PERMETHRIN
EXPLANATION
Permethrin, a mixture of 4 stereoisomers has been reviewed for
acceptable intake by previous JMPR's in 1979, 1981 and 1982 Annex 1,
FAO/WHO 1980a, 1982a and 1983a). The 1982 JMPR established an ADI for
the 40:60 cis:trans mixture of permethrin stereoisomers only since it
recognized that other mixtures of permethrin stereoisomers in
different isomeric ratios would require independent evaluation. The
present evaluation related to permethrin mixture in which the
cis:trans ratio is nominally 25:75.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Toxicological studies
Special Study on Carcinogenicity
Mice
Groups of 75 male and 75 female Anglia CFLP mice received
permethrin (25:75) in their diet at 10, 50 and 250 mg/kg/day for
91 weeks. Control groups consisted of 100 animals of each sex. No
significant differences in mortality were apparent between the treated
and control animals. Body weight gains of treated animals were
comparable to controls. The food intake of the high dose female group
was decreased in the final ten weeks of treatment only.
At necropsy, there were slight but significant increases in liver
weight of high-dose males and in renal weight of high-dose females.
Lymphoid hyperplasia, malignant lymphoma and reticulum cell sarcoma
were frequent in all groups but their incidences were unrelated to
treatment. The incidence of pulmonary adenoma was increased in high
dose females and reduced in high dose males in comparison to controls.
However, these incidences remained within historical control ranges
for this strain. Hemangiomas and hemangiosarcomas occurred in the
liver and at other sites in each sex, but were not related to
treatment. The results of this study do not indicate any carcinogenic
potential for permethrin (James et al., 1980).
Special Study on Dermal Sensitisation
Guinea Pigs
Permethrin (25:75) in corn oil (1% w/v) or Freund's complete
adjuvant (1% w/v) did not induce dermal sensitisation in groups of
10 male guinea pigs when applied as a 25% dispersion in petrolatum.
The positive control, 2,4-dinitrochlorobenzene, (5% w/v) in petrolatum
produced marked sensitisation. Thus, permethrin (25:75) did not
produce either dermal irritancy or sensitisation under test.
conditions (Chesher & Malone, 1974b).
Special Study on Teratogenicity
Groups of 22-23 female Wistar rats received permethrin (25:75) at
0 or 200 mg/kg in corn oil by daily oral savage on days 6-16 of
pregnancy inclusive. Treatment was without apparent effect on maternal
bodyweight gain or general condition. The animals were sacrificed on
day 20 so that their uterine contents could be examined. Treatment had
no effect on the number of corpora lutea, implantations, live fetuses,
early and late fetal deaths and fetal abnormalities. Examination of
the fetuses, including dissection and skeletal staining, showed no
morphological effects of treatment. These results indicate that
permethrin (25:75) is not fetotoxic in rats at 200 mg/kg/day
(James, 1974).
Special Study on Neurotoxicity
Rats
Groups of 10 male and 10 female Sprague Dawley rats received
permethrin (25:75) (94.5% pure) in the diet at 0, 4000, 6000 and
9000 ppm for 21 days. All treated animals developed severe trembling
and lost weight. Some of the high-dose rats of each sex died.
Subsequent histopathological examination of brain, spinal cord,
trigeminal and dorsal root ganglia, proximal and distal root trunks as
well as terminal motor and sensory nerves revealed no consistent
histopathological abnormality (Dayan, 1980).
Special Study on Ocular Irritancy
Rabbits
Permethrin (25:75) (40% in corn oil) did not produce any ocular
effects when instilled (0.1 ml) into the ocular sac of New Zealand
rabbits (Chesher & Malone, 1974c).
Special Studies on Mutagenicity
Mutagenicity study results are presented in Table 1.
Special Studies on Reproduction
Rats
In a 3-generation reproduction study, groups of 20 male and
20 female Wistar COBS rats received permethrin in the diet at 0, 5, 30
and 180 mg/kg/day during growth, mating, gestation, parturition and
lactation for 3 generations, each with 2 litters.
Fetal toxicity and teratogenicity was assessed in the second
pregnancy of the F2 generation
Table 1: Special Studies on Mutagenicity
Test System Test Organism Concentration Result Reference
Ames Test S. typhimurium Permethrin (25:75) Negative Simmon, 1976
± metabolic TA 1535, TA 1537, 1, 50, 100, 250,
activation TA 1538, TA 98, 500, 1000 (ug/plate)
TA 100 N-methyl-N-nitro-
N-nitrosoguanidine Positive
4-O-tolylazo-O- Positive with
toluidine (ug/plate) metabolic
activation
E. coli WP2 Permethrin (25:75) Negative Simmon, 1976
1, 50, 100, 250,
500, 1000 ug/plate
Ames Test S. typhimurium Permethrin (25:75) Negative Clive, 1979
TA 1535, TA 1537, 1.3, 2.5, 5, 10, 20,
TA 1538, TA 98, 30, 40, 50 ug/plate
TA 100
Mouse Lymphoma L5178Y Permethrin (25:75) Negative Clive, 1977
Assay ± Mouse Lymphoma Cells 0, 31, 47, 62, 94, 125
Metabolic activation (ug/ml) 0, 20, 30, 40,
50 (with activation)
ethylmethane sulphonate Positive
(620 ug/ml)
Table 1: Special Studies on Mutagenicity (cont'd)
Test System Test Organism Concentration Result Reference
2-acetylaminofluorene Positive
(with activation)
(50 ug/ml)
dimethyl nitrosamine Positive
(75 ug/ml)
Dominant Lethal CD-1 mice Permethrin (25:75) Negative Chesher et al., 1975b
Assay (452 mg/kg)
trimethyl phosphate Positive
Treatment with permethrin had no effect on general behaviour, and
condition, food intake, bodyweight gain, pregnancy rate of the dams.
No effects were seen on parturition, sex ratio or pup weight. A small
number of rats of each group developed eye abnormalities, including
ocular hemorrage and chronic glaucoma but there was no relationship to
treatment. Examination of F3b fetuses showed no treatment-related
effect on sex ratio, bodyweight or the occurrence of visceral or
skeletal abnormalities. The results of this study indicate that
permethrin (25:75) has no effect on the reproduction of rats at doses
up to 180 mg/kg/day (James, 1979).
Acute Toxicity
The acute toxicity of permethrin (25:75) to groups of 6 female
C.S.E. Wistar rats was determined in 5 different vehicles as tabulated
(Table 2). Most symptoms of acute poisoning developed within 12 hours
of dosing and were compromised of muscular tremors, hypersensitivity
to stimuli with dullness and staining of abdominal fur. Most deaths
occurred between 1 and 3 days (Wallwork & Malone, 1974).
Table 2: Acute Toxicity of Permethrin (25:75) to Rats in Different
Vehicles
Vehicle LD50 (mg/kg)
110% w/v neat undiluted permethrin [control] > 20,090
40% w/v corn oil 4,672
40% w/v petroleum distillate > 8,000
40% w/v dimethyl sulphoxide > 8,000
20% w/v glycerol > 5,048
The influence of diet on acute toxicity was compared in fed and
starved rats. Groups of female Sprague-Dawely rats, either fed
ad libitum or starved for 24 hours beforehand, received a single
oral dose of permethrin (25:75) (94.1% purity) in corn oil solution
(40% w/v) at 750, 1500, 3,000 or 6,000 mg/kg. The signs of toxicity
were similar in fed and starved rats and included body tremor,
hypersensitivity to sound or touch, splayed gait or walking in tip toe
and convulsions. Permethrin was more toxic in starved (LD50
3,000 mg/kg) than in fed animals (LD50 4,251 mg/kg)
(Piercy et al., 1976).
The acute dermal toxicity of permethrin (25:75) applied in xylene
(40% w/v) to female Sprague-Dawley rats exceeded 2,000 mg/kg
(Harper, et al., 1976). The acute dermal toxicity to male rats
similarly exceeded 2,000 mg/kg (Harper et al., 1977).
Short term studies
Mice
Groups of six mature female mice received daily oral doses of
permethrin (25:75) corn oil at 0, 200, 400 and 800 and 1600 mg/kg for
10 consecutive days. The animals were sacrificed on the 11th day so
that clinical chemical, hematological parameters and organ weights
could be recorded.
Signs of acute toxicity, namely spasm and convulsion were seen
only in the high dose group, half of which died after the initial
dose. There were no significant changes observed in hematology,
clinical chemistry or body weights. The mice treated at 800 and
1600 mg/kg exhibited increased liver weights
(Wallwork et al., 1974a).
Rats
Groups of 5-6 female Charles River CDI rats received permethrin
(25:75) in corn oil at 0, 200, 400 or 800 mg/kg by daily savage for
ten days. The animals were sacrificed on the eleventh day so that
hematological, clinical chemical parameters and organ weights could be
investigated.
At 800 mg/kg, signs of toxicity occurred after each dose and
4 rats died. At 400 mg/kg, slight muscle fasciculation and
hypersensitivity to stimuli developed only after the initial two
doses. Toxicity was not observed at 200 mg/kg. At necropsy, there was
a dose-related increase in absolute and relative liver weight and
increase in hepatic aspartate amino-transferase, alanine
amino-transferase and lactate dehydrogenase activities
(Wallwork et al., 1974b).
Rabbits
Groups of 5 female Dutch rabbits received permethrin (25:75) in
ten daily doses by savage in corn oil at 0, 200, 400 or 800 mg/kg. The
animals were necropsied on the eleventh day so that clinical chemical,
hematological parameters and organ weights could be investigated.
One rabbit, dosed at 400 mg/kg, exhibited mild hyperactivity and
muscular fasciculation at days six and seven only. Although all
animals, including controls, exhibited some degree of weight loss, it
was most marked in the high-dose group. There were no significant
hematological or clinical chemistry findings but there was some
decrease in liver and kidney weight and also some enlargement of
adrenal gland weights in all treated groups (Chesher & Malone, 1974a).
Dogs
Two Beagle dogs received daily oral doses of permethrin (25:75)
(500 mg/kg) for 14 days. There were no clinical signs of toxicity or
significant effects of treatment on body weight, clinical chemistry or
hematological parameters (Chesher et al., 1975a).
Groups of 4 male and 4 female beagle dogs received encapsulated
permethrin [(25:75) 4.5% w/v] at 0, 10, 50 or 250 mg/kg for 6 months.
No signs of toxicity were observed in any group and treatment was
without effect on body weight. Ophthalmoscopy and electrocardiography
were unremarkable as were routine hematological, clinical chemistry
and urinalysis.
At necropsy, there were no gross pathological or significant
histopathological findings. Hematological and clinical chemistry
parameters, including plasma antipyrine elimination rate, were
unaffected by treatment. The results of this study indicate that daily
oral doses up to 250 mg/kg did not adversely affect the dogs
(Reynolds et al., 1978).
Long term studies
Rats
Groups of 60 male and 60 female Wistar SPF rats received 0, 10,
50 or 250 mg/kg bw/day permethrin (25:75) in their diet for 103
consecutive weeks. From week 90 onward a low incidence of generalized
body tremor occurred in high-dose rats but survival was reduced in
high-dose males only. Body weights and food consumption were not
affected by treatment. Ophthalmoscopy and hematological, clinical
chemistry and urinalysis parameters remained within normal limits
throughout treatment.
At necropsy, there was a significant increase in absolute and
relative liver weight of high-dose male rats. Histopathology showed a
dose-related periacinar hyper-trophy of hepatocytes in mid- and
high-dose males only. There were no treatment-related increases in
neoplasms. The results of this study do not indicate any oncogenic
potential for permethrin and indicate a no-observed effect level of
10 mg/kg/day (McSheehy & Finn, 1980).
Observations in humans
Two human volunteers, who consumed about 2 and 4 mg of permethrin
(25:75), respectively, excreted 18-37% and 32-39% of the administered
dose, detected as the metabolite, 3-(2,2-dichlorovinyl)-2,2-dimethyl-
cyclopropanecarboxylic acid, after acid hydrolysis of their urine
collected over 24 hours (Cridland & Weatherley, 1977a; Cridland &
Weatherley, 1977b).
In a study to assess the degree of dermal absorption of
permethrin from impregnate clothing, a group of 10 male volunteer
soldiers wore military clothing for 48 hrs which had been previously
treated with an aqueous suspension of permethrin (0.2% w/v).
Subsequent analysis showed that the mean concentration of the uniform
shirts and trousers was 0.32 g permethrin (25:75)/100 g. However, the
average individual exposure to permethrin was 3.8 mg/day. No
volunteers complained of irritancy and there were no findings on
physical examination (Farquhar et al., 1981a).
Two of 17 volunteers developed mild erythema when dermally
exposed to permethrin [(25:75) 1% w/w in soft paraffin] for up to
9 days using a patch test (Pegum & Doughty, 1978).
To assess the human tolerance, absorption and persistence of
permethrin when used as a human pedunculicide (to be used against
lice), 10 adult volunteers (4 men, 6 women) were treated with 15-40 ml
of permethrin (25:75) (1%) head louse solution. Their hair was allowed
to dry naturally and then washed with baby shampoo. Urine samples were
collected at 0-24, 24-48. 120-144 and 336-360 hrs to permit estimation
of dermal absorption. On assessment, 3 of 10 volunteers developed
mild, patchy erythema which faded between days 4-7. Excretion of
permethrin in the first 24 hours was only about 1% of the applied
dose, whilst the cumulative maximum was only about 5.5 mg over 14 days
(Farquhar et al., 1981b).
As part of a Stage V evaluation of permethrin (25:75) (5% WDP) in
Nigeria, medical surveillance, including urinalysis of staff engaged
in bagging, mixing or spraying was undertaken. Medical history, pulse
and blood pressure were recorded and urine collected twice daily. This
surveillance revealed no effects attributable to permethrin. Despite
their use of protective clothing, up to 2 mg of permethrin was
excreted within 24 hrs of exposure to up to 6 kg of permethrin
(Rishikesh et al., 1978).
To assess the safety of permethrin dusts for control of human
body lice, approximately 350 people were individually dusted with 50 g
of powder containing either 2.5 or 5.0 g/kg of permethrin. Urine
samples, taken at the time of treatment and subsequently, indicated
that maximal absorption of permethrin was 39 µg/kg, 24 hr after
treatment (Nassif et al., 1980).
COMMENTS
As noted by the 1982 JMPR, the acute toxicity of permethrin
(25:75 cis-, trans-) is less than that of permethrin (40:60). On
short-term administration to rats and mice, permethrin (25:75) was of
similar toxicity to permethrin (40:60). Permethrin (25:75) is not
mutagenic in short term tests or in a dominant lethal assay and this
isomeric mixture is not carcinogenic in mice or rats. It is also not
teratogenic in, and does not adversely affect the reproduction, of
rats. Chronic feeding of permethrin (25:75) to rats for 2 years
increased the liver weights of male rats, as did permethrin (40:60).
The toxicological profile of permethrin (25:75) thus resembles
that of permethrin (40:60), although it is less acutely toxic.
Accordingly, the meeting agreed to extend the previously established
ADI for permethrin (40:60) to include permethrin (25:75).
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT (for the nominal 40% cis-, 60%
trans- and 25% cis-, 75% trans- materials)
Rat: 100 ppm in the diet, equivalent to 50 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.05 mg/kg bw.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THIS COMPOUND
Observations in man.
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