbonyl or methylene labelled) for three days at a
rate equivalent to approximately 80 mg/kg in the diet. Residues in
eggs were present primarily (> 75%) in the yolks in which
radioactivity reached a plateau after 5-8 days of 0.3-0.5 mg
permethrin equivalents/kg in the 10-dose study and 0.6 mg/kg
(trans-isomer administered) or 2.1-2.8 mg/kg (cis-isomer administered)
in the 3-dose study. Permethrin was the major compound identified in
the eggs (52-62%). The cis and
trans-3-(2,2-dichlorovinyl)-2,2-dimethylyclopropane carboxylic acids
(I & II) and 3-phenoxybenzyl alcohol (III) (Figure 2) were the major
metabolites in eggs, each normally accounting for less than
approximately 10% of total radioactivity. The carboxylic acids were
present both free and as the glucuronide and taurine conjugates.
Other metabolites arose from hydroxylation in the 4'-position of the
"alcohol" moiety and in the trans-2-methyl moiety in the "acid" part
of the molecule.
The hens were sacrificed four hours after receiving the final dose in
the 10-dose study and six days after receiving the final dose in the
3-dose study. As in the case of eggs, residues in fat derived from
both "acid" and "alcohol" labels were similar. Permethrin itself
represented the major residue in the fat. Compounds I - III and
3-phenoxybenzoic acid (IV) were also identified (each less than 10% of
the total radioactivity in the fat). In both muscle and liver, higher
residues were detected in hens dosed with "acid" labelled permethrin
than with "alcohol" labelled. The cis- and
trans-3-(2,2-dichlorovinyl)-2,2 dimethylcyclopropane carboxylic acids
(I and II) were the major residues identified in these tissues. Blood
levels declined rapidly during the first 24 hours after administration
(Gaughan et al., 1978 b; Leahey et al. 1977b).
In a study with non-radiolabelled 40:60 cis:trans permethrin, groups
of 40 laying hens were fed on diets containing approximately 0.4, 3.4
and 33 mg/kg for 28 days and then returned to a control diet for an
additional 14 days. Samples of eggs laid during the study were
analysed for permethrin residues by the gas chromatographic method
described under "Methods of Residue Analysis" below. Five hens per
group were sacrificed after 21, 28, 35 and 42 days of the study and
tissues analysed for permethrin.
At the 0.4 mg/kg dietary inclusion rate no residues of permethrin were
detected on the albumen and yolks of egg (limit of detection 0.02
mg/kg) or in the muscle, skin and liver (limit of detection 0.01
mg/kg). At the higher dietary inclusion rates no permethrin was
detected in egg albumen. In yolks, permethrin residues were up to
0.05 mg/kg and up to 0.64 mg/kg respectively at the 3.4 and 33 mg/kg
treatment levels. Residues did not accumulate and declined rapidly
when feeding finished reaching non-detectable levels (less than 0.02
mg/kg) before the end of the 14-day recovery period in both cases. At
the 3.4 mg/kg dietary inclusion rate, permethrin residues in muscle,
skin and liver were non-detectable; i.e., less than 0.01 mg/kg. At
the 33 mg/kg rate permethrin residues in liver were also
non-detectable; low residues in muscle and skin of 0.05-0.08 mg/kg
fell to 0.02 mg/kg before the end of the recovery period (Edwards and
Swaine, 1977).
ON PLANTS
In general, permethrin residues from foliar sprays are not
translocated from site of deposition, nor is there any appreciable
uptake into the aerial parts of plants from soils. Permethrin per
se is relatively persistent on plant surfaces.
On leaf surfaces, permethrin is degraded mainly by ester cleavage,
which occurs more rapidly with the trans-isomer than the
cis-isomer. The major degradation products are the cis-and
trans-isomers of 3-(2,-2-dichlorovinyl) 2,2-dimethylcyclopropane
carboxy acid (DCVA) and 3-phenoxybenzyl alcohol (3-PBA), which occur
both free and as conjugates (Gatehouse et al., 1976a, b; Gaughan
et al., 1976; Gaughan and Casida, 1978; Ohkawa et al., 1977;
Selim and Robinson, 1977 a, b).
The degradation of 14C permethrin has been studied on cotton leaves,
bean seedlings, cabbage leaves and apple fruits. In all cases
permethrin degraded comparatively slowly. Unchanged permethrin
accounted for 23-58% of the radioactivity on cotton leaves after 28
days (Gatehouse et al., 1976b) more than 80% of the radioactivity in
apple fruits after 28 days and more than 60% of the radioactivity on
cabbage leaves after 42 days (Gatehouse et al., 1976b). On bean
plants trans-permethrin was shown to degrade more readily than
cis-permethrin ("half-lives" of 7 and 9 days respectively) (Gaughan
and Casida, 1978; Ohkawa, et al, 1977). Both isomers undergo ester
cleavage and oxidation of the phenoxy group; the resulting acid and
alcohol metabolites form conjugates with glucose. The major
metabolites derived from the alcohol moiety were the glucosides of
3-phenoxybenzyl alcohol, 3-(2'-hydroxyphenoxy) benzyl alcohol and
3-(4'-hydroxyphenoxy)benzyl alcohol. Those derived from the acid
moiety were principally the glucosides of
3-(2,2-dichlorovinyl)2,2-dimethylcyclopropane carboxylic acid (cis
and trans-isomers).
In addition to the major metabolites mentioned above, other
metabolites were identified. These included 3-phenoxybenzoic acid,
the 2'-hydroxy and 4'-hydroxy derivatives of permethrin, and oxidation
products of the geminal methyl group of the
dichlorovinyl-dimethyl-cyclopropane carboxylic acid. Ohkawa (1977)
outlines the probable metabolic pathways on bean plants which seems
generally representative of the metabolic fate of permethrin on
plants.
Only minimal degradation was noted for permethrin applied directly to
cottonseed, lint and bolls (Gatehouse et al, 1976b; Selim and
Robinson, 1977b).
The available metabolism studies with radiolabelled permethrin provide
qualitative evidence of the residues to be expected under actual use
conditions. Data on field-treated crops analyzed by chemical methods
for the parent, 3-PBA, and DMA showed residues of DMA and 3-DCVA
always much lower than those for permethrin (Table 5).
In a special review of synthetic pyrethroids, the Pesticide Chemistry
Commission of IUPAC found that the terminal residues of permethrin in
plants are likely to be unchanged permethrin, and free and conjugated
3-phenoxybenzyl alcohol (3-PBA) and (DCVA) the cyclopropane carboxylic
acid (IUPAC 1979). The IUPAC report also noted the desirability of
outdoor plant metabolism experiments to detect other possible
photoproducts as terminal residues.
Permethrin and its metabolites are effectively non-systemic in plants
(Gaughan and Casida, 1978; Leahey et al, 1976; Munger, 1975; Ohkawa
et al, 1977; Selim and Robinson, 1977a), and residue levels in
rotational crops are minimal. The uptake of permethrin and/or its
metabolites by rotational crops was first examined in studies in which
14C-permethrin (cyclopropane or phenyl labelled) was applied to soil
at 1.1 or 2.2 kg ai per ha (up to 20 times the highest likely use
rate). Lettuce, cotton, wheat and sugar beet were sown as
representative rotational crops up to 120 days later. Under the
conditions of the research greenhouse, the rotational crops were found
to contain small radioactive residues - e.g. less than 0.05 ppm
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid
equivalents at harvest in crop parts used for human consumption, or
less than 0.25 ppm in crop parts used for animal feed, when rotational
crops were sown 120 days after spraying. Almost invariably higher
residues were obtained from soils treated with 14C-"alcohol"-labelled
permethrin than when the same soils had been treated with
14C-labelled permethrin. Total radioactive residues were normally
below 0.05 ppm 3-phenoxybenzyl alcohol equivalents both in silage and
mature crops sown after 120 days. The major constituents of the
"acid" labelled residue were the cis- and trans-isomers of
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (I and
II - see Figure 2) and
3-(2,2-dichlorovinyl)-2-methylcyclopropane-1,1-dicarboxylic acid (VI),
all of which have been shown to be metabolites of permethrin in the
rat.
IN SOIL
In both laboratory and the field, permethrin is rapidly degraded in
soil in which it has a "half-life" of 1/2-6 weeks under aerobic and
under anaerobic conditions. This degradation is due mainly to the
action of microorganisms. Extractable soil degradation products
include permethrin hydroxylated in the 4'-position of the terminal
benzene ring, 3-phenoxybenzyl alcohol, 3-phenoxybenzoic acid, the
cis-and trans-isomers of
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acids and
derivatives of those acids obtained by hydroxylation in the
gem-dimethyl groups in the 2-position of the cyclopropane ring, all of
which have been identified as animal metabolites (see Section on
Biochemical Aspects) and all of which undergo further degradation.
Extensive evolution of 14CO2 from four positions in the molecule
(i.e. using vinyl, cyclopropane, methylene and phenyl labelling) has
been demonstrated, for example, 17-80% in 20 weeks under aerobic
conditions (Arnold et al., 1976a, b; Kaneko et al., 1978; Kaufmann
et al., 1977; Ussary, 1977 n; Williams and Brown, 1979). Permethrin
and its metabolites have low mobilities in soil, considerably less
than that of atrazine which is recognised as being only moderately
mobile in soil (Kaneko et al, 1978; Prashad et al, 1977).
FATE ON PROCESSING AND COOKING
Cotton, Soybeans
Cotton processing residue studies have been reported in the USA.
Permethrin residues in cottonseed oil were usually smaller than those
in ginned cottonseed, being consistently well below 0.1 mg/kg at
effective use rates. Residues in cottonseed hulls and cottonseed cake
were also very small. Residues in linters and linter motes were
greater than those in raw cottonseed, but neither of these fractions
is used for food or feed purposes (Fujie, 1976b, c; Ussary, 1976d).
In similar studies on residues in soybean fractions obtained from
crops sprayed in the USA, although residues on hulls were slightly
larger than on the whole bean, there was no concentration in the
processed fractions, meal, edible oil, and soapstock. The meeting
concluded that an MRL of 0.1 mg/kg would be appropriate for both of
these edible oils.
Apples, Pears and Grapes
Permethrin residues in whole apples remain in the pomace when the
juice is commercially extracted. In studies in the USA, residues in
juice were non-detectable throughout (i.e. less than 0.01 mg/kg),
which is consistent with the low solubility of permethrin in water.
Residues on fresh apples were concentrated by a factor of 25-30 in dry
apple pomace. The pomace is used as animal feed (Ussary, 1977 o, p).
Ninety-seven percent of the residue in whole pears is removed during
the commercial canning process (Ussary, 1977n). Pomace, juice and
wine obtained from grapes containing 0.09 mg/kg showed no detectable
permethrin residues (limits of detection 0.01 mg/kg in wine, 0.05
mg/kg in pomace and juice) (Ussary, 1979e).
Tomatoes
As with apples, permethrin residues in whole tomatoes remain primarily
in the pomace during processing. Permethrin levels in tomato juice,
tomato puree and tomato ketchup were consistently much smaller than
those found in whole tomatoes. The pomace is used as animal feed
(Fujie, 1979c; Ussary, 1977q).
Evidence of Residues in Food in Commerce
The meeting received no reports of findings of permethrin in foods in
commerce. It probably would not be detected by the multi-residue
methods currently used in national surveillance programs.
METHODS OF RESIDUE ANALYSES
The special review of pyrethroids by the Pesticide Chemistry
Commission (IUPAC 1979) included a survey of methods for permethrin
available in the open literature. Some nine methods were discussed
which involved gas chromatography with either electron capture, flame
ionization, or conductivity detection (Williams 1976; Lauren and
Henzell, 1977; George, et al, 1977; Simonaitis and Cail, 1977; Chiba
1978; Fujie and Fullmer, 1978; Williams and Brown, 1979; Chapman and
Harris, 1978; Chapman and Simmons, 1977). One colorimetric method has
been published (Desmarchelier, 1976) for permethrin residues in
grains.
All of the authors reported satisfactory recoveries of permethrin in
one or more substrates at lower detection limits on the order of 0.01
mg/kg. The GLC methods differed mainly in the initial extraction
solvent, partitioning systems, chromatographic cleanup columns and
elution solvents. Gel-permeation chromatography was used in one
method as an alternative to partitioning between solvents (Fujie and
Fullmer, 1978). By selection of the GLC column packing, it is
possible to measure the cis and trans-isomers separately or as a
single peak.
The residue methods employed in the supervised trials and other
experiments on fate of residues by the manufacturers are mostly
unpublished. The coordinated data submission to the meeting
(Manufacturers, 1979) contains a general discussion of the
methodology.
A general description of the methods and references to specific
reports on analytical procedures in the manufacturers submissions are
as follows:
Samples are macerated with 20% acetone in hexane or hexane:isopropanol
2:1. Extracts can be cleaned up by gel permeation, by Florisil or by
small silica gel columns, used either singly or in combination.
Permethrin residues are then determined by gas-chromatography using an
electron capture detector. Alternatively a conductivity detector
(Coulson) has been used successfully. Recoveries are essentially
quantitative and the method has been applied successfully to a wide
range of crops. As reported by Fujie (1977c, d); Swaine et al.,
(1978); Ussary (1977m, 1978k) residues are stable under deep freeze
conditions in which crop samples are stored pending analysis. A lower
detection limit of 0.01 mg/kg (total permethrin content) can normally
be achieved. Depending upon the conditions of gas-chromatography
which are chosen, the cis and trans isomers of permethrin can be
determined either separately or together (Edwards et al, 1976;
Fujie, 1977e; Ussary 1976e, 1977r).
Maceration with 20% acetone in hexane is a more efficient extraction
system than a two-hour exhaustive reflux or maceration in acetone,
methanol or 20% chloroform in methanol (Edwards et al., 1976).
The basic method has been applied successfully to the determination of
permethrin in soil and in water; where essentially quantitative
recoveries are again obtained (Ussary, 1977r). Of the various
solvents tried, 20% acetone in hexane was found to be the most
efficient in extracting permethrin residues from soil which had been
treated at 1 ppm six weeks earlier. There was no advantage in using
hot extraction over extraction at room temperature with the solvent of
choice (Edwards and Ward, 1977b).
With minor modifications, the method can be used to determine
permethrin in milk, meat and eggs. Milk samples are extracted with
n-hexane:acetone 1:1, tissue samples with n-hexane:acetone 4:1. The
acetone is removed by washing with water and the permethrin
partitioned from n-hexane into dimethylformamide. The
dimethylformamide extract is dissolved in 1% aqueous sodium sulphate
and the permethrin back-extracted into n-hexane. The extract is
cleaned up using a Florisil column, and permethrin is determined by
gas chromatography using an electron capture detector. The limit of
detection of the method is 0.01 mg/kg for the combined isomers and
recovery values for samples of meat and milk fortified at 0.01-0.1
mg/kg are normally greater than 70%. Mean recoveries of 89%-92% have
been obtained from milk and 86%-88% from tissues of cows and hens
(Edwards and Iswaren, 1977; Edwards and Swaine, 1977). 20% acetone in
hexane has been shown to be an efficient solvent for extracting
permethrin residues from animal tissues (Edwards and Sapiets, 1978).
The method for permethrin analyses in meat and milk is also applicable
to eggs. These are extracted with n-hexane:acetone 1:1 and the
extract washed with 10% aqueous sodium chloride to remove acetone, and
cleaned up by solvent partition with dimethylformamide and by using a
Florisil column. The limit of detection is 0.02 mg/kg for the
combined isomers and recovery values from yolks and albumen fortified
at 0.01-0.1 mg/kg are generally in the ranges of 70-90% and 60-90%
respectively (Edwards and Swaine, 1977).
The technique of multiple ion detection is suitable for the
qualitative and quantitative confirmation of residues in crops, milk,
eggs and animal tissues. Samples of permethrin in n-hexane obtained
by the preferred residue analytical methods are examined by gas
chromatography linked to mass spectrometry using multiple ion
detection. Three or more of the most abundant m/e values present in
the mass spectrum of permethrin are continuously monitored throughout
the gas chromatographic run and recorded using a multi-pen recorder.
Qualitative confirmation of permethrin residues is given by the
appearance of a peak at the correct retention time for all the
specific m/e values monitored. In addition, the ratios between the
peaks given for each m/e value should be identical to that observed
for permethrin analytical standards. Quantitative confirmation is
carried out by comparison of the peak height or peak area, measured
for the most abundant m/e value recorded, against those obtained with
external standards of permethrin (Swaine and Edwards, 1977).
Residue of both the free and conjugated major plant metabolites of
permethrin, namely cis- and trans-isomer of
3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCVA)
and of 3-phenoxybenzyl alcohol (3-PBA), can also be determined by gas
chromatography. Samples are extracted with 2:1 methanol:water and
lipids removed by partitioning with dichloromethane. The methanol is
then removed using rotary evaporation, the aqueous solution made 1N
with HCl and refluxed to free the conjugated residues. The residues
are then extracted by partitioning with n-hexane. The n-hexane is
then removed and the 2,2,2-trichloroethyl ester of DCVA and the
heptafluorobutyryl ester of 3-PBA are formed simultaneously. The
derivatives are then analysed by gas-liquid chromatography using
electron capture detection (Ussary, 1979g). Limits or detection are
in the range of 0.02-0.10 mg/kg for DCVA and 0.02-0.05 mg/kg for
3-PBA. Recoveries are generally in the range of 70-85%.
Confirmation of the metabolite residues is possible using
gas-chromatography linked to mass spectrometry with multiple ion
detection, similar to the procedure reviewed above for permethrin
(Swaine et al., 1978).
Validation in government regulatory laboratories: U.S.A. Environmental
Protection Agency laboratories have reported a validation trial on two
methods to be used for tolerance enforcement purposes. Methods
designated as "FMC 33297 Analytical Procedures - Soil, Soybeans,
Cottonseed, 1/17/75" and "ICI Residue Analytical Method No. 31,
Determination of Residues Permethrin in Milk and Animal Tissues,
7/1/77" were tested and found satisfactory in cottonseed at 0.5 and
1.0 mg/kg and in milk at 0.05 and 0.10 mg/kg.
NATIONAL RESIDUE LIMITS
The following national MRLs were reported to the meeting:
mg/kg
Australia
Lettuce 5
Brussels sprouts 2
Cabbage and cole crop 1
Tomatoes 0.4
Cottonseed 0.2
Fat of meat of cattle 0.1 (provisional)
Milk and milk products 0.05 "
Sweet corn, potatoes 0.05 "
Canada
Grapes 2
Apples, pears, peaches 1
Cucumbers, tomatoes 0.5
Netherlands
Endive 2
Apple, cabbage 1
Eggplant, cucumber, melon,
peppers, tomatoes 0.5
New Zealand
Kiwifruit 2
Pipfruit, brassicas 1
South Africa
Grapes, tomatoes, apples,
pears, maize (green cob) 0.5
Peas 0.1
U.S.A.
Cottonseed 0.5
Eggs, milk, meat, meat fat,
meat by-products 0.05
APPRAISAL
Permethrin is used to control pests on a wide range of vegetables,
fruits and field crops. Many countries are still evaluating numerous
proposals for use and many of the present use authorizations are under
conditional or probationary provisions in the various national laws.
Four major producers collaborated in supplying to the meeting a
substantial amount of residue and toxicology data. The technical
grade chemical occurs as a mixture of 4 stereoisomers in which ratios
can vary with the method of synthesis. The isomer ratios
significantly affect the chemical and biological properties, and this
monograph is based entirely on products containing the cis:trans
isomers in an approximate 40:60 ratio as currently produced.
Although the chemical has broad potential applications in animal
health, on forage crops, and in post-harvest treatments, the meeting
postponed consideration of residues from those uses until more
information becomes available.
Permethrin has no appreciable systemic action, and residues are
moderately persistent on surfaces. It is subject to photolysis,
hydrolysis, and conjugation and the metabolic pathways are similar in
plants and animals except for the conjugating moieties. The major
terminal residues on crops were unchanged permethrin, free and
conjugated 3-phenoxybenzyl alcohol (3-PBA) and the cyclopropane
carboxylic acid derivative (DCVA). There is no appreciable build-up
from repeated applications in normal spray schedules and no
significant difference in residue levels attributed to use of
different formulations.
Permethrin is degraded in soil by micro-organisms and strongly
adsorbed. It has very limited value as a soil insecticide showing a
half-life of between ´ and 6 weeks. It is not persistent in natural
waters.
Numerous analytical methods for residues have been reported. All
(except one colorimetric procedure) are based on GLC with electron
capture, conductivity, or flame ionization detectors with various
cleanups including liquid-liquid partitioning, gel permeation, and
chromatographic columns. The cis and trans isomers can be measured
separately or together, depending on choice of the column. The
methods have been adapted to various substrates. A lower limit of
detection of 0.01 mg/kg is generally attainable. GLC/mass
spectrometry was cited as a procedure for qualitative and quantitative
confirmation of residues.
The free and conjugated metabolites DCVA and 3-PBA can also be
determined by GLC/EC after derivatization. Conjugates are freed by
refluxing in acid and determined as the 2,2,2-trichloroethyl ester of
DCVA and the heptafluorobutyl ester of 3-PBA. The lower limits of
detection are reported to be 0.02-0.10 mg/kg DCVA and 0.02-0.05 mg/kg
3-PBA (depending on substrate).
Since the metabolite residues at harvest are smaller than the parent
compound, it is anticipated that the method for permethrin per se
would routinely be used by regulatory authorities. As far as could be
determined by the meeting however, permethrin would not be recovered
by the prevailing multi-residue screening methods employed in various
national food surveillance or "market basket" programs.
RECOMMENDATIONS
The extensive data from supervised residue trials made available to
the meeting support the residue limits listed below. Because of the
recent commercial introduction and continuing worldwide development of
the product however, the meeting was unable to ascertain exactly what
constitutes good agricultural practices at this time. For this
reason, the meeting concluded that the levels should be designated as
temporary MRLs until such time as definitive information on worldwide
good agricultural practices are made available.
The temporary MRLs refer to permethrin per se regardless of the
proportions of stereoisomers, and excluding metabolites.
Commodity Limits mg/kg (temporary)
* Beans, whole green 0.5
* Blackberries 1
* Broccoli 2
* Brussels sprouts 1
* Cabbage 5
* Carrots 0.1
* Cauliflower 0.5
* Celery 5
* Chinese Cabbage 5
* Coffee beans 0.05**
* Cottonseed 0.5
* Cottonseed oil 0.1
* Cucumbers 0.5
* Currants, (black, red, white) 2
* Dewberries 1
* Dry beans 0.1
* Eggplant 1
* Gherkins 0.1
* Gooseberries 2
* Grapes 1
* Hops (dried) 50
* Japanese radish 0.1
* Kale 2
* Kiwi fruit 2
* Kohlrabi 0.1
* Leeks 5
* Lettuce 20
* Loganberries 1
* Melons 0.1
* Mushrooms 0.1
* Oranges 0.5
* Peas (shelled) 0.1
* Peppers 1
* Pome fruits 2
* Potatoes 0.05**
* Rape seed 0.05**
* Raspberries 1
* Savoy Cabbage 5
* Soybeans 0.1
* Spinach 2
* Spring onions 5
* Squash 0.1
* Stone fruits 2
* Strawberries 1
* Sugar beets 0.05**
* Sweet corn 0.1
* Tea (dried, black, green) 20
* Tomatoes 2
** results at or about limit of determination
FURTHER INFORMATION
Required by 1981
1. Pharmacokinetic data on the potential bioaccumulation of
permethrin and/or metabolites.
2. Observations in man, especially those with high level of
occupational exposure to evaluate the potential susceptibility of
man to the neurological disruption noted in rodents.
3. Results of additional supervised residue trials on oranges and
other citrus varieties in representative citrus-growing countries.
4. Results of additional residue trials on kale, spinach and other
leafy vegetables.
5. Data from supervised trials on primary animal feed crops; data on
residues in meat, milk and eggs at feeding levels commensurate
with expected levels in animal feeds.
6. Data on residues in meat, milk and eggs from direct treatment of
food animals and animal premises.
7. Data from post-harvest uses of permethrin.
8. Information on world-wide good agricultural practices (i.e.
authorized national use patterns).
9. Information on any future changes in manufacturing processes
which substantially alter the ratio of cis- and trans-isomers
in the technical grade product.
Desirable
1. Characterization studies on the photodecomposition products.
2. Selected surveys of residues in crops known to have been treated
under practical circumstances.
REFERENCES
Anderson, D. and Richardson, C.R. - Permethrin (PP557): Cytogenetic
Study in the Rat. (1976) Unpublished ICI Central Toxicology Lab.
Arnold, D.J., Cleverley, B.A. and Hills, I.R. "Laboratory Studies of
the Degradation of Permethrin in Soil" Report No. TMJ 1287B. (1976a).
Degradation in Soil under Laboratory Conditions. No. TMJ4J1427.
(1976b).
Degradation in Soil under Laboratory Conditions (III) No. TMJ1512:
Extraction and Identification of the Bound Residues of the Pesticide
in soil". (1977a).
ICI Plant Protection Division Report No. TMJ1518B. (1977b),
Unpublished.
Bewick, D.W. and Leahey, J.P. "Permethrin: Absorption in Cows "ICI
Plant Protection Division Report No. TMJ1357B (1976), Unpublished.
The Analysis of the Permethrin Metabolite
3-(2,2-dichlorovinyl)-2-methylcyclopropane-1, 2-2-dicarboxylic Acid in
the Excreta of Rats Given a Single Oral Dose of 14C-Permethrin.
(1978) Unpublished ICI Plant Protection.
Beyers, F.H. "Determination of Permethrin Residues in Grapes". South
African Bureau of Standards Report to ICI South Africa Ltd., No.
17/36/8 (1979), Unpublished.
Billups, L.H. Histopathologic Examination of a Twenty-Four Month
Toxicity/Carcinogenicity Study of Compound FMC33297 in Rats. (1978a)
Unpublished Environmental Pathology Services submitted by FMC
Corporation.
Twenty-four Month Toxicity/Carcinogenicity Study of Compound
FMC33297 in Rats. (1978b) Unpublished Environmental Pathology
Services, FVC Corp.
Bradbrook, C., Banham, P.B., Gore, C.W., Pratt, I. and Weight, T.M.
PP557: A study of the Reversibility of Hepatic Biochemical and
Ultrastructural Changes in the Rat. (1977) Unpublished ICI Central
Toxicology Laboratory.
Bratt, H., Mills, I.H. and Slade, M. PP557: Tissue Retention in the
Rat. (1977) Unpublished ICI Central Toxicology Lab.
Bratt, H. and Slade, M. Tissue Retention in the Dog. (1977)
Unpublished ICI Central Toxicology Laboratory.
Braun, W.G. and Killeen, J.C. - Acute Oral Toxicity in Rat: Compound
No. FMC33297. Bio-Dynamics Inc., submitted by FMC Corporation. (1975).
Braun, W.G. and Rinehart, W.E. - A twenty-four Month Oral
Toxicity/Carcinogenicity Study of FMC33297 in Rats. Bio-Dynamics, Inc.
submitted by FMC Corporation. (1977).
Butterworth, S.T.G. and Hend, R.W. - Toxicity Studies on the
Insecticide WL 43470: A Five-Week Feeding Study in Rats. (1976)
Unpublished Shell Research Ltd.
Carlson, G.P. The Induction of Cytochrome P-450 and Cytochrome C
Reductase by FMC Compounds. (1976) Unpublished, School of Pharmacy and
Pharmacol Sciences, Purdue University, submitted by FMC Corporation.
Chapman, R.A., and Harris, C.R. - J. Chrom., 166, 513-518.
Chapman, R.A. and Simmons, H.S. - J.A.O.A.C., 60, 977-978.
Cheong, H. "Analysis of Permethrin in Kiwi fruit". ICI New Zealand
(1977-79), Unpublished.
Chiba, M. J. Environ. Sci. Health, Part B 13, 261-268.
Chipman, Inc., Canada. "Summaries of Residues Data - apples, pears,
peaches, grapes, cabbages, cucumbers and sweet corn". (1978-79).
Clapp, M.J.L., Banham, P.B., Chart, I.S., Glaister, J. Gore, C. and
Moyes, A. - PP557: 28-Day Feeding Study in Rats. (1977a) Unpublished
ICI Central Toxicology Lab.
Clapp, M.J.L., Banham, P.B., Glaister, J.R. and Moyes, A. - PP557:
28-Day Feeding Study in Mice. (1977b) Unpublished ICI Central
Toxicology Laboratory.
Clark, D.G. Toxicology of WL 43479: Acute Toxicity of WL 43479.
(1978) Unpublished Shell Research Ltd.
Desmarchelier, J.M. - J. Stored Prod. Res. 12, 245-252.
Edwards and others - Permethrin: PP557 - Preliminary Method and
Residue Data for 1975 UK Trials". Report No. AR2668B (1976).
Edwards and others - "Residue Transfer and Toxicology Study with Cows
Fed Treated Grass Nuts" Report No. TMJ1519/B; "Incorporation of
Permethrin in the Diet of Laying Hens: Residues in Eggs and Tissues"
Report No. TMJ1510/B; "Cotton Extractability Study" Report
No.TMJ1452B; "Permethrin Residue Summary: Residues in Crop Samples
Analysed During 1975-77, Part I: Cereal, Seed and Leguminous Crops"
Report No. TMJ1562A; "Soil Extractability Study" Report No. TMJ1461B;
(1977).
"The extraction of the Pesticide from Animal Tissues" Report No.
RJ0009B; "Residues in Crop Samples Analysed During 1975-77. Part II:
Leaf, Root and Forage Crops" Report No. TMJ1566A. (1978) ICI Plant
Protection Division (Unpublished).
Edwards, D.B., Osborn, B.E., Dent, N.J. and Kinch, D.A. - Toxicity
Study in Beagle Dogs (Oral Administration for Three Months). (1976)
Unpublished Inveresk Research International Ltd. submitted by ICI Ltd.
Elliot, M., James, N.F., Pulmans, D.A., Gaughan, L.C., Unai, T. and
Casida, J.E. - Radiosynthesis and Metabolism in Rats of the 1R Isomers
of the Insecticide Permethrin. J. Agric. Food Chem., 24(2): 270-276.
Elliot, M., Farnham, A.W., Janes, N.F., Needham, P.H., Pulman, D.A.,
Stevenson J.H. Nature, 246, 169.
Fujie, G.H. "Determination of Parent FMC 33297 Residues In/On Ginned
Cottonseed" Report No. W-0059; "Determination of Residues in
Cottonseed and Cottonseed By-products from a Cottonseed Processing
Study" W-0091; "Determination of Residues in Cottonseed and Cottonseed
By-Products From a Cottonseed Processing Study" W-0105; Determination
In/On Lettuce" W-0122; "Determination of Residues In/On Ginned
Cottonseed" W-0167; "Determination of Residues In/On Ginned Cottonseed
Treated In An Aerial Application Spray Program" W-0208; "Cold Storage
Stability of Residues In/On Ginned cottonseed," W-0203; "Cold Storage
Stability of Residues In/On Various Crops" W-0206; "Analytical
Procedures - Soil, Soybean and Ginned Cottonseed" W-0053;
"Determination of Residue Levels In/On Soybeans From Comparative
Air/Ground Application Trials" W-0231; "Determination of Residues
In/On Soybean Processing Products from a Soybean Processing Study",
W-0232; "Determination of Residues on Lettuce" W-0239; "Determination
of Residues In/On Tomatoes" W-0237; "Determination of Residues on
Tomatoes and Tomato Processing Products from Juice, Puree and Whole
Pack Tomato Processing Studies" W-0233; (1976 to 1979) Unpublished
Reports from FMC Co.
Fujie, G.H. and Fullmer, O.H. - J. Agric. Food Chem., 26, 395-398.
Fullmer, O.H. "Determination of Parent FMC33297 Residues In/On
Soybeans, Cabbage, Brussels sprouts, Broccoli, Cauliflowers and
Tomatoes" Nos. W-0123, W-0125; W-0126 and W-0209. (1976 to 77)
Unpublished reports from FMC Corp.
Gatehouse, D.M., Leahey, J.P. and Carpenter, P.K. - Permethrin
Degradation on Cotton. ICI Plant Protection Division Report No.
AR2701B (1976b), Unpublished.
Gaughan, L.C., Unai, T. and Casida, J.E. - Permethrin Metabolism In
Rats and Cows in Bean and Cotton Plants. Paper delivered at 172nd ACS
National Meeting, San Francisco (August 1976).
"Permethrin Metabolism in Rats". J. Agric. Food Chem 25 (1), 9-17.
Gaughan, L.C. and Casida J.E. "Degradation of Trans- and
Cis-Permethrin in Cotton and Bean Plants". J. Agric. Food Chem.,
26, (3), 525-8.
Gaughan, L.C., Ackerman, M.E., Unai, T. and Casida, J.E. "Distribution
and Metabolism of Trans- and Cis- Permethrin in lactating Jersey
Cows" J. Agric. Food Chem. 26 (3), 613-618.
Gaughan, L.C., Robinson, R.A., and Casida, J.E. "Distribution and
Metabolic Fate of Trans- and Cis- Permethrin in laying Hens" J.
Agric. Food Chem., 26 (6), 1374-1380.
George, D.A., Halfhill, J.E., McDonough, L.M. Synthetic
Pyrethroids, Ed. M. Elliot, ACS Symposium Series 42, 201-210.
Glaister, J.R., Pratt, I. and Richards, D. - Effects of High Dietary
Levels of PP557 on Clinical Behaviour and Structure of Sciatic Nerves
in Rats. (1977) Unpublished ICI Central Toxicology Laboratory.
Glenn, M.S. and Sharpf, W.G. ACS Symp. Ser 42, 116. (1977).
Hart, D., Banham, P.B., Chart, I.S., Glaister, J.R., Gore, C.W.,
Pratt, I., and Weight, T.M. - PP557: Whole Life Feeding Study in
Mice: Chronic Evaluation up to 52 Weeks. (1977a) Unpublished ICI
Central Toxicology Lab.
Hart, D., Banham, P.B., Glaister, J.R., Pratt, I. and Weight T.M.
00557: Whole Life Feeding Study in Mice. (1977b) Unpublished ICI
Central Toxicology Laboratory.
Hart, D., Banham, P.B., Gore, C.W., Pratt, I. and Weight, T.M. PP557:
Liver Hypertrophy Study in Rats-Dietary Administration Over 26 Weeks.
(1977c) Unpublished ICI Central Toxicology Lab.
Hend, R.W. and Butterworth, S.T.G. - Toxicity of Insecticides: A
Short-Term Feeding Study of WL 43379 in Rats. (1977) Unpublished Shell
Research Ltd.
Hodge, M.C.E., Banham, P.B., Glaister, J.R., Richards, D., Taylor, K.
and Weight, T.M. PP557: Three Generation Reproduction Study in Rats.
(1977) Unpublished ICI Central Toxicology Laboratory.
Hogan, G.K. and Rinehart, W.E. - A Twenty-Four Month Oral
Carcinogenicity Study of FMC 33297 in Mice. (1977) Unpublished
Bio-Dynamics Inc. submitted by FMC Corporation.
Holmstead, R.L., Casida, J.E., Ruzo, L.O. and Fulmer, D.G. "Pyrethroid
Photodecomposition: Permethrin". J. Agr. Food Chem. 26: 590-95.
Hunt, L.M. and Gilbert, B.N. - Distribution and Excretion Rates of
14C-Labelled Permethrin Isomers Administered Orally to Four Lactating
Goats for 10 Days. J. Agric. Food Chem. 25(3); 673-6.
Jaggers, S.E. and Parkinson, G.R. - Permethrin: Summary and Review of
Acute Toxicities in Laboratory Species. (1979) Unpublished ICI Central
Toxicology Lab.
Kadota, T., Miyamoto, J., and Ito, N. - Six-Month Subacute Oral
Toxicity of NRDC 143 in Sprague-Dawley Rats. (1975) Unpublished
Sumitomo Chemical Co.
Kaneko, H., Ohkawa, K. and Miyamoto, J. "Degradation and Movement of
Permethrin Isomers in Soil" J. Pesti. Sci., 3, 43-51.
Killeen, J.C. and Rapp, W.R. - A Three Month Oral Toxicity Study of
FMC 33297 in Beagle Dogs. (1976a) Unpublished Bio-Dynamics Inc.
submitted by FMC Corporation.
A Three Month Oral Toxicity Study of FMC 33297 in Rats. (1976b)
Unpublished Bio-Dynamics Inc. submitted by FMC Corporation.
Kohda, H., Kadota, T. and Miyamoto, J. Teratogenic Evaluation with
Permethrin in Rats. (1976a) Unpublished Sumitomo Chemical Co.
Teratogenic Evaluation with Permethrin in Mice. (1976b) Unpublished
Sumitomo Chemical Co.
Acute Oral, Dermal and Subcutaneous Toxicities of Permethrin in Rats
and Mice. (1979a) Unpublished Sumitomo Chemical Co.
Khoda, H., Kanedo, H., Ohkawa, H., Kadota, T. and Miyamoto, J. Acute
Intraperitoneal Toxicity of Fenvalerate Metabolites in Mice. (1979b)
Unpublished Sumitomo Chemical Co., Ltd.
Lauren, D.R. and Henzell, R.F. Proc. 30th N.W. Weed and Pest Control
Conf., 207-211. (1977).
Leahey, J.P. and Others. "Permethrin Degradation Studies on Apples
and Cabbage" No. AR2645B; "Rotational Crop Study" No. TMJ1501B;
"Identification of Residues in Sugar Beet Grown in Soil Treated with
14C-Permethrin" No. TMJ1508B; Metabolism and Residues in Goats" No.
TMJ1516B; "Metabolism in Hens" No, TMJ1509B. ICI Plant Protection
Division (1976-77), Unpublished.
Longstaff, E. Permethrin: Short-Term Predictive Tests for
Carcinogenicity: Results from the Ames Test. (1976) Unpublished ICI
Central Toxicology Lab.
Manufacturers. Consolidated Summary of residue data submitted by FMC
Corp., Shell Int. Chemical Co., Ltd., Sumitomo Chemical Co. Ltd., and
Imperial Chemical Industries Ltd. (1979).
McGregor, D.B. and Wickramaratne, G.A. de S. - Dominant Lethal Study
in Mice of ICI-PP557. (1976a) Unpublished Inveresk Research
International Ltd. submitted by ICI Ltd.
Teratogenicity Study in Rats of ICI-PP557. (1976b) Unpublished
Inveresk Research International Ltd. submitted by ICI Ltd.
Mills, I.H. and Mullane, M. PP557: Absorption and Excretion in the
Rat. (1976) Unpublished ICI Central Toxicology Lab.
Mills, I.H. and Slade, M. PP557: Absorption Distribution and Excretion
in the Dog. (1977) Unpublished ICI Central Toxicology Laboratory.
Milner, C.K. and Butterworth, S.T.G. - Toxicity of Pyrethroid
Insecticides: Investigation of the Neurotoxic Potential of WL 43479 to
Adult Hens. (1977) Unpublished Shell Research Ltd.
Munger, D.M. - Uptake of Permethrin by Cotton Plants. FMC Report
M.3791, (1979).
Newell, G.W. and Skinner, W.A. - In Vitro Microbiological Mutagenicity
Study of an FMC Corporation Compound. (1976) Unpublished Stanford
Research Institue submitted by FMC Corporation.
Nomura, Y. and Segawa, T. - Pharmacological Study of Permethrin:
Effects on Isolated Ileum, Nictiating Membrane, Respiration, Blood
Pressure and Electrocardiography. (1979) Unpublished Sumitomo Chemical
Co.
Ohkawa, H., Kaneko, H., and Miyamoto, J. - Metabolism of Permethrin in
Bean Plants. J. Pesticide Sci. 2, 67-76.
Parkinson, G.R., Berry, P.N., Glaister, J., Gore, C.W., Lefevre, V.K.
and Murphy, J.A. - PP557 (Permethrin). Acute and Sub-Acute Toxicity.
(1976) Unpublished ICI Central Toxicology Lab.
Parkinson, G.R. - Permethrin: Acute Toxicity to Male Rats. (1978)
Unpublished ICI Central Toxicology Lab.
Prashad, S., Stevens, J.E., and Newby, S.E. "Mobility of Permethrin
and its Degradation Products in Soil". ICI Plant Protection Division
Report No. AR2716B (1977), Unpublished.
Rapp, W.R. - Twenty-Four Month Oral Toxicity/Oncogenicity Study of
FMC33297 in Mice. Histopathology Report. (1978) Unpublished Report
from McConnel and Rapp submitted by FMC Corporation.
Richards, F., Banham, P.B., Chart, I.S., Glaister, J.R., Gore, C.W.,
Pratt, I., Taylor, K. and Weight, T.M. - PP557: Two-Year Feeding Study
in Rats. (1977) Unpublished ICI Central Toxicology Lab.
Ross, D.B. et al. - Examination of Permethrin (PP557) for
Neurotoxicity in the Domestic Hen. (1977) Unpublished Huntingdon
Research Center submitted by FMC Corp. and ICI Ltd.
Selim, S. and Robinson, R.A. "Uptake of Permethrin by Cotton Plants"
No. M-4099; "Degradation On Cotton Leaf" No. M-4118. FMC Report
(1977), Unpublished.
Shell International Chemical Co. Ltd. Shell Chimie S.A. Nine internal
reports on residue trials. (1976-79), Unpublished.
Swaine, H. and others. "Confirmation of Residues of Permethrin Using
Gas Chromatography Mas Spectrometry In the Multiple Ion Detection
Mode"; "Crop Rotation Study" No. TMU0378/B; "Residues in Crop Samples
Analysed During 1975-77. Fruit Crops (Excluding Solanaceous Fruits.
No.RJ0022A; "Cucurbits And Solanaceous Crops" No. RJ0023A; "Residues
In Crop Samples Analysed During 1977-78: Fruit Crops (Excluding
Solanaceous Fruits) No. RJ0078A; "In Cucurbits and Solanaceous Crops"
No. RJ0079A; "Cereal Seed and Leguminous Crops" No. RJ0080A;"Leaf,
Root and Forage Crops" No. RJ0081A; "In Garden and Household Products"
No, RJ0082A. (1977-79) Unpublished reports submitted by ICI Plant
Protection Ltd.
Schroeder, R.E. and Rinehart, R.E. -A Three Generation Reproduction
Study of FMC33297 in Rats. (1977) Unpublished Bio-Dynamics Inc.
submitted by FMC Corp.
Shirasu, Y., Moriya, M. and Ota, T. - Mutagenicity of S-3151 in
Bacterial Test Systems. (1979) Unpublished Sumitomo Chemical Co.
Shono, T., Ohsawa, K. and Casida, J.E. - Metabolism of
Trans-Permethrin and Cis-Permethrin, Trans-Cypermethrin and
Cis-Cypermethrin, and Decamethrin Microsomal Enzymes. J. Agric. Food
Chem. 27(2): 316-25.
Soderlund, D.M. and Casida, J.E. - Effects of Pyrethroid Structure on
Rates of Hydrolysis and Oxidation by Mouse Liver Microsomal Enzymes.
Pest. Biochem. Physiology 7: 391-401.
Suzuki, H. - Studies on the Mutagenicity of Some Pyrethroids on
Salmonella Strains in the Presence of Mouse Hepatic S9 Fractions.
(1977) Unpublished Sumitomo Chemical Co., Ltd.
Takahashi, K., Okuda, No. and Shirasu, Y. - Effects of Permethrin on
Hexobarbital-Induced Sleeping Time in Mice and Electroencephalography
in Rabbits. (1979) Unpublished Sumitomo Chemical Co.
Ussary, J.P. - Over 100 individual unpublished reports on residues
following field application on different crops and following
post-harvest processing. (1976-79) Submitted by ICI Americas Inc.
Williams, I.H. Pestic. Sci., 7, 336-338
Williams, I.H. and Brown, M.J. "Persistence of Permethrin and WL 43775
in Soil". J. Agric., Food Chem, 27, (1), 130-132.
See Also:
Toxicological Abbreviations
Permethrin (EHC 94, 1990)
Permethrin (HSG 33, 1989)
Permethrin (ICSC)
PERMETHRIN (JECFA Evaluation)
Permethrin (Pesticide residues in food: 1980 evaluations)
Permethrin (Pesticide residues in food: 1981 evaluations)
Permethrin (Pesticide residues in food: 1982 evaluations)
Permethrin (Pesticide residues in food: 1983 evaluations)
Permethrin (Pesticide residues in food: 1984 evaluations)
Permethrin (Pesticide residues in food: 1987 evaluations Part II Toxicology)
Permethrin (JMPR Evaluations 1999 Part II Toxicological)
Permethrin (UKPID)
Permethrin (IARC Summary & Evaluation, Volume 53, 1991)