838. Bifenthrin (Pesticide residues in food: 1992 evaluations Part II Toxicology)

BIFENTHRIN

First draft prepared by E. Bosshard
Federal Office of Public Health
Schwerzenbach, Switzerland

EXPLANATION

Bifenthrin is a synthetic pyrethroid insecticide and acaricide
that was reviewed for the first time by the present Meeting.

EVALUATION FOR ACCEPTABLE DAILY INTAKE

BIOLOGICAL DATA

Biochemical aspects

Absorption, distribution, excretion and biotransformation

Absorption, distribution, excretion and biotransformation of
bifenthrin was investigated in hens, rats and goats. Alcohol
(phenyl)- and acid (cyclopropyl)-¹⁴C-bifenthrin were utilized.

Hens

Laying hens (20/group) were dosed with encapsulated ¹⁴C-
labelled bifenthrin for 10 days at a level equal to 40 ppm. Excreta
and eggs were collected on specified days and prepared for analysis.
The hens in the control and treatment groups were sacrificed for
tissue collection within 24 h of the final dose. Measurable ¹⁴C-
residues were found in all treated group's tissues, excreta, egg
white and egg yolk. Maximum residues in egg yolk were about 3 ppm,
in egg white 0.04 ppm. The highest tissue concentration was found in
fat and liver with values of about 2 ppm. ¹⁴C-bifenthrin was
eliminated primarily via the excreta (Jameson et al., 1986).

White Leghorn laying hens were dosed orally with either acid-
¹⁴C or alcohol-¹⁴C-bifenthrin for 10 days with doses of 2 mg/kg
bw. Residues in livers of acid-¹⁴C-bifenthrin treated hens
consisted mainly of hydroxymethyl-bifenthrin and fatty acid
conjugates (palmitate, oleate), TFP acid¹, hydroxymethyl TFP acid
and the parent compound. A similar metabolic pattern was identified
from hens treated with alcohol-¹⁴C-bifenthrin. Hydroxylation of
the 2-methyl group of the cyclopropyl ring is the major metabolic
pathway in poultry. The presence of fatty acid conjugates of the
hydroxymethyl-bifenthrin represents a new process in the
biotransformation of this pyrethroid (Singer et al., 1987).

Laying hens were orally dosed with ¹⁴C-bifenthrin for 10 days
at dose levels of 4 mg/animal. Analysis of tissues and eggs from
treated laying hens showed that unchanged bifenthrin (40-50%) and
the fatty acid conjugates with palmitic or oleic acid (20-40%) are
the major constituents of the residues in the tissues. A minor
metabolite is the unconjugated hydroxymethyl-bifenthrin (Tullman et
al., 1987).

¹ Cis, trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-
dimethyl-cyclopropanecarboxylic acid

The metabolism of bifenthrin in poultry appears to start by
hydroxylation of the 2-methyl carbon of the cyclopropane ring,
followed by fatty acid conjugation (Wu, 1987).

Rats

Rats were treated with a single oral dose of 5 mg/kg bw alcohol
(phenyl)-¹⁴C-labelled bifenthrin. About 76%-79% of the
administered radioactivity was eliminated via the faeces and 6-7%
via urine within the first 48 h. A total of about 90% was recovered
in excreta after 7 days. Radiocarbon residues in most tissues were
< 0.1 ppm, except for liver (up to 0.1 ppm), skin (up to 0.4 ppm)
and fat (up to 1.7 ppm). A significant portion of parent chemical
was excreted unchanged in the faeces (El Naggar et al., 1983).

Excretion of bifenthrin following oral administration of a
single dose of 2.7 mg/kg bw to female or 5.2 mg/kg bw to male bile
duct-cannulated rats was investigated in urine, faeces and bile.
Signs of stress, evidenced by low biliary volume, decreased
defecation and a high fatality rate as a consequence of
intoxication, was noticed among the male rats. Therefore the
bifenthrin dose was reduced in female rats. In female rats an
average of about 30% of the radioactivity was excreted in bile,
about 15% in the urine and about 49% in the faeces. In male rats
excreted radioactivity averaged 19%, 11% and 25% of the ¹⁴C-dose
in bile, urine and faeces, respectively. Over 90% of the excreted
¹⁴C-residue in the bile was in form of polar conjugates and less
than 1% could be attributed to the parent compound. Total absorption
of bifenthrin using the sum of average biliary and urinary excretion
and tissue concentrations determined in this study yields a value of
about 50% in females and 36% in males, respectively (El Naggar et
al., 1991).

Male and female rats were dosed with ¹⁴C-bifenthrin in one of
the following dose regimens: control (vehicle only), a single low-
dose of 4 mg/kg bw, multiple low-doses of 4 mg/kg bw/day of non-
radiolabelled test material over a two-week period, followed by a
single radiolabelled dose of 4 mg/kg bw or a single high-dose of 35
mg/kg bw. In a preliminary study total recovery in expired air was
less than 1% of the dose administered; thus expired air was not
collected during the definitive study. The majority of the
radioactivity was found in faeces ranging from about 71%-84% of the
total dose while 9%-15% of the applied radioactivity was eliminated
in the urine. After application of low-doses the majority of
radioactivity in urine and faeces was eliminated within 36 h after
treatment, whereas after application of the high-dose the majority
of the applied dose was eliminated after only 72 h.

Tissues and carcass contained a total of about 3%-5% of the
dose. Highest residues were found in fat with values of slightly
more than 1 ppm after low-dose application and 8 and 16 ppm in males

and females, respectively, after application of the high-dose.
Residue levels in other organs were in most cases < 0.2 ppm after
low-dose administration and < 1 ppm after high-dose administration
(Cheng et al., 1988).

Male and female rats were orally dosed with acid- and alcohol-
¹⁴C-labelled bifenthrin at single dose levels of 4 mg/kg bw or 35
mg/kg bw. Additional groups of rats were dosed once daily with
unlabelled bifenthrin for 14 days at 4 mg/kg bw/day followed by a
single low dose of radiolabelled bifenthrin. A majority of ¹⁴C-
radioactivity was excreted in faeces and ranged from about 66%-73%
(alcohol-¹⁴C-label) and 69-83% (acid-¹⁴C-label). In the urine,
elimination ranged from 20-25% and 13-22% for both ¹⁴C-labels,
respectively. Total tissue residues amounted to about 3%. The
majority of ¹⁴C-residue was eliminated within 12-72 h after
dosing. Analysis of the ¹⁴C-residues showed that the parent
compound was the major product. Faecal metabolites were mainly
derived from hydroxylated (on either the biphenyl and/or cyclopropyl
part of the molecule) parent compound. Urinary metabolites were the
result of hydrolytic and oxidative-hydrolytic processes. Slight sex
differences and differences between the various dosing regimens were
observed in metabolite distribution. The amount of parent compound
eliminated in the excreta was lower in females (17%-26%) than in
males (25%-44%). Multiple low-doses when compared with a single low-
dose showed a decrease in the amount of parent chemical within the
same ¹⁴C-label, and a noticable increase in hydrolytical
degradates indicating a significant inductive effect on esterase
activities (El Naggar et al., 1986; Selim, 1986a).

Female and male rats were dosed with acid-¹⁴C and alcohol-
¹⁴C-bifenthrin, respectively, using the following dose regimens:
single oral low-dose of 5.4 mg/kg bw; single oral high-dose of 36-43
mg/kg bw depending on sex; multiple oral low-doses of 4.9 mg/kg bw.
For the multiple oral low-dose regimen, rats were dosed once daily
with unlabeled bifenthrin for 14 days followed by a single low-dose
of ¹⁴C-labelled chemical on the 15th day. A majority of ¹⁴C-
residues were excreted in faeces and urine within 48-72 h. Faecal
metabolites were excreted primarily as non-conjugates while urinary
metabolites were eliminated in both conjugated and non-conjugated
form. Metabolic profiles appeared to be similar among the three
dosing regimens, while excretion rate appeared to be slower in high
dose rats.

Analyses of metabolite fractions indicated that the major
faecal metabolites were primarily derived from hydroxylated parent
compound, such as: hydroxymethyl bifenthrin, 4'-OH bifenthrin, 3'or
4'-OH-hydroxymethyl bifenthrin. Hydrolytic products related to mono-
and dihydroxylated intact parent chemical were also detected

including 4'-OH BP acid¹, 4'-OH BP alcohol², dimethoxy BP acid
and dimethoxy BP alcohol. Analyses of metabolites from urine
fractions indicated that the majority of ¹⁴C-residues were also
from hydrolytic or oxidative degradation resulting in metabolites
such as: 4'-OH BP acid, BP acid, 4'-OH BP alcohol, dimethoxy BP
acid, 4'-Methoxy BP acid, dimethoxy BP alcohol, BP alcohol, TFP
acid, cis- and trans-hydroxymethyl TFP acid (Wu et al., 1988).

¹⁴C-labelled bifenthrin was administered orally to female
rats for 70 days at a dose level of 0.5 mg/kg bw/day. Animals were
sacrificed daily during the dosing period and radiocarbon levels
were measured in blood, tissues and organs. Average peak
concentrations of radioactivity were 9.6 ppm in fat, 1.7 ppm in
skin, 0.4 ppm in liver, 0.3 ppm in kidney, 1.7 ppm in ovaries, 3.2
ppm in sciatic nerve, 0.06 ppm in whole blood and 0.06 ppm in
plasma. Analyses were extended for an additional 85 days following
cessation of dosing (depuration phase). Half-lives of 51 days (fat),
50 days (skin), 19 days (liver), 28 days (kidney), and 40 days
(ovaries and sciatic nerve) were estimated from ¹⁴C-depuration.
Plasma concentrations of radioactivity were similar from days 21 to
70 (0.04-0.06 ppm) and decreased to 0.01 ppm at 78 days and to <
0.01 ppm thereafter. Whole blood levels were similar to plasma
indicating no specific accumulation. Analysis of fat revealed that
parent chemical accounted for a majority (65%-85%) of the ¹⁴C-
residues in fat. Three metabolites accounted for the remaining
radiocarbon residues (Hawkins et al., 1986).

Bifenthrin was administered once orally to male rats at dose
levels of 4 or 35 mg/kg bw using alcohol-¹⁴C-labelled compound.
Mean peak concentrations of ¹⁴C in blood of about 0.6 and 3 µg/ml
for the low- and high-dose, respectively, were reached 4-6 h after
dosing. Twenty-four hours after dosing about 0.2 µg/ml and 2 µg/ml
were measured in the plasma at the two dose levels, respectively
(Selim et al., 1986b).

Male rats were given either a single oral low dose of 4 mg/kg
bw or a high-dose of 35 mg/kg bw of alcohol-¹⁴C-bifenthrin. Plasma
samples were analyzed for parent compound and metabolites. The major
products found were parent compound, the hydrolysis product BP
alcohol and the oxidized hydrolysis product, BP acid each
representing about 20-30% of the total radioactive residues (Tullman
and Robinson, 1986).

Bifenthrin (aqueous emulsion) was dermally administered to a
shaved area on the back of rats at a dose of 36 µg/rat. A mean of
about 4% of the administered dose remained on the washed dosed skin

¹ BP acid = 2-methyl-3-phenylbenzoic acid
² BP alcohol = 2-methyl-3-phenylbenzyl alcohol

site following treatment. Concurrently a mean of about 97% of the
dose was recovered in the skin wash. After a contact time of 24 h,
19% of the dose was recovered on the skin and about 73% in the skin
wash. Radioactivity in the residual carcass was less than 2%. About
1.4% was excreted in the urine and 1.8% in the faeces 24 h post-
dose. Thus dermal absorption is low (Braun et al., 1990).

Rats were treated dermally with single doses of 49.2, 514 or
5253 µg ¹⁴C-labelled bifenthrin/rat (proposed dosage levels: 0.05,
0.5 and 5.0 mg/rat). The average amount of test material
eliminated in the urine and faeces within 24 h was less than 1% of
the applied dose. Measurable amounts of 0.01 µg/ml were only
detected in blood 4 h after application of the highest dose of 5253
µg bifenthrin. Twenty-four hours after application the concentration
had increased to 0.02 µg/ml. The amount of bifenthrin present in the
carcasses, 24 h after application, corresponded to about 0.4% for
the highest dose group and 0.8% for the other dose groups. Average
amounts absorbed into and through the skin 24 h after application
varied between 45 and 71% for the different dose groups (Craine et
al., 1986).

Goats

Lactating goats were orally dosed with ¹⁴C-labelled
bifenthrin for 7 con-secutive days at a dose level of 2 mg/kg
bw/day. About 90%-98% of the ¹⁴C-residue in milk samples were
found to be the parent compound. Milk also contained about 4-5 minor
degradates (El Naggar et al., 1984).

Analysis of tissues and milk from goats administered ¹⁴C-
labelled bifenthrin at dose levels of 2 mg/kg bw/day for seven
consecutive days showed the parent compound to be the major product
in milk, contributing about 75%-82% of total ¹⁴C-residues (ca. 1
ppm). Fat contained 78%-80% (ca. 1.7 ppm) parent compound, muscle
74%-88% (ca. 6.2 ppm), heart 77% (ca. 0.4 ppm), kidney 16%-22% (0.1
ppm) and liver 19%-44% (0.8 ppm). Biphenyl acid was the major
metabolite identified in kidney and liver amounting to 42% (0.2 ppm)
and 31% (0.6 ppm), respectively, and was a minor metabolite in milk.
Biphenyl alcohol was detected in milk, fat, kidney and liver at
lower levels (< 1-3%). Other metabolites, including 4'-hydroxy-
bifenthrin, hydroxymethyl-bifenthrin, hydroxymethyl-TFP acid³ and
BP aldehyde⁴ were detected in minor amounts. A majority of the
¹⁴C-residues were isolated as organosoluble, non-conjugated
products. Certain hydrolytic and intact ester metabolites of the
parent chemical were found to be conjugated with polar and nonpolar
substrates (El Naggar et al., 1986a).

³ Cis, trans-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2-methyl,
trans-hydroxy-methyl-(1-¹⁴C)-cyclopropanecarboxylic acid
⁴ 2-Methyl-3-phenylbenzaldehyde

Lactating goats were orally dosed with acid (cyclopropyl)-¹⁴C
or alcohol (phenyl)^-14C-bifenthrin at 2 mg/kg bw/day for 7
consecutive days. ¹⁴C-Residues from acid-¹⁴C and alcohol-¹⁴C
were comparable. Steady state concentration in milk was reached
within 4 days from the beginning of dosing and ranged from about
0.8-1.5 ppm. Maximum residues in liver, fat, kidneys and heart were
3.9 ppm, 2.8 ppm, 1.0 ppm and 0.6 ppm, respectively. About 40%-52%
of the dose was excreted in faeces and 8%-17% in the urine (Predmore
et al., 1984).

Toxicological studies

Acute toxicity studies

The predominant clinical signs in the animal species tested
were clonic convulsions, tremors and oral discharge. The results are
summarized in Table 1. Bifenthrin has moderate acute toxicity and is
classified as moderately hazardous by WHO (WHO, 1992).

Table 1: Acute toxicity of bifenthrin

Species Sex Route LD₅₀ Reference
(mg/kg bw)

Mouse M,F oral 43 Freeman (1983)

Rat M,F oral 56 Freeman et al. (1982)
Freeman et al. (1983a)
Rabbit M,F ip 799 Freeman et al. (1986)
dermal > 2000 Freeman et al. (1983b)

Irritation and sensitization

Instillation of 0.1 ml in the eyes of rabbits caused slight
irritation reactions (Freeman et al., 1983c). No irritation was
observed after dermal application on abraded and intact skin of
rabbits (Freeman et al., 1983d). After dermal treatment of guinea-
pigs with undiluted material no sensitization reaction was noted
(Freeman et al., 1983e).

Short-term toxicity studies

Mice

Two sequential 28-day dietary studies were conducted with
groups of mice (Swiss Webster 10/sex/group). In the first study
bifenthrin was administered in the diet at concentrations of 0, 50
(500), 100, 200 or 300 ppm. Since there were no significant
treatment-related adverse effects in the 50 ppm group, it was

changed to a dietary concentration of 500 ppm for the last 2 weeks
of the study. Therefore a second study was initiated with dosage
levels of 0, 500, 600, 750 or 1000 ppm. Tremors and clonic
convulsions were the most consistent clinical signs of intoxication
noted in males and females of the 750 and 1000 ppm groups prior to
death. Tremors were also prevalent in males and females surviving
dietary treatment of 500 and 600 ppm.

In the 1000 ppm, 7/10 males and all females died. Deaths
occurred also at 750 and 600 ppm in females only. No consistent
influence on body-weight was noticed among the treatment groups.
Food consumption was depressed in males at 1000 and 750 ppm during
most of the study and in females in all dose groups in the first
study week. Changes in mean organ weights were slight and showed no
dose-response relationship. The NOAEL was 300 ppm equal to 69 mg/kg
bw/day for males and 84 mg/kg bw/day for females (Rand et al.,
1983a).

Rats

In a 28-day range-finding study, groups of rats (Sprague-
Dawley, 10/sex/group) were fed dietary levels of 0, 50, 100, 200,
300 or 400 ppm. All rats in the 400 ppm group died by day 15 of the
study. Clinical signs consisting of clonic convulsions and tremors
were observed at dose levels of 200 ppm and higher. Deaths occurred
also at 300 ppm (6/10 males and 1/10 females). No further results
are recorded for the study group at 400 ppm. Body-weight gain was
reduced in the 300 ppm dose group and at 200 ppm in males at the
beginning of the study. Food consumption was depressed at 200 and
300 ppm particularly during the first study weeks. Changes in the
organ weights usually did not follow a dose-related pattern with the
exception of an increase in adrenal weight and depressed testes
weight in males at 300 ppm. At 300 ppm in males relative organ
weights of the brain and kidney were elevated; in females at this
dose level an elevation of the relative brain, kidney and liver
weights were observed. No other parameters were investigated. The
NOAEL was 100 ppm equal to about 11 mg/kg bw/day (Rand et al.,
1983b).

Tehnical bifenthrin (90% cis/10% trans-isomer) was
continuously administered in the diet of rats (Sprague-Dawley:
15/sex/dose) for at least 90 days at concentrations of 0, 12, 50,
100 or 200 ppm. For this study only a summary report was available.
An additional 10 animals in the control and 200 ppm group were
observed for a period of 28 days without treatment to discover
reversibility or appearance of delayed effects. The only significant
treatment-related effect consisted of tremors in all test animals of
the 200 ppm group. This effect was reversible and was not observed
during the 28-day post treatment period. The treatment did not cause
effects on mortality, body-weight development, food consumption,
ophthalmologic examination, haematology, clinical chemistry, organ

weights or gross and histopathological examination. The NOAEL in
this study was 100 ppm equivalent to 5 mg/kg bw/day (Rand et al.,
1984).

Rabbits

Technical bifenthrin was applied to the shaved skin of rabbits
(New Zeeland white; 6/sex/group) for at least 6 h/day at dosages of
0, 25, 50, 100 or 500 mg/kg bw/day for 21 consecutive days. One
female at 500 mg/kg bw/day died on day 19 most probably due to
ingestion of the test material. The other animals at 500 mg/kg
bw/day showed tremors and loss of muscle control as the most
consistent sign of intoxication. The treatment did not influence
body-weight gain, food consumption, values of haematology and
clinical chemistry with the exception of an increased platelet count
in males at 500 mg/kg bw/day and elevated kidney- and liver-weights
in females at this dose level. The NOAEL in this study was 100 mg/kg
bw/day (De Prospo et al., 1984).

Dogs

In a 13-week subchronic oral capsule study, groups of dogs
(beagle: 4/sex/dose) were treated with technical bifenthrin (purity
88.4%) at levels of 0, 2.5, 5.0, 10 or 20 mg/kg bw/day. There were
no treatment-related effects on survival, food consumption,
ophthalmologic examination, haematology, clinical chemistry, organ
weights, gross and microscopic pathology. Compound-related tremors
were observed at doses of 5 mg/kg bw/day and above. Signs of ataxia
and languid appearance were noted at 20 mg/kg bw/day with single
findings at 10 and 5 mg/kg bw/day. Less frequent or isolated signs
of compound-related effects included salivation, lacrimation or
mydriasis. Slightly reduced body-weight gain was observed at 20
mg/kg bw/day in females. The NOAEL in this study was 2.5 mg/kg
bw/day (Serota et al., 1984).

In a 52-week oral capsule study, groups of dogs
(beagle;4/sex/dose) were treated with technical bifenthrin (purity
88.4%) at dose levels of 0, 0.75, 1.5, 3.0 or 5.0 mg/kg bw/day. No
treatment-related effects concerning survival, food consumption,
ophthalmology, haematology, clinical chemistry, urinalysis, organ
weights, gross pathology and histopathology were observed. Dose-
related tremors appeared at doses of 3 and 5 mg/kg bw/day after 15
weeks of treatment disappearing again following 29 weeks of
treatment. The body-weight gain was decreased in males at 5 mg/kg
bw/day. The NOAEL in this study was 1.5 mg/kg bw/day (Serota et
al., 1985).

Long-term toxicity/carcinogenicity studies

Mice

In a lifetime feeding study technical bifenthrin (purity 88.4%)
was administered continously over at least 20 months in the diet of
mice (Swiss Webster; 50/sex/dose) at concentrations of 0, 50, 200,
500 or 600 ppm (these levels refer to concentrations of pure
bifenthrin). The treatment did not affect significantly the survival
rate of the animals although single early deaths after 1-2 weeks of
study occurred at 500 and 600 ppm. The predominant clinical sign of
toxicity consisted of tremors occurring at 500 and 600 ppm. Single
males at 200 ppm exhibited also minimal clinical signs of toxicity.
Body-weight gain was reduced in all dose groups in males and in the
500 and 600 ppm group in females, but no distinct dose-effect
relationship was observed. A treatment-related depression in food
consumption was observed in the first week of the study only in the
two highest dose groups. The treatment did not affect the
haematological parameters and organ-weights. Histopathological
examination revealed an increase in urinary bladder tumours in high-
dose males. The tumours were originally described as leiomyosarcoma
of the urinary bladder wall by the study author with incidences of
2/48 (4%), 6/50 (12%), 8/50 (16%), 7/50 (14%) and 14/49 (29%), in
the control, 50, 200, 500 and 600 ppm groups respectively. The
tumours were also noted in females including one control animal, but
no dose-effect relationship was present. The data have been
reassessed by a panel of pathologists who concluded that the tumours
were of vascular origin. The panel reported incidences of 10, 14,
16, 16, and 27% in control through the high-dose group,
respectively. So far lesions of this morphology have only been
reported infrequently in the literature probably due to variations
in diagnoses. They are described only in the mouse and predominantly
in males. The historical control incidence is not known,
furthermore, no lesions of this morphological type have been
reported in the human urinary bladder. According to the reassessment
of the histological data the tumours occurring in the submucosa of
the mouse bladder are of low malignant potential (slow growth, no
metastasis). Statistical analysis of the data produced equivocal
results leading to the conclusion of the study reviewers (Butler et
al., 1991) that the results do not provide persuasive evidence of
a compound-related effect. Although the statistical analysis of the
tumour data does not indicate unambiguous significance of the
increase in incidence of bladder tumours, the lack of such
significance being used as the only criterion to rebut tumorigenic
potential is not sufficient to exclude a possible tumorigenic
potential of the compound. In addition, an increased incidence of
liver hyperplasia/adenoma/carcinoma was observed in the high dose
males. A significant trend was noted for carcinoma incidence which
occurred in 0/49, 0/50, 1/50, 2/49 and 2/49 at 0, 50, 200, 500 and
600 ppm respectively. The NOAEL in this study was 50 ppm equal to
7.6 mg/kg bw/day concerning clinical effects in males and 200 ppm

equal to 37 mg/kg bw/day in females, respectively (Geiger et al.,
1986).

Rats

In a two-year feeding study in rats (Sprague-Dawley;
50/sex/dose) technical bifenthrin (purity 88.4%) was administered at
dietary concentrations of 0, 12, 50, 100 or 200 ppm. The treatment
did not influence mortality, parameters of clinical chemistry,
urinalysis, organ weights, gross and microscopic examination.
Numerous instances of tremors were observed in all males and females
of the 200 ppm group between day 4 through about day 30, in single
animals and at single instances also in the other dose groups. Due
to the low number of animals and incidences and the lack of a dose-
relationship, the tremors observed at lower dose levels are not
considered treatment-related. A treatment-related decrease in body-
weight gain was observed in females at 200 ppm. Erythrocyte counts
were reduced in males at 200 ppm. In this study, bifenthrin did not
show any tumorigenic potential. The NOAEL in this study was 100 ppm
equal to 4 mg/kg bw/day in males and 7.5 mg/kg bw/day in females
(McCarty et al., 1986).

Reproduction studies

Rats

Only a summary report was available for evaluation of this
study. Bifenthrin (technical) was administered in the diet at
concentrations of 0, 30, 60 or 100 ppm to groups of rats
(25/sex/group) over two consecutive generations. The dietary levels
represent concentrations of bifenthrin after correcting for purity.
There was no influence on mortality. At 100 ppm tremors were
observed in lactating dams of the P₁ and F₁ generation. Females
of the P₁ generation showed reduced body-weight gain on days 7 and
14 of the lactation period. Food consumption was depressed in the
F₁ group at 100 ppm in the males during a single week of exposure.
The treatment did not have any effects on the reproductive
performance or litter size, litter weight or survival of the
progeny. Changes in organ weights at 100 ppm consisted of an
elevation of the brain weights of P₁ females. No histomorphologic
alterations were observed in tissues from parental or weanling
animals. A NOAEL of 60 ppm equivalent to 3 mg/kg bw/day is proposed
(DeProspo et al., 1986).

Special studies on delayed neurotoxicity

Rats

Groups of rats (COBS/Wistar; 3 males/dose group) were orally
treated with dose levels of 0, 1, 3, 10 or 30 mg/kg bw/day for 5
consecutive days. Parameters investigated included alertness,

locomotor activity, apathy, tremor and abnormal gait. Rats at 30
mg/kg bw/day showed tremor, abnormal gait, respiratory depression
and signs of CNS depression (apathy, paralysis). Deaths occurred
after developing convulsions. No effects were recorded during the 7-
day period after termination of dosing with 1, 3 and 10 mg/kg bw/day
(Algate et al., 1985).

The minimum effective dose of 30 mg/kg bw/day which caused
neurological signs such as paralysis as determined in the Irwin
dose-range test (Algate et al., 1985) was used in a tilting-plane
test. The test compound was administered orally to groups of rats
(5/sex) on two consecutive days. The tilting-plane test (parameter:
angle of inclination at which the animals began to slide down a
tilted platform) was performed every second day from days 2-16 of
the study. The results did not reveal impairment of performance by
the treatment and this gave no indication of a delayed neurotoxic
effect (Algate et al., 1985).

Hens

In a neurotoxicity study, female domestic hens were orally
treated with a single dose of 5000 mg/kg bw followed by a repeat
dose after 21 days in birds showing negative response at this dose
level (LD₅₀ > 5000 mg/kg bw). The second dose was followed by a
22-day observation period. Clinical signs of toxicity consisting of
unsteadiness and trembling appeared within about 22 h after dosing.
Some mortalities occurred in all groups. Surviving birds had
recovered from the clinical signs a few days after second dosing.
The treatment did not produce clinical signs of delayed
neurotoxicity. No histological examination of the nervous tissue was
performed (Roberts et al., 1984).

Special studies on embryotoxicity and teratogenicity

Rats

In a teratogenicity study, groups of rats (25
females/dose/group) were orally treated (gavage) on days 6 through
15 of gestation with doses of 0, 0.5, 1 or 2 mg/kg bw/day.
Estimation of dose levels were based on a previous pilot teratology
study, where doses of 2.5 mg/kg bw/day resulted in the death of some
dams (DeProspo et al., 1983b). An aqueous aspirin suspension (250
mg/kg bw/day) served as positive control. Tremors were observed as
the predominant sign of toxicity among animals receiving 2 mg/kg
bw/day. Body-weight gain did not differ between the different
groups. No treatment-related effects were observed concerning the
reproduction parameters (pregnancy, number of corpora lutea,
implantations, resorptions or litter size). Malformations occurred
only sporadically in all groups and without dose relationship. The
study did not reveal any teratogenic activity of bifenthrin at the
dose levels tested . The NOAEL in this study was 1 mg/kg bw/day for

maternotoxicity and > 2 mg/kg bw/day for embryo fetotoxicity
(Freeman et al., 1984b).

Rabbits

In an oral teratology study groups of rabbits (20
females/dose/group) were treated with doses (stomach tube) of 0,
2.7, 4 or 8 mg/kg bw on days 7 through 19 of gestation. The
recommended dose levels were estimated from a previous dose range
finding study (DeProspo et al., 1983a). Observations of tremors
were noted for most of the animals receiving 8 mg/kg bw/day and head
and fore limb twitching were observed during the second half of the
dosing period among most of the animals receiving 4 or 8 mg/kg bw.
The application of the test material did not affect the body-weight
of the dams, the reproduction parameters, viability or body-weight
of the pups, nor the incidence of external and visceral anomalies.
The study therefore gave no indication for a teratogenic potential
at the dose-levels administered. The NOAEL was 2.7 mg/kg bw/day for
maternotoxicity and > 8 mg/kg bw/day for embryo-fetotoxicity
(Freeman et al., 1984a).

Special studies on genotoxicity

Based on the results of genotoxicity essays given in Table 2,
the Meeting concluded that bifenthrin was unlikely to present a
genotoxic hazard.

COMMENTS

After oral administration of bifenthrin to rats the compound
was absorbed and eliminated mainly via faeces (70-80% within 48 h).
Urinary excretion amounted to 5-10% of the administered doses.
Biliary excretion was shown to range from 20-30%. Hydrolysis and
hydroxylation were the majors steps in the biotransformation.

Bifenthrin has moderate acute toxicity and is classified as
moderately hazardous by WHO (WHO, 1992).

Following dietary administration to rats for 90 days at
concentrations of 0, 12, 50, 100 or 200 ppm bifenthrin, tremors were
the only treatment-related effect occurring at 200 ppm. The NOAEL
was 100 ppm, equivalent to 5 mg/kg bw/day.

In a 13-week oral toxicity study in dogs at doses of 0, 2.5,
5.0, 10 or 20 mg/kg bw/day administered in capsules, the NOAEL of
2.5 mg/kg bw/day was based on the occurrence of tremors at 5.0 mg/kg
bw/day and higher. In a one-year oral toxicity study in dogs at
doses of 0, 0.75, 1.5, 3.0, or 5.0 mg/kg bw/day administered in
capsules, the NOAEL of 1.5 mg/kg bw/day was based on the appearance
of the same clinical signs.

In a lifetime feeding study with mice at dietary concentrations
of 0, 50, 200, 500 or 600 ppm over at least 20 months, a NOAEL
(based on tremors at 200 ppm in males and 500 ppm in females) was 50
ppm, equal to 7.6 mg/kg bw/day in males, and 200 ppm, equal to 37
mg/kg bw/day, in females. Treatment at 600 ppm equal to 103 mg/kg
bw/day caused an increased incidence of submucosal tumours
(hemangiomas) in the urinary bladder in male animals. This finding
was of marginal statistical significance, but tumorigenic potential
for bifenthrin in mice cannot be excluded.

In a two-year feeding study with rats at concentrations of 0,
12, 50, 100 and 200 ppm, the NOAEL was 100 ppm equal to 4 mg/kg
bw/day in males and 7.5 mg/kg bw/day in females. Higher dose levels
caused tremors and a reduction in body-weight gain. Bifenthrin was
not carcinogenic in rats.

In a multigeneration study in rats at dietary concentrations of
0, 30, 60 or 100 ppm, the NOAEL was 60 ppm equivalent to 3 mg/kg
bw/day, based on changes in brain weight at 100 ppm. Reproduction
was not impaired by treatment.

In a teratogenicity study in rats at gavage dose levels of 0,
0.5, 1 or 2 mg/kg bw/day, the NOAEL was 1 mg/kg bw based on the
occurrence of tremors at 2 mg/kg bw in the dams. There was no
evidence of teratogenicity.

In a teratogenicity study in rabbits at gavage dose levels of
0, 2.7, 4 or 8 mg/kg bw/day, the NOAEL was 2.7 mg/kg bw/day. Doses
of 4 and 8 mg/kg bw/day caused tremors and twitching. No
teratogenic, foetotoxic or embryotoxic effects were found.

After reviewing the available genotoxicity data, the Meeting
concluded that bifenthrin was unlikely to present a genotoxic
hazard.

The results of the long-term studies in rats and mice and a
series of studies designed to evaluate genotoxicity indicated that
bifenthrin is unlikely to pose a carcinogenic hazard to humans.

An ADI was allocated on the basis of the NOAEL of 1.5 mg/kg
bw/day in the one-year study in dogs using a 100-fold safety factor.
This result was supported by the same NOAEL in the rat teratology
study, although in the latter study gavage, rather than dietary
administration, was used.

Table 2. Results of genotoxicity assays on bifenthrin

Test system Test object Concentration Results Reference
(purity)

Ames assay S. typhimurium 75 - 7500 µg/plate negative Haworth (1983)
± activation
(techn. mat.)

Ames assay S. typhimurium 8 - 5000 µg/plate precipitation
5000 µg/plate at negative Kennelly et al. (1988)
± activation (88.4%)

Mouse lymphoma L 5178 Y mouse non-activated:
assay lymphoma cells 0.018 - 0.24 µl/ml positive¹ Kirby (1983)
(TK +/- locus) activated:
0.0075 - 0.1 µl/ml
(88.3%)

Mouse lymphoma L 5178 Y mouse 15.8 - 500 µg/ml negative Kennelly (1986)
assay lymphoma cells ± activation
(HGPRT locus) (purity not specified)

CHO/HGPRT Chinese hamster without activation: negative
mutation assay ovary cells 250 - 1000 µg/ml
with activation: inconclusive² Thilagar (1984a)
20 - 50 µg/ml (88.3%)

CHO/HGPRT Chinese hamster 10 - 100 µg/ml
ovary cells ± activation negative Heidemann et al. (1989)
(90.6%)

Chromosome Chinese hamster 1000 - 10 000 µg/ml negative Thilagar (1984b)
aberration assay ovary cells ± activation
(techn. mat.)

DNA repair rat primary 0.01 - 2.0 µl/ml positive³ Thilagar (1983a)
test (UDS) hepatocytes (techn. mat.)

Table 2 (cont'd)

Test system Test object Concentration Results Reference
(purity)

DNA repair rat primary 0.5 - 2.5 µl/ml negative Thilagar (1983b)
test (UDS) hepatocytes (techn. mat.)

DNA repair rat primary 1 - 100 µg/ml negative Fautz et al. (1989)
test (UDS) hepatocytes (90%)

Sister chromatid Chinese hamster 1 - 60 µg/ml negative Heidemann (1989)
exchange ovary cells (CHO) ± activation
(90.6%)

Transformation BALB/3T3 3 - 100 µg/ml negative Putman (1983a)
test mouse embryo without activation
cells (techn. mat.)

5 day rat 3, 10, 30 mg/kg negative Putman (1983b)
Cytogenetics oral
assay (in vivo) (techn. mat.)

Recessive lethal Drosophila 50 and 100 µg/ml negative Benson (1984)
assay (in vivo) melanogaster (88.4%)

¹ After metabolic activation: positive answer at the highest concentration of 0.1 µl/ml without
metabolic activation in most concentration positive, no distinct dose-effect relationship.

² In the activation system at the lowest dose of 20 µg/ml postive response; no dose-response relationship.

³ Slightly positive answer at the highest dose level of 2 µg/ml.

TOXICOLOGICAL EVALUATION

Level causing no toxicological effect

Mouse: 50 ppm, equal to 7.6 mg/kg bw/day (20-month feeding
study)

Rat: 100 ppm, equal to 4 mg/bw/day (two-year feeding study)
1 mg/kg bw/day (teratogenicity study)
60 ppm, equivalent to 3 mg/kg bw/day (multi-generation
reproduction study)

Rabbit: 2.7 mg/kg bw/day (teratogenicity study)

Dog: 1.5 mg/kg bw/day (one-year study)

Estimate of acceptable daily intake for humans

0-0.02 mg/kg bw

Studies which will provide information valuable in the continued
evaluation of the compound

Observations in humans.

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* FMC 54800 = Bifenthrin

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Jameson, C.E., Cuirle, E.M., Landholt, K., Robinson, R.A., Shaffer,
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Kennelly, J.C., Garner, J.V., & Weiner, M. (1986). Study to
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Putman, D.L., Bullock, W.L., Malloy, A.V., McCarvill, J., & Putman,
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Putman, D.L., Bullock, W.L.. Malloy, A.V., Melhorn, J.M., & Putman,
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Rand, G.M. Bullock, W.L., Flechter, M.J., McCarty, J.D., Norvell,
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Rand, G.M. Barta, W.D., Bullock, W.L., Flechter, M.J., Kikta, E.J.,
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Rand, G.M. (1984) Ninety-day feeding study in rats with FMC 54800
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Roberts, N.L. Bullock, W.L., Hakin, B., Malloy, A.V., & Shillam,
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Selim, S., Chun C,L., El Naggar, S.F., Isbell, D., Mazur, P., &
Patterson, R. (1986b). The kinetics of FMC 54800 in the blood of
rats following a single oral dose. Unpublished report No. PC-0048
from Biological Test Center, Irvine, CA, USA. Submitted to WHO by
FMC Corporation.

Serota, D.G., Alsaker, R.D., Bullock, W.L., Daywkins, B.G., Hagen,
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report No A83-820. Unpublished report prepared by Hazleton
Laboratories America, Inc. for FMC Corp., Princeton, NJ, USA.
Submitted to WHO by FMC Corporation.

Serota, D.G., Alsaker, R.D., Hagen, W.H., Marshall, P.M., Ruoff,
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report No. A83-821. Unpublished report prepared by Hazleton
Laboratories America, Inc. for FMC Corp., Princeton, NJ, USA.
Submitted to WHO by FMC Corporation.

Singer, S.S., Barge, M., Cuirle, E.M., El Naggar, S.F., Robinson,
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metabolite residue in liver. Unpublished report No. P-1834 from FMC
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Thilagar, A., Brauninger, R.M., Bullock, W.L., Karten, P.V.,
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synthesis in rat primary hepatocytes: FMC 54800 technical. FMC
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Associates for FMC Corp., Princeton, NJ, USA. Submitted to WHO by
FMC Corporation.

Thilagar, A., Brauninger, R.M., Bullock, W.L., Karten, P.V., &
Malloy, A.V. (1983b). Unscheduled DNA synthesis in rat primary
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Thilagar, A., Bullock, W.L., Karten, N.S., Kott, S., & Malloy, A.V.
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Corporation.

Thilagar, A., Bullock, W.L., Karten, N.S., Kott, S., Kumaroo, P.V.,
& Malloy, A.V. (1984b). Chromosome aberrations in Chinese hamster
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Tullman, R.H. & Robinson, R.A. (1986). Analysis of FMC 54800
residues in plasma from rats dosed orally with ¹⁴C FMC 54800.
Unpublished report No. P-1448 from FMC Corp., Princeton, NJ, USA.
Submitted to WHO by FMC Corporation.

Tullman, R.H., El Naggar,S.F., Barge, M., Curle, E.M., Robinson,
R.A., & Tullman, R.H. (1987). Nature of the residue livestock.
Metabolism of FMC 54800 in the laying hen. Nature of the residue in
adductor muscle, abdominal fat and egg yolk. Unpublished report No.
P-1840 from FMC Corp., Princeton, NJ, USA. Submitted to WHO by FMC
Corporation.

WHO (1992). The WHO recommended classification of pesticides by
hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
Available from the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland.

Wu, J. (1987). Nature of the residue: livestock. Metabolism of FMC
54800 in the laying hen. Nature of the nonextractable residue in
liver. Unpublished report No. P-1840 from FMC Corp., Princeton, NJ,
USA. Submitted to WHO by FMC Corporation.

Wu, J., Barge, M., Cuirle, E.M., & Robinson, R.A. (1988). Metabolism
of ¹⁴C-bifenthrin (FMC 54800) in rats - analyis and quantitation
of metabolites in excreta. Unpublished report No. PC-0093 from
Xenobiotic Laboratories, Inc., Princeton, NJ, USA. Submitted to WHO
by FMC Corporation.

    See Also:
       Toxicological Abbreviations
       Bifenthrin (UKPID)