CYFLUTHRIN
EXPLANATION
This chemical has not been previously evaluated by the WHO
Expert Group.
Cyfluthrin is a synthetic pyrethroid insecticide that is marketed
under the trade name "Baythroid". The technical grade compound is
described by the sponsor as "a mixture of four diastereoisometric
enantiomer pairs".
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical Aspects
1. Absorption, distribution, and excretion
Male and and female rats were divided into four groups (4-5
rats/sex/group) and treated according to the following protocol:
Group A: single i.v. dose of 0.5 mg/kg.
Group B: single oral dose of 0.5 mg/kg.
Group C: 14 consecutive oral doses of 0.5 mg/kg (Unlabeled),
followed by a single oral dose of
0.5 mg/kg of the radiolabelled test substance.
Group D: single oral dose of 10 mg/kg.
Excreta and tissue samples were collected to assess absorption,
elimination, and distribution of the test compound.
After i.v. administration, the plasma half-life [t(1/2)] of
elimination was found to be biphasic, with a t(1/2) for the rapid
phase of about 2 hours, and a t(1/2) for the slow phase of about
20 hours. Elimination in the male was slightly faster than in the
female, consequently the Area Under the Curve (AUC) for females was
larger than for males. About 60% of the administered dose was
eliminated in the urine in the first 24 hours, with only an additional
5% eliminated over the next 24 hours, approximately 20% of the
administered dose was eliminated in the feces in the first 24 hours;
an additional 3-4% was eliminated after 48 hours. Only a trace amount
of radiolabel was recovered in expired air. The ratio of urinary/fecal
metabolites was about 2.9 in males and 2.3 in females.
The apparent volume of distribution was calculated to be 18% for
males and 16% for females, which is consistent with distribution
primarily to the extracellular fluid compartment. Six to 7% of the
administered dose was recovered from the bodies of rats sacrificed 48
hours after the i.v. dose. The GI tract accounted for about 0.7% of
the dose. The remainder of radioactivity was distributed among all
tissues, with the highest relative concentrations occurring in the
following tissues (in descending order): fat, ovaries, adrenal, liver,
and spleen. The lowest relative distribution was recorded for the
brain, suggesting that the test material does not readily penetrate to
that compartment. With the exception of the relatively high recovery
from ovaries, no difference in tissue retention between males and
females was apparent.
A single oral administration of 0.5 or 10 mg/kg had little effect
on elimination. The t(1/2) of absorption was calculated to be about
0.5 hours, and was independent of dose. Elimination was also biphasic,
with a rapid t(1/2) of about 2-3 hours, and a slow phase of about 9-12
hours. The ratio of urinary/fecal metabolites in males was about 3.0
in the low dose group, and about 2.0 in the high dose group. For
females these values were 1.6 in the low dose group and 1.2 and 2.2 in
two different high dose groups. Distribution to tissues was similar to
that observed after i.v. administration, however only about 2% of the
administered dose was retained after 48 hours.
The multiple dose experiment yielded results essentially similar
to those obtained after a single dose, however excretion in the female
was found to be monophasic, with a t(1/2) for elimination of about 6
hours. The ratio of urinary/fecal excretion was higher in males (2.8)
than in females (1.8) (Klein et al., 1983).
The second study group of 1-5 male rats was administered single
doses of 0.5 mg/kg and 10 mg/kg orally, and 0.5 mg/kg i.v. and
intraduodenally. A group of 5 females was also administered a single
oral dose of 0.5 mg/kg.
Recovery of radiolabel in excreta was similar to the observed in
the previous study, as about 55-70% of an administered dose was
eliminated in the urine within 48 hours, and about 25-35% was
eliminated in the feces over this time period. Cannulation of bile
ducts indicated that about 34% of an administered dose was excreted
into the bile, and about 12% was recovered in feces. The study authors
concluded that a small amount of material excreted into the bile was
reabsorbed by enterohepatic circulation. About 1-1.5% of an
administered oral dose was retained in the body (excluding GI tract),
with no effect of dose on the percentage retained. About 5% was
retained after i.v. administration, and about 0.5% was retained after
intraduodenal administration.
The study authors concluded that the "excretion behaviour of the
radioactivity shows a marked dependency on the route of
administration". The present reviewer cannot agree with this
conclusion, as the differences between the groups were modest, at
best. The only group which appeared to be significantly different was
the intraduodenal group, which excreted about 1/2 as much label via
the feces as other test groups.
Animals were administered 10 mg/kg orally, than sacrificed at
various times in order to assess the time course of distribution and
elimination of radiolabel. At 1.5 hours after administration, 38% of
the administered dose was retained in the body (excluding the GI
tract). This value rapidly declined so that after 24 hours only 4.2%
remained, and by 10 days only 0.23% of the administered dose remained
in the body. The half-lives of absorption and elimination were similar
to those obtained in the previous study.
At initial measurements (1.5 hours), the greatest relative amount
of radiolabel was found in plasma, liver and kidney. By the end of
10 days, 0.2% of the administered dose remained in the body, with the
greatest relative amounts found in fat, liver, sciatic nerve and
adrenal glands. The elimination from tissues was biphasic, with a
t(1/2) for the rapid phase that ranged from 2.1 hours (adrenal) to
7.5 hours (sciatic nerve). For the majority of tissues the slow phase
t(1/2) was between 51 and 87 hours, however fat and sciatic nerve had
somewhat longer half-lives for this phase, 101 and 113 hours,
respectively.
The study report noted that 5 minutes after an i.v. injection,
the distribution of radiolabel was "essentially a representation of
the distribution of blood in the body". Four hours after an oral dose
of 10 mg/kg, a similar pattern was noted, with the distribution of
label related to regional blood flow and excretion routes. By 24 hours
after an oral dose, "high concentrations are evident in all fatty
tissues and in skin", with intermediate shadings in tissues such as
liver and kidney, and light shadings in remaining tissues (Weber and
Suwelak, 1983).
In a study to assess the effect of the formulation vehicle on the
rate of absorption, male Wistar rats (14/dose) were given a single
dose by gavage of 10 mg/kg as a 0.2% solution in Lutrol (polyethylene
glycol 400) or a 0.1% emulsion in Cremophor EL/distilled water. Two
rats from each group were sacrificed 0.5, 1, 2, 4, 6, 16 and 24 hours
after treatment. Blood was sampled by cardiac puncture, and stomachs
were removed and analysed for contents.
It was found that absorption was much more rapid with the
Cremophor EL/distilled water emulsion, as cyfluthrin was detected in
the blood after 30 minutes and reached a peak concentration within
1 hour. In contrast, cyfluthrin could not be detected in the blood of
rats treated with the Lutrol solution until after 4 hours, and peak
concentrations were not obtained until after 6 hours. Predictably,
concentrations of cyfluthrin in the stomach were higher in rats tested
with Lutrol than in rats treated with Cremophor EL/distilled water;
this effect was most apparent at early time points (Eben et al.,
1982).
2. Biotransformation
Groups of male rats (number unspecified) were administered a dose
of 10 mg/kg, and urine was collected over 0-8 hours and from
8-24 hours after administration. As an initial analysis by thin-layer
chromatography revealed no difference in metabolites between animals,
urine samples were pooled by collection time for identification of
metabolite structures. It was found that about 60% of the urinary
radioactivity was excreted in a conjugated form (glucuronide or
sulfate), and was tentatively identified as conjugate(s) of
4'-hydroxy-3-phenoxy-4-fluourobenzoic acid. After acid hydrolysis, a
second major metabolite (about 40% of excreted radioactivity) was
tentatively identified as conjugate(s) of 3-phenoxy-4-fluorobenzoic
acid (Ecker, 1982).
A second study was conducted to more fully characterize the
metabolic pathway for cyfluthrin. Excreta were collected from animals
treated as described above in the study by Klein et al. (1983). The
major metabolite was identified as a conjugate of 4'-hydroxy-
3-pheoxy-4-fluorobenzoic acid (FCR3145), which accounted for about
40-50% of recovered urinary radioactivity from rats given sample or
multiple doses of 0.5 mg/kg. A slight sex difference was noted, as
females tended to excrete more of this metabolite (about 5% of
recovered radioactively) in the feces in an Unconjugated form than did
males. Males and females given the high dose of 10 mg/kg excreted
about 35% of recovered activity as the urinary conjugate of FCR3145,
whereas females excreted about 5% more of recovered activity as free
(unconjugated) FCR3145, compared to males. A greater percentage of
radioactivity was recovered in the feces as unmetabolized parent
(FCR1272) after repeated oral doses (12-16%, as compared to <1% for
single low doses) or after a single high dose (17-19%) (Ecker, 1983).
A proposed metabolic pathway is described in Figure 1.
3. Effects on enzymes and other biochemical parameters
See "Special Studies on Neurotoxicity" for a description of
studies assessing the effects of cyfluthrin on neurotoxic esterage
activities.
A published literature review paper discussed the mechanism of
toxicity of the pyrethroid class of insecticides in the vertebrate
nervous system. Although this paper did not specifically address
cyfluthrin, the mechanism of toxicity of this compound is likely to be
similar to that of other members of this class of insecticides.
Structure-activity studies of a number of pyrethroid insecticides
suggest that these chemicals bind to a receptor with a specific chiral
formation.
The reviewed literature suggest that the pyrethroids interfere
with the sodium channel of nerve cell membranes, causing channels that
are open to remain open, resulting in n delay in re-polarization of
the nerve. The alpha-cyano pyrethroids (of which cyfluthrin is a
member) appear to be much more potent in this regard, and also differ
somewhat from other pyrethroids in that repeated stimulation of
peripheral myelinated nerves in the presence of an alpha-cyano
pyrethroid results in a gradual depolarization of the nerve membrane
with resultant suppression of the action potential. In contrast, these
compounds cause long-lasting trains of repetitive firing in afferent
sensory nerves, and this phenomenon is thought to account for facial
paresthesias observed in humans following exposure to alpha-cyano
pyrethroids. No anticholinesterase activity was noted with these
compounds (Vijverberg and Van den Bercken, 1982).
TOXICOLOGICAL STUDIES
A. Special Studies
Special Studies on Carcinogenicity
Mice
See under "Long-term Studies".
Rats
See under "Long-term Studies".
Special Studies on Neurotoxicity
Hens
Cyfluthrin was tested for acute delayed neurotoxicity in the
White Leghorn hen in several experiments. These experiments produced
symptoms of excitation and behavioural disorders, and mortality, in
birds given single or multiple oral doses as high as 5000 mg/kg.
Systematic histopathologic examinations did not reveal any evidence of
treatment-related lesions to nerve tissues, nor was any effect on
neuropathic target esterage (NTE) activity noted. Exposures by
inhalation or dermal routes also failed to produce evidence of
neurotoxicity (Thyssen et al., 1981; Hixson, 1981; Thyssen and Mohr,
1980; Pauluhn and Kaliner, 1983; Flucke and Eben, 1985;
Sacchse, 1986).
Rats
In a short-term study deigned to detect morphological changes in
the nervous system in rats, a group of 50 male Sprague-Dawely rats was
administered by gavage a dose of 80 mg/kg of technical cyfluthrin
(95% purity) for 5 consecutive days, at which time the dose was
lowered to 40 mg/kg for treatment over days 6-14 due to the onset of
symptoms of toxicity. A group of 25 male rats served as a vehicle
control group. At the end of the 14-day treatment period rats were
observed for 3 months without additional treatments. Ten treated rats
and 5 control rats were sacrificed 1 day, 5 days, and 1, 2, and 3
months after the final dose of test chemical. Rats were perfused with
formalin, and after preparation of tissues, examined by light
microscopy for changes in central and peripheral nervous tissue, and
in skeletal muscle. In addition, 2 rats from the treated group and 1
control rat were assessed at each time point (except at 2 months) for
changes in these tissues visible by electron microscopy.
During treatment, all rats displayed symptoms of abnormal gait
and most (47/50) were noted to have excess salivation. These symptoms
were not evident by 5 days after the end of treatment. Body weight
gain was lower in treated rats than in control rats during the 14-day
treatment period, however little difference in weight gain was
apparent during the 3-month observation period.
At the initial sacrifice, 6/8 treated rats were noted to have
"single fiber degeneration associated with axonal swelling and
myelinic fragmentation" of sciatic nerve. No changes were noted in
other nerve tissues, and no changes were noted in any control rats.
The incidence of fiber degeneration decreased over time, so that at
5 days and 1 month after treatment 3/8 rats were noted with this
lesion, and at 2 months 2/9 were observed with this lesion.
By 3 months, no rats were noted to have any significant lesions of the
nervous system.
Examination of sciatic nerve sections under electron microscopy
revealed "dilatation of neurotubules accompanied by proliferation of
neurofilaments and degeneration of mitochondria" in treated rats
examined at 1 day, 5 days and after 1 month. A similar lesion was
reported in the femoral nerve of a single male in 5 days. No
significant lesions were noted at 3 months, nor were changes reported
in other tissues. These findings were not noted in control rats. The
study authors concluded that the findings were treatment-related, but
reversible after withdrawal of treatment (Oikawa et al., 1983a).
In another short-term study, male and female Wistar rats
(5/sex/dose) were treated with 0 or 60 mg/kg/day by gavage for
14 days. A supplementary group of 5 male rats was treated with
50 mg/kg/day for 14 days. Behaviour, appearance and body weights were
recorded over the treatment period. At the end of treatment, rats were
sacrificed and perfused with 10% formalin. Brain, spinal column,
sciatic nerve and femoral muscle were removed and processed for
examination under light microscopy.
Treated rats Were noted to have disturbances in gait, tremor and
salivation from day 2 until sacrifice. Four male rats treated with
60 mg/kg died over days 5-8. Body weight gain was similar in control
and treated females, however weight gain was diminished in treated
males. Gross examination of tissues at necropsy did not reveal any
significant difference between control and treated rats. The only
significant finding reported after microscopic examination of tissues
was small, fresh hemorrhage of the brain in the 4 male rats that died
during the treatment. The study authors concluded that this finding
was the result of "a terminal cardiovascular disorder with necrosis of
the vascular walls" (Heiman and Kaliner, 1983). The present reviewer
is of the option that this finding is apparently related to treatment,
and unlikely to be of spontaneous origin.
In a 5-month study, male and female Wistar rats (15/sex/dose)
were given daily doses by gavage that ranged from 30 to 80 mg/kg/day.
The dose was varied intermittently with the purpose of inducing
symptoms of acute toxicity after each dose. For the most part, doses
of 60 or 80 mg/kg were given. Rats were observed daily for changes in
appearance or behaviour, and body weights were recorded weekly. At the
end of the treatment period, rats were sacrificed and examined for
grossly-visible changes, and selected organ weights were recorded.
Samples of liver were assessed for mixed-function oxidase (MFO)
activity, however the biological fraction measured was not specified.
Liver, kidney, adrenal, brain, spinal cord, and sciatic nerve from
5 males and females of the control and treated groups were processed
for microscopic examination.
Rats were observed to exhibited the characteristic symptoms of
acute toxicity of this compound: uncoordinated gait, tremor and
excessive salivation. It could not be determined from the submitted
data whether males and females were equally affected. Body weight gain
was decreased by about 20-25% in treated males, however weight gain in
females was not affected by treatment. Two control males and 2 control
females died during the treatment period, and 8 treated males and 2
treated females died over this interval. No effect on MFO activity was
evident. No treatment-related gross lesions were noted. Decreases in
liver and kidney weights were noted in treated miles, however these
changes were likely related to decreased body weight gain in these
animals. Microscopic examination did not reveal any treatment-related
lesions. However, in the opinion of the reviewer, this study may be
criticized by the failure to perform histological examinations of rats
that died on test. Therefore, this study does not confirm or refute
the findings of the previous study regarding lesions of the brain
noted in male rats that died during treatment (Thyssen and Vogel,
1982).
In a study to assess the effect of treatment on neuromuscular
function, groups of 10 male Wistar rats were given single oral doses
(method not specified) of 0-1.0 mg/kg of cyfluthrin. Diazepam
(5 mg/kg) was administered as a positive control, and cyfluthrin
administered over a range of 0-1.0 mg/kg served as a reference
chemical. After treatment with the test chemical, rats were observed
at various intervals after treatment to determine their ability to
retain their grip on a tilted plane. The experimental variable was the
angle of the plane at which rats lost their grip.
A dose-related, statistically significant decrease in the angle
at which rats lost their grip was noted after treatment with
cyfluthrin. This effect was maximal after 5 hours, and the apparent
NOEL was 0.01-0.03 mg/kg. The positive control diazepam and reference
chemical cypermethrin also produced similar results (Polacek, 1984).
Special Studies on Embryotoxicity/Teratogenicity
Rats
Female BAY:FB30 rats (25/group) were mated and administered doses
of technical cyfluthrin ("approx. 85%" purity) of 0, 3, 10, or
30 mg/kg by gavage over days 6-15 of presumed gestation. All doses
were administered in Lutrol at a constant volume of 5 ml/kg body
weight. Animals were observed for signs of toxicity, and were weighed
periodically. On day 20 of gestation, rats were sacrificed by CO2
asphyxiation, and uteri were removed to assess the effect of treatment
on fetal development. Approximately 1/3 of the fetuses in each litter
were examined for visceral defects by a modified Wilson technique, and
the remainder were cleared and stained for evaluation of skeletal
defects.
Rats in the mid and high dose groups were reported to have "a
high stepping gait from the second week of application. Individual
animals in the top dosage group were occasionally ataxic or exhibited
decreased motility". No mortalities were recorded.
No effect of treatment on maternal weight gain was apparent.
No effects on litter size, resorption frequency, fetal body
weights, or placental weight were apparent. Similarly, no evidence of
a treatment-related effect on the incidence of malformations or
skeletal variations was noted in this study. The study authors
concluded that "neither...embryotoxic damage nor a specific
teratogenic effect was established".
The gait disturbances were considered to be treatment-related. In
an addendum to the study report, this phenomenon was described as
typical of the pyrethroid class of insecticides. Although this sign is
considered to be evidence of cyfluthrin toxicity, the authors felt
that the effect could not be considered as evidence of a delayed
neurotoxicity syndrome (Schluter, 1982).
A second teratology study was conducted in outbred female Wistar
(KFM-Han) rats (25/group). Rats were administered doses of technical
cyfluthrin (93.4% purity) of 0, 1, 3, or 10 mg/kg by gavage. Doses
were administered in 1% Cremophor EL at a volume of 10 ml/kg. Rats
were observed twice/day for mortality and signs of toxicity. Body
weights were recorded daily, and food consumption was recorded on days
6, 11, 16 and 21 of gestation. On day 21 of presumed gestation, dams
were sacrificed by CO2 asphyxiation, and ovaries and gravid uteri
were removed by caesarean section for assessment of potential
developmental effects. About 1/3 of the live fetuses in each litter
were fixed and examined by the Wilson technique, whereas the remaining
2/3 were cleared and stained for examination of skeletal effects.
No treatment-related signs or mortalities were noted. Mean weight
gain in high dose dams was slightly lower than in controls, as was the
group mean body weight gain corrected by subtraction of the weight of
uterine contents. The study authors concluded that this finding could
not be attributed to the test article, since the major difference in
weight gain in this group occurred over days 0-6, before initiation of
treatment. Food consumption also tended to be lower in the high dose
group during this period.
At study termination, the numbers of pregnant rats were 25 in the
control, 25 in the low dose, 22 in the mid dose and 24 in the high
dose group. One mid dose dam was found to have aborted all fetuses,
and one high dose dam had total resorption of a litter. At necropsy,
no effect of treatment on pre- or post-implantation loss, litter size,
fetal viability, or fetal body weight was apparent. No effect of
treatment on the incidences of malformations or fetal variations was
apparent. The study authors concluded that the only effect of
treatment was a slight reduction in maternal food consumption in the
high dose group, and "all other recorded parameters showed no evidence
of effects upon the development of dams and fetuses" (Becker, 1983).
Rabbits
Groups of female Himalyan rabbits, strain CHBB:HM (15/dose) were
given doses of 0, 5, 15 or 45 mg/kg/day of technical cyfluthrin (95.0%
purity) by gavage over days 6-18 of presumed gestation. All doses were
administered in a 0.5% Cremophor EL emulsion at a constant volume of
5 ml/kg body weight. Rabbits were observed for clinical signs of
toxicity, and were weighed periodically during gestation. On day 29 of
gestation, rabbits were sacrificed by "a single intrapulmonary
injection of T61 ad us. vet.", and uteri were examined to assess the
effects of treatment on fetal development. Fetuses were weighed, then
dissected and examined for visceral abnormalities. Fetuses were then
processed and stained for skeletal examinations.
No signs of toxicity were observed in does during gestation that
were attributable to treatment, and no mortalities were recorded. No
effect of treatment on maternal body weight gain was apparent. Of the
15 rabbits/dose that were mated, 15, 15, 13 and 14 rabbits of the
control, low, mid and high dose groups, respectively, were found to
have been fertilized at necropsy. Of the rabbits that were fertilized,
2 high dose rabbits aborted (on gestation days 25 and 28), and a third
high dose animal had complete resorption of its litter. All other dose
groups carried fetuses through day 29, therefore the effects noted in
the high dose group were likely treatment-related.
No effect of treatment on fetal body weight, placenta weights or
litter size was noted. The incidence of resorptions appeared to be
dose-related: 0.6, 0.7, 1.4 and 1.8 resorptions per litter for
control, low, mid and high dose does. However, the only change that
was statistically significant was in the mid dose group;
interpretation is further complicated by the statistically significant
higher implantation rate in this group. A higher incidence of
arthtogryposis (persistent flexure or contracture of a joint) was
noted in treated litters than in control, with fetal incidences of 0,
2.4%, 2.2% and 4.3% and litter incidences of 0%, 6.796, 15.4% and 9.1%
for the respective dose groups. The study authors noted that this
finding is the most common spontaneous malformation in this strain of
rabbits, with an average fetal incidence of 0.76%. Other data
available to this reviewer (submitted by the sponsor to the U.S. EPA)
indicate that the historical control range of fetal incidences for
this finding is 0-5.4%, and that of litters is 0-33%. Therefore, it is
concluded that the test material had no effect of treatment on the
incidences of visceral or skeletal abnormalities. Based on the 2
abortions and single incidence of total resorption in the high dose
group, the study authors concluded that NOEL for embryo and maternal
toxicity was the mid dose, 15 mg/kg (Roetz, 1983).
Special Studies on Mutagenicity
Cyfluthrin did not have any mutagenic properties when tested in a
number of in vivo and in vitro systems, which included assessments
of gene mutations (bacteria and mammalian cells), DNA damage (bacteria
and mammalian cells), and clastogenic effects ( in vitro and
in vitro mammalian cells).
Summary results are presented in Table 1.
Special Study on Reproduction
Rats
Groups of male and female Wistar (BOR:WISW) rats were fed diets
containing 0, 50, 150 or 450 ppm of technical cyfluthrin (90.8%
purity). Ten males and 20 females were assigned to each test group.
The study was conducted for three generations with two litters
produced from each generation: F1a and F1b litters from F0 parents;
F2a and F2b litters from F1b parents; and F3a and F3b litters from F2b
parents. Each male was mated with two females. The following
parameters were assessed: fertility, litter size, fetal viability
during gestation and lactation, fetal birth weight, and parental
weight gain. F2b parental animals and F3b pups were sacrificed and
examined for changes in organ weight and gross or microscopic
appearance.
Table 1. Summary of Special Studies on Mutagenicity for Cyfluthrin
Test System Test object Concentration of Purity Results Reference
Cyfluthrin Used
CHO/HGPRT Chinese hamster 0-10 ug/ml 94.7% Negative(1) Yang & Louie,
gene mutation ovary cells, 1985
assay (with CHO-K1-BH4
and without
activation
Ames test (with S. typhimurium 0-24000 ug/plate 83.65 Negative(2) Herbold, 1980a
and without TA98, TA100,
activation) TA1535, TA1537
Unscheduled Primary 0-5000 ug/ml 94.7% Negative(3) Curren, 1985 DNA
synthesis hepatocytes
from male
S-D rats.
DNA repair B. subtilis 100-10000 95% Negative(4) Moriya & Ohta,
assay (with H17 and M45 ug/disk 1982
and without (rec +/-)
activation)
Mouse NMRI mice 0. 7.5 and 83.6% Negative(5) Herbold, 1980b
micronucleus 15 mg/kg (2 doses)
test
(1) The positive controls, EMS and BaP, gave the expected positive results.
(2) The positive controls, endoxan and trypaflavin gave the expected positive results.
(3) The positive control, DMBA, gave the expected positive result.
(4) The positive control, mitomycin C, gave the expected positive result.
(5) This study is unacceptable as the doses did not produce any toxicity.
Table 1. Summary of Special Studies on Mutagenicity for Cyfluthrin (cont'd)
Test System Test object Concentration of Purity Results Reference
Cyfluthrin Used
DNA repair B. subtilis 200 ug/disk 95% Negative(6) Nagane et al.
assay (with NIG17 & NIG45 1982
and without (rec +/-)
activation)
Ames test (with S. typhimurium 0-25000 ug/plate 95% Negative(7) Moriya &
and without TA98, TA100, Ohta, 1982
activation) TA1535, TA1537,
TA1538;
E. coli WP2
Ames test (with S. typhimurium 0-5000 ug/plate 95% Negative(8) Nagane et al.,
and without TA98, TA100,
activation) TA1535, TA1537,
TA1538;
E. coli WP2
Reverse mutation S. cervevisiae 0-10000 ug/ml 95% Negative(9) Rabenold &
(with and without S138 & S211a Brusick, 1982a
activation)
(6) The positive control, AF-2, gave the expected positive response.
(7) The positive controls, AF-2, ENNG, 2-NF, 9-AA and 2-AA gave the expected positive results.
(8) The positive controls, B-propiolactone, 9-AA, 2-NF, AF-2, and 2-AAF gave the expected positive results.
(9) The positive controls, quinacrine mustard, EMS, and sterigmatocystin gave the expected positive results.
Table 1. Summary of Special Studies on Mutagenicity for Cyfluthrin (cont'd)
Test System Test object Concentration of Purity Results Reference
Cyfluthrin Used
Mitotic cross-over, S. cerevisiae 0-10 mg/ml 95% Negative(10) Rabenold &
reverse mutation strain D7 Brusick, 1982b
and gene conversion
(with and without
activation)
Dominant lethal NMRI mice 0, 30 and 60 83.6% Negative(11) Herbold, 1980c
study mg/kg (1 dose)
In vitro CHL Chinese 3.3 x 10-5 93.7% Negative(12) Sasaki et al.,
cytogenetics hamster lung to 3.3 x 10-3 M 1986
(with and without cells
activation)
Sister chromatid Chinese hamster 3-40 ug/ml Technical Negative(13) Putnam, 1985
exchange ovary cells (-activation)
(with and without (ATCC #CCL 61) 63-1000 ug/ml
activation) (+activation)
DNA repair E. coli strains 0-1000 ug/plate 95.0% Negative(14) Herbold, 1981
(with and without (K 12) p3478
activation) W 3110
(10) The positive controls, EMS and sterigmatocystin, gave the expected positive results.
(11) The study is unacceptable as no positive control was tested.
(12) The positive controls, Mitomycin C and BaP, gave the expected positive results.
(13) The positive controls, TEM and cyclophosphamide, produced the expected positive responses.
(14) The positive control, MMS, produced the expected positive response.
No effect of treatment on appearance, behaviour, or survival was
noted. Parental body weight gain was consistently decreased in the
high dose (450 ppm) dose group, but was not affected in the other
treatment groups. Based on food consumption and body weights, the mean
compound intake was calculated by the study authors to be; 0, 3, 7,
11.8, and 39.6 mg/kg/day for the respective male treatment groups and
0, 5.4, 15.4, and 50.2 mg/kg/day for females.
No effect of treatment on fertility or incidence of stillborn
pups was evident. No consistent effect of treatment on birth weight or
litter size at birth was apparent. A decrease in the lactation index
(survival of pups over days 5-28 of lactation) was noted in high dose
pups in all matings, and in addition a decrease in the viability index
(number of pups surviving from birth through 5 days of lactation) was
noted in mid and high dose pups from the F3a and F3b matings. Weight
gain of pups over 28 days of lactation was consistently, suppressed in
the mid and high dose groups. At necropsy, decreased absolute liver
and kidney weights were noted in mid and high dose parental rats,
however no effect on relative organ weights was apparent, and the
effect on absolute organ weight was likely related to decreased body
weight gain in these animals. The study authors concluded that "50 ppm
FCR 1272 administered in the feed ration is the no observable effect
level in regard to reproduction" (Loser and Eiben, 1983).
B. Acute Toxicity
Technical cyfluthrin possesses a moderate order of acute
toxicity. Tetrazepam, a centrally-acting benzodiazepine muscle
relaxant, provided partial protection against the lethal effects of an
oral dose, however complete protection could not be obtained
regardless of dose or route of administration (Heimann, 1983a).
Combination studies of cyfluthrin with methamidophos, dichlorvos,
or propoxur did not reveal any evidence of synergism with these
organo-phosphate insecticides (Heimann, 1983b; Flucke, 1984a; Flucke,
1984b).
The results of acute toxicity studies are summarized in Table 2.
Technical cyfluthrin was shown to cause moderate irritation to
the eye (Flucke and Thyssen, 1980). Technical cyfluthrin does not
appear to cause skin sensitization (Mihail, 1981a; Mihail, 1981b).
Table 2. Acute Toxicity Studies With Cyfluthrin*
Species Sex Route LD50 LC50 Reference
(mg/kg) (g/L)
Mouse M oral 291 - Flucke & Thyssen, 1980
F 609
M s.c. >2500 - "
F >2500 - "
Rats M oral 869 - "
F (fed) 1271
M oral 590 - "
F (fasted) 1189
M i.p. 66 - "
F 104
M inhalation > 1089 "
F (1 hr exp) > 1089 "
M inhalation 469-592 "
F (4 hr exp) 469-592 "
M dermal >5000 "
F (24-hr exp) >5000 "
Hen F oral 4500 Sachsse & Zbinden, 1985
(PEG veh.)
Hen F oral >5000 Sachsse & Zbinden, 1985
(cremophor/
water veh.)
Hen F inhalation >596 Pauluhn & Kaliner, 1983
(4 hr exp.)
Rabbit M oral >1000 Flucke & Thyssen, 1980
Dog M oral > 100 "
Sheep M/F oral 1000 Hoffmann, 1981
(approx.)
* Technical cyfluthrin was tested in these studies.
C. Short-Term Studies
Rats
Groups of male and female Wistar rats (20/sex/dose) were
administered doses of 0, 5, 20, or 40 (80) mg/kg/day of technical
cyfluthrin (85% purity) by gavage for 28 consecutive days. A high dose
of 80 mg/kg/day was administered during weeks 1 and 3, and
40 mg/kg/day was given during weeks 2 and 4. The high dose was lowered
after the first week due to toxicity in treated males, however as
these symptoms disappeared after 1 week at the lower dose, the high
dose was again raised in the 3rd week. A group of rats from each dose
group was maintained on control diets without additional treatment for
6 weeks in order to assess recovery. Rats were observed daily for
changes in appearance or behaviour, and body weights were recorded
weekly. Clinical chemistry studies were conducted at the end of the
28-day treatment interval and at the end of the 6-week recovery
period. At the end of the treatment period, one-half of the surviving
rats in each treatment group were sacrificed, and the remaining
animals were sacrificed after the 6 week recovery period. Animals were
examined for grossly visible lesions, changes in organ weights, and
microscopic changes. A standard set of tissues and organs was
examined.
Physical examinations of high-dose rats revealed symptoms of
acute toxicity characteristic of this chemical: uncoordinated
movements, salivation, ataxia, hyperkinesis, etc. The symptoms were
described as most severe during weeks 1 and 3 (when a high dose of
80 mg/kg/day was administered), and minimal during weeks 2 and 4 (when
the high dose was lowered to 40 mg/kg/day). Only "minimal" behaviour
disorders were noted in high dose males for the first 7 days of the
recovery period. Six high dose males died, 5 during the first week of
treatment, and one other on day 21. A single high dose female died on
day 26. No deaths were noted during the recovery period. Mean body
weights were decreased by about 10% in high dose males, whereas body
weights were not affected by treatment in females. During the recovery
period, the weight gain deficit noted in high dose males during
treatment was not apparent, and these animals were apparently able to
recover from the slight retardation of weight gain. No effect of
treatment on hematology parameters was noted, and no
toxicologically-relevant changes in serum enzyme activities or
electrolyte concentration were apparent. The results of urinalysis
were considered to be normal. Similarly, no changes in these
parameters were apparent at the end of the recovery period.
At necropsy, increased absolute and relative adrenal and liver
weights were noted in high dose male and female rats sacrificed after
the 28-day treatment period. At the end of the recovery period, the
only significant changes noted were decreases in absolute and relative
liver weights, and slight, dose related increases in the absolute and
relative adrenal weights in high dose females.
No treatment-related gross lesions were reported at either
sacrifice. Microscopic examinations similarly did not reveal any
treatment-related lesions (Flucke and Schilde, 1980).
In a subchronic feed study, groups of male and female Wister rats
(30/sex/dose) were fed diets containing 0, 30, 100, or 300 ppm of
technical cyfluthrin (84.2% purity) for 3 months. Rats were observed
daily for changes in appearance or behaviour, and body weights were
recorded weekly. Clinical chemistry studies were conducted after 1 and
3 months of treatment, and additional enzyme induction studies were
conducted after 1 week, 1 month and 3 months of treatment. At the end
of the treatment period, surviving rats in each treatment group were
sacrificed, and examined for grossly-visible lesions, change sin organ
weights, and microscopic changes. A standard set of tissues and organs
was examined. Animals that died during treatment were necropsied, and
tissues were prepared for microscopic examination if suitable.
No effect of treatment on appearance or behaviour was noted, nor
was any effect on survival apparent. No treatment-related changes in
food consumption or body weight gain were noted, and average compound
intake was calculated to be 2.2, 7.4 and 22.5 mg/kg/day for the
respective treatment groups. No significant effects were noted in
hematology, serum chemistry or urinalysis studies. A slight increase
in liver microsomal enzyme activity was noted after 1 week of
treatment, however no changes were apparent after 3 months of
treatment.
At final necropsy, no grossly-visible lesions or
treatment-related changes in organ weights were noted. Microscopic
examinations also did not reveal any treatment-related toxicity. The
study authors concluded the the highest dose tested of 300 ppm was
without adverse effects (Loser and Schilde, 1980).
In another subchronic feeding study, male and female
Sprague-Dawley rats (28/sex/dose) were fed diets containing 0, 100,
300, or 1000 ppm of technical cyfluthrin (95% purity) for 3 months.
Twenty rats from each group were scheduled for sacrifice after
3 months of treatment, and the remaining 8 rats from each group were
maintained on control diets for 1 additional month prior to sacrifice.
Test diets were analysed periodically to insure stability and
homogeneity. Rats were observed daily for changes in appearance or
behaviour, and body weights were recorded weekly. Clinical chemistry
and urinalysis studies were conducted after 3 months of treatment, or
after the 1 month recovery period, surviving rats in each treatment
group were sacrificed, and examined for grossly-visible lesions,
changes in organ weights, and macroscopic changes. A standard set of
tissues and organs was examined. Animals that died during treatment
were necropsied, and tissues were prepared for microscopic
examination.
Most high dose rats displayed symptoms of toxicity within the
first few weeks of treatment that included abnormal gait and excess
salivation. The number of rats that displayed these symptoms decreased
over the treatment period, so that by the end of 3 months, no abnormal
symptoms were noted. No effect of treatment on survival was apparent.
Body weight gain was retarded in high dose males and females, and was
about 10% less than control body weight gain by the end of treatment.
Some rebound in weight gain was apparent in high dose females during
the recovery period, however body weights of high dose males remained
depressed. The observed effects on weight gain were apparently related
to decreased food consumption. No effect of treatment on hematology or
urinalysis parameters was noted. Serum chemistry studies revealed the
following: increased BUN in mid and high dose males and high dose
females, increased SGOT in high dose males, and dose-related decreases
in blood glucose levels in male sand females, statistically-
significant in mid and high dose males and high dose females.
Paradoxically, SGPT activity appeared to be decreased in treated males
and females. No significant changes in serum chemistry values were
apparent at the end of the recovery period.
At necropsy, alterations in organ weight were noted in high dose
rats at both sacrifices that were likely related to weight gain
deficits; otherwise no treatment-related effect on organ weights was
apparent. No treatment-related gross changes were noted. The only
significant finding after histopathologic examinations of rats
sacrificed at 3 months was an increased incidence of single fiber
degeneration of the sciatic nerve in 5/20 high dose males and
3/20 high dose females, as compared to an incidence of 0 in the
control, low and mid dose groups. In the 1 month recovery group, the
incidence of this finding was 1/8 high dose males, and 0/8 in all
other groups. The study authors concluded that the dose without
adverse effects was 100 ppm, equal to 6.2 mg/kg/day (Oikawa and
Iyatomi, 1983b).
In a short-term inhalation study, male and female Wister rats
(10/sex/dose) were exposed to atmospheres containing aerosols of
0, 10, 50, or 250 µg/L technical cyfluthrin nominal concentrations
(0, 2.3, 11.5 and 69.6 g/L analytical) for 6 hours/day × 5 days/week ×
3 weeks (total of 15 exposures). The solvent used in the generating
system (and the control atmosphere) was a 1:1 mixture of ethanol and
polyethylene glycol 400 (Lutrol), and the reported purity of the test
material was 85.3%. Analysis of particle size showed that >90% of the
particles were <3 µm in diameter, and were within the range the study
authors considered respirable. Exposure of rats was restricted to the
head/nose region. Rats were observed daily for changes in appearance
or behaviour, and body weights were recorded weekly. Rectal body
temperatures were measured after 1, 5, 10 and 15 exposures. Clinical
chemistry and urinalysis studies were conducted on 5 rats/sex/dose
after the last exposure. At the end of the treatment period, surviving
rats in each treatment group were sacrificed, and examined for
grossly-visible lesions and changes in organ weights. Five
rats/sex/dose were examined for microscopic changes.
Signs of ungroomed coat, abnormal gait, and increased salivation
were noted in mid and high dose rats. A single unscheduled death was
noted in the high dose female group, and was likely related to
treatment although a detailed necropsy was not possible due to severe
autolysis. Body weight gain was retarded in all treatment groups, as
treated rats either lost body weight or failed to gain weight during
the treatment period. Body temperatures appeared to be consistently
lowered after treatment (as compared to mean pre-treatment values),
however the effect was not consistent throughout the treatment period,
and is of uncertain toxicological significance. Hematology, serum
chemistry and urinalysis studies did not reveal any significant
effects. No evidence of induction of liver drug metabolism enzymes was
apparent.
At necropsy, no treatment-related gross lesions were noted, and
slight organ weight alterations were likely related to effects of
treatment on body weight gain. Microscopic examinations revealed
treatment-related increases in inflammation of trachea and in the
incidence of emphysema in high dose males and females. The study
authors concluded that the no effect-concentration could not be
determined due to effects on body weight gain in all treatment groups.
As effects were noted at all concentration levels, the study was
repeated with aerosol concentrations of 0, 2, 10 and 50 µg/L nominal
concentrations (0, 0.4, 1.4 and 10.5 µg/L analytical). All other
aspects of the study protocol were unchanged, however clinical
chemistry studies were not repeated.
Behavioral changes were noted only in the high dose rats during
the final week of treatment, and decreased body weight gain was
observed only in high dose rats. At sacrifice, no treatment-related
gross lesions were noted, and absolute and relative liver weights were
decreased in mid and high dose males. No treatment-related lesions
were noted after microscopic examinations. The study authors concluded
that an aerosol of 0.4 µg/L was without significant toxic effect
(Thyssen and Mohr, 1980).
In a subchronic inhalation study, male and female Wistar rats
(10/sex/dose) were exposed to atmosphere containing aerosols of
0, 0.5, 3.0, or 20 µg/L of technical cyfluthrin nominal concentrations
(0, 0.09, 0.71 and 4.52 µg/L analytical) for 6 hours/day × 5 days/week
× 13 weeks (total of 63 exposures). The solvent used in the generating
system (and the solvent control atmosphere) was a 1:1 mixture of
ethanol and polyethylene glycol 400 (Lutrol), and the reported purity
of the test material was 94.9%. Analysis of particle size showed that
>85% of the particles were <5 m in diameter, and were within the
range that the study authors considered respirable. Rats were observed
daily for changes in appearance or behaviour, and body weights were
recorded weekly. Clinical chemistry and urinalysis studies were
conducted on all rats after 6 weeks of treatment and at study
termination. At the end of the treatment period, surviving rats in
each treatment group were sacrificed, and examined for grossly-visible
lesions and changes in organ weights. A standard set of tissues was
examined for microscopic changes.
Signs of "non-specific disturbed behaviour" were observed in all
high dose males and all mid and high dose females. Dose-related
decreases in body weight gain of about 10-20% were noted in all male
treatment groups, and slight decreases of about 5% were observed in
mid and high dose females. No effect of treatment on hematology, serum
chemistry, or urinalysis parameters was apparent. Alterations in the
absolute weights of several organs were noted in mid and high dose
males and females, and were probably related to decreased weight gain
in these groups. No treatment-related lesions were revealed by
microscopic examinations. The study authors concluded that the lowest
concentration tested, 0.09 µg/L was without toxic effect (Pauluhn and
Mohr, 1984). The present reviewer disagrees with this conclusion, as
body weight gain was decreased in all male treatment groups. Since
control and test chemical animals were similarly restrained and
exposed, in the reviewer's opinion the body weight decrease in low
dose males was not likely to be due to the exposure paradigm.
Rabbits
In a short-term study, male and female White New Zealand rabbits
(6/sex/dose) were exposed by dermal application to 0 (solvent only),
50 or 250 mg/kg of technical cyfluthrin (83.5% purity). The skin of 3
rabbits/sex/dose was abraded prior to application of the test
chemical. Animals were exposed for 6 hours/day × 5 days/week × 3 weeks
(total of 15 exposures) to a total applied volume of 0.5 ml/kg. At the
end of each 6-hour application, treated skin was washed. Rats were
observed daily for changes in appearance or behaviour, and body
weights were recorded weekly. The application site was examined for
signs of skin irritation. Clinical chemistry and urinalysis studies
were conducted on all rats prior to the initiation of treatment and at
study termination. At the end of the treatment period, surviving rats
in each treatment group were sacrificed, and examined for
grossly-visible lesions and changes in organ weights. A selected
number of tissues from control and high dose rabbits, along with
testes from mid dose rabbits, were examined for microscopic changes.
No changes in appearance or behaviour were reported, and all
rabbits survived the treatment period. No toxicologically-significant
effect on weight gain was apparent. No local skin reactions were noted
that were related to treatment. Hematology, serum chemistry and
urinalysis studies were not affected by treatment. No alterations in
organ weights, or treatment-related gross or microscopic lesions were
noted (Flucke and Vogel, 1980).
Dogs
In a subchronic toxicity study, male and female beagle dogs
(6/sex/dose) were fed diets containing 0, 65, 200, and 600 ppm of
technical cyfluthrin (90.8% purity) for 6 months. Treatment was
initiated in November 1979, and terminated in May, 1980. Dogs were
initially offered a total of 300 grams of food for about 20 hours/day
(330 grams/day over weeks 20-26). Test compound intake was calculated
to 0, 2.0, 6.5, and 19.9 mg/kg/day for the respective treatment groups
in week 26 (male and female combined). Tap water was available
ad libitum. Food consumption was measured daily. Dogs were examined
daily for signs of toxicity, and reflexes, pulse and body temperature
were determined before treatment initiation, and after 4, 7, 13, and
26 weeks of treatment. Body weights were determined weekly.
Ophthalmoscopic examinations were conducted before treatment
initiation, and after 4, 7, 13, and 26 weeks of treatment. Blood was
sampled at the same times as the detailed physical examinations for
measurement of hematology and clinical chemistry parameters. Urine was
also collected on this schedule.
At termination, dogs were anesthetized and sacrificed by
exsanguination. Standard necropsy techniques were followed, and the
standard set of tissues was collected for evaluation.
Signs of uncoordinated gait and stiff movements of the hind limbs
were noted in high dose dogs beginning with week 21 of treatment. By
the end of treatment, 5/6 high dose males and 3/6 high dose females
were observed on one or more occasions with these signs. No
treatment-related deaths were noted. Decreased body weight gain was
noted in mid and high dose males and females, and although not
strictly dose-related, these changes did appear to be related to
treatment. No effect of treatment on food consumption was apparent. No
treatment-related effects were revealed by ophthalmoscopic
examinations. Hematology, serum chemistry and urinalysis studies were
considered to be within normal limits. At necropsy, no treatment-
related effects on organ weights or gross or microscopic pathology
was apparent. No lesions of the nervous system were noted to
correlate with the observed physical signs. The study authors
concluded that the lowest dose tested, 65 ppm (equal to about
2 mg/kg/day), was the NOEL for this study (Hoffman and Kaliner, 1981).
Groups of beagle dogs (6/sex/dose) were fed diets containing
0, 40, 160, and 640 ppm of technical cyfluthrin (90.8% purity) for
12 months. Treatment was initiated in January 1982, and terminated in
January, 1983. Dogs were initially offered a total of 300 grams of
food for about 20 hours/day. The amount of food offered was gradually
increased over the course of the study so that by week 27 dogs were
given 430 grams food/day. Tap water was available ad libitum. Food
consumption was measured daily. By study termination, test compound
intake was equal to about 1.4, 5.1, and 22.9 mg/kg/day (both sexes)
for the respective dose groups. Dogs were examined daily for signs of
toxicity, and were given a complete physical examination before
treatment initiation, and after 6, 13, 26, 39 and 52 weeks of
treatment. Body weights were determined weekly. Ophthalmoscopic
examinations were conducted before treatment initiation, and after
5, 13, 29, 39 and 52 weeks of treatment. Blood was sampled at the same
times as the detailed physical examinations for measurement of
hematology and clinical chemistry parameters. Urine was also collected
on this schedule.
At termination, dogs were anesthetized and sacrificed by
exsanguination. Standard necropsy techniques were followed, and the
standard set of tissues was collected for evaluation. Only tissues
from control and high dose dogs were evaluated for histopathological
changes.
Clinical examinations revealed in two high dose males a syndrome
characterized by clumsy, stiff movements of the hindquarters and a
reluctance to move. These observations were noted during week 36 in
one dog and in week 37 in another. These findings were not noted at
subsequent examinations, even though "the dogs continued to be
closely observed for a repetition of this movement". Other
treatment-related findings in high dose dogs included increased
tendency to vomit, and "pasty to liquid feces". Clinical observations
in the low and mid dose groups did not reveal any treatment-related
changes. No mortalities were recorded in the study, and
ophthalmoscopic examinations did not reveal any treatment-related
changes.
A decrease in mean body weight of about 5-10% relative to control
was noted in high dose males. This effect was most apparent in the
second half of the study. Body weights in other treatment groups were
not affected by treatment. A treatment-related effect on food
consumption was not evident, and water consumption was also normal.
No effect of treatment on hematology, clinical chemistry or
urinalysis parameters was apparent.
At necropsy, no treatment-related lesions were noted after gross
examination. The absolute and relative weight of spleen was increased
by abut 70% in high dose females, and was noted in most dogs in that
group. Other organ weights were normal. No microscopic changes were
noted in any tissue that were considered to be treatment-related.
Congestion of the spleen was noted in a single high dose female,
however spleens from other high dose females were not similarly
affected. Microscopic examinations of the sciatic nerve similarly did
not reveal any evidence of injury to correlate with observed physical
signs.
The study authors concluded that the NOEL for this study was
160 ppm, equal to 5.1 mg/kg/day, based on decreased weight gain and
disturbances in the gait of males fed diets containing 640 ppm
(Hoffman & Schilde, 1983).
D. Long Term Studies
Mice
Groups of CF1/W74 SPF mice (50/sex/dose) were fed diets
containing 0, 50 ppm, 200 ppm or 800 ppm of technical cyfluthrin
(90.8% purity) for 23 months. Treatment was conducted from November,
1980 to October, 1982. Control or test diets and water were offered
ad libitum. The dietary intakes of test compound were equal to
11.6, 45.8, and 194.5 mg/kg/day in males and 15.3, 63.0, and
259.9 mg/kg/day in females. The results of analyses of the test
material or of test diets were not presented. Animals were examined
twice/day for abnormalities of behaviour and appearance. Body weights
and food consumption were determined weekly.
Blood was sampled at 0, 6, 12, 18 and 23 months from
10 mice/sex/dose for assessment of hematology and clinical chemistry
parameters. A standard battery of test/examinations was conducted.
Urinalyses were not performed. The fluoride content of bones and teeth
was determined for 5 mice/sex/dose after 23 months of treatment.
Mice that died on test, moribund animals, and all mice surviving
to 23 months were subjected to complete necropsies. Mice were
anesthetized with ether and sacrificed by exsanguination. Animals were
dissected, and organs were weighed. The standard set of tissues was
examined for microscopic changes.
No effect of treatment on clinical signs was apparent. Survival
was somewhat lower in mid and high dose females (74% and 68%
mortality, respectively vs. 52% control), however mortality incidence
did not appear to be related to dose and the differences were not
statistically significant at study termination. Mean body weights were
reduced in high dose females in a doze-related, statistically
significant manner. Mean body weights in treated males were
occasionally significantly different from control, however the changes
did not appear to be related to dose. Food intake was not affected by
treatment.
No toxicologically significant effect of treatment on hematology
parameters was apparent. Although occasional statistically significant
differences were noted between control and treated group, the effects
were not dose related. Statistically significant increases in serum
alkaline phosphatase activity were noted in all treated males after
6, 12, and 18 months of treatment. This effect was not strictly
dose-dependant, however all treated groups were consistently elevated
over the first 18 months of treatment. At study termination, however,
there was little apparent difference between control and treated
groups, and the highest individual values were recorded in the control
group. SGPT was slightly elevated in high dose males after 6 and
18 months of treatment, but not after 12 months. The reported high
values in controls at study termination prevented any meaningful
comparison with treated mice at this time point. Clinical chemistry
studies in the females did not reveal any treatment-related effects.
No effect of treatment on the fluoride content of teeth or bones was
noted.
At necropsy, no effect of treatment on absolute or relative organ
weights was noted.
After gross and microscopic examinations, no toxicologically
significant differences in the incidences of neoplastic or
non-neoplastic lesions were noted. No dose-related changes in the
histology of the liver were noted that correlated with the apparent
increases in serum ALP or SGPT activities. The study authors concluded
that cyfluthrin was negative for oncogenic effects in mice, and the
NOEL was 200 ppm based on slight alterations in body weight gain at
800 ppm (Suberg and Loser, 1983a).
Rats
Groups of male and female Wistar [SPF] rats (65/sex/dose) were
fed diets containing 0, 50 ppm, 150 ppm or 450 ppm of technical
cyfluthrin (90.8% purity) for 2 years. Treatment was initiated in
September 1980 and concluded in September 1982. Control or test diets
and water were offered ad libitum. The dietary concentrations were
equal to 2.0, 6.2, and 19.2 mg/kg/day in males and 2.7, 8.2, and
25.5 mg/kg/day in females based on average food consumption on body
weights over the course of the study. The test material and test diets
were analysed periodically to insure stability. Animals were examined
twice/day for abnormalities of behaviour or appearance. Body weights
were recorded weekly through study week 27, biweekly from week 27 to
week 74, and then weekly until study termination. Food consumption was
measured weekly.
Blood was sampled at 6, 12, 18, and 24 months from
10 rats/sex/dose for an assessment of hematology and clinical
chemistry parameters. Serum protein electrophoresis was performed on
blood sampled at 12 months. A standard battery of tests/examinations
was conducted, and in addition on study day 7, 5 rats/sex/dose were
sacrificed for measurement of mixed function oxidase activities and
liver cytochrome P450 content. After 12 and 24 months of treatment,
the fluoride content of bones and teeth was determined. Urine was
collected on the same schedule as blood for standard urinalysis
determinations.
Ten rats/sex/dose were sacrificed after 12 months of treatment,
of which 5/sex/dose were perfused with 10% buffered formalin prior to
gross examination and dissection. All other rats that died on test,
moribund animals, and all rats surviving to 2 years were subjected to
complete necropsies. Rats were anesthetized with ether and sacrificed
by exsanguination. Animals were dissected, and organs were weighed
(except for animals perfused with formalin). The standard set of
tissues was examined for microscopic changes.
No effect of treatment on clinical signs or mortality was
apparent. Survival in all groups was greater than 80% at study
termination, mean body weights were significantly decreased throughout
the study by about 8-10% in males and females fed the high dose
(450 ppm) diet, and were significantly decreased by about 5% in mid
dose (150 ppm) males during the first year of treatment. Food
consumption was not affected by treatment.
No effect of treatment on hematology parameters was apparent. The
results of clinical chemistry studies were essentially unremarkable,
although increases in alpha-1-globulin in mid and high dose females
(measured at 12 months) was statistically significant and appeared to
be dose-related. However, corresponding changes in other globulin
bands or in the A/G ratio were not noted, therefore the study authors
considered this finding to be of questionable toxicological
significance. No effect of treatment on urinalysis parameters was
apparent. Measurement of MFO activities after 7 days of treatment
suggested an induction of N-demethylase activity in the high dose
groups. Activity in high dose males was increased by about 30%
compared to controls but was not statistically significant, whereas
activity in high dose females was increased by about 70% (p<0.01).
O-Demethylase activity was not affected, nor was cytochrome P450
content. No treatment-related changes in the fluoride content of teeth
and bones were noted after 12 months, however by 24 months dose
related increases were noted in the bones of mid and high dose males
and high dose females.
At necropsy, organs weights were altered in a manner related to
body weight changes. Absolute weights of several organs were slightly
decreased in high dose males and females, however relative organ
weights were not affected in a dose-related manner. No effect of
treatment on the incidence of microscopic lesions was apparent. The
total number of tumors, the distribution of specific tumor types, and
the number and distribution of chronic lesions were not affected by
treatment. The study authors concluded that cyfluthrin is not
oncogenic in the rat. The NOEL for chronic toxicity was 50 ppm, equal
to 2.0 and 2.7 mg/kg/day in males and females, respectively, based on
decreases in body weight gain in the mid and high dose groups (Suberg
and Loser, 1983b).
Observations in Humans
Examinations of laboratory workers revealed that cyfluthrin
caused a topical skin effect, characterized by a stinging sensation in
the affected areas. Areas most commonly affected were the face, and
mucosal tissues (e.g. prepuce). It was noted that this chemical
adheres strongly to skin and is not washed off by soap and water, so
that it is possible to contaminate various parts of the body with
cyfluthrin present on the hands (Flucke and Lorke, 1979).
COMMENTS
Cyfluthrin has not been previously evaluated by the WHO Expert
Group, but was evaluated by the FAO Panel in 1986.
Adequate data were submitted to characterize the rates of
absorption and elimination of cyfluthrin. Approximately 60-70% of an
oral dose is eliminated via the urine, and the remainder via the
feces. No potential for bioaccumulation is known. Cyfluthrin is
readily metabolized, and is excreted as a glucuronide or sulphate
conjugate.
Special studies on carcinogenicity, mutagenicity, teratogenicity,
and reproductive toxicity demonstrated no effects.
Long-term feeding studies on mice, rats and dogs did not reveal
any evidence of organ-specific toxicity. The only significant effects
noted in these studies were retardation of weight gain and alterations
of organ weights secondary to body weight effects.
TOXICOLOGICAL EVALUATION
LEVELS CAUSING NO TOXICOLOGICAL EFFECTS
Mouse: 200 ppm, equivalent to 30 mg/kg bw/day
Rat: 50 ppm, equal to 2 mg/kg bw/day
Dog: 160 ppm, equal to 5.1 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.2 mg/kg bw.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
Observations in man.
REFERENCES
Becker, H., 1983. Embryotoxicity (including teratogenicity) study with
FCR 1272 in the rat. Unpublished report no. R2773 from Research and
Consulting Company, AG, Itingen, Switzerland. Submitted to WHO by
Bayer AG, Leverkusen, FRG.
Curren, R., 1985. Unscheduled DNA synthesis in rat primary
hepatocytes. Unpublished report no. 701 (Mobay) from Microbiological
Associates, Bethesda, MD., submitted to WHO by Bayer AG,
Leverkusen, FRG.
Eben, A., Heimann, K.-G., and Machemer, L., 1982. Comparative study of
rats on absorption of FCR 1272 after single oral administration in
polyethylene glycol 400 or Cremophor EL/water as formulation vehicle.
Unpublished report no. 10715 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Ecker, W. (1982). Biotransformation of (F-phenyl-UL-14C)-cyfluthrin;
characterization and preliminary identification of metabolites.
Unpublished report No. 1632 from Bayer Institute of Pharmacokinetics,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W., 1984a. FCR 1272, DDVP study for combination toxicity.
Unpublished report no. 12567 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W., 1984b. FCR 1272, Propoxur study for combination toxicity.
Unpublished report no. 12544 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W. and Lorke, 1979. Irritant effects after work with FCR 1272.
Memorandum dated 8.10.79 from Bayer Institute of Toxicology, submitted
to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W. and Thyssen, J., 1980. FCR 1272. Acute toxicity studies.
Unpublished report no. 8800 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W. and Vogel, O., 1980. FCR 1272. Subacute dermal toxicity
study on rabbits. Unpublished report no. 8928 from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W. and Schilde, B., 1980. FCR 1272. Subacute oral toxicity
study on rats. Unpublished report no. 9039 from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Flucke, W. and Eben, A., 1985. FCR 1272, Study for effect on the
neurotoxic target enzyme (NTE) with the chicken (gallus domesticus).
Unpublished report no. 13821 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Heimann, K.-G., 1983a. Test to determine antidote effect against FCR
1272 toxicity in rats. Unpublished report no. 11854 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Heimann, K.-G., 1983b. Cyfluthrin and methamidophos study for
combination toxicity. Unpublished report no. 12003 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Heimann, K.-G. and Kaliner, G., 1983. FCR 1272. Study for neurotoxic
effect on rats after subacute oral administration (with addendum).
Unpublished report nos. 12338 and 12338-A from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Herbold, B., 1980a. FCR 1272. Salmonella/microsome test for detection
of point-mutagenic effects. Unpublished report no. 9273 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Herbold, B., 1980b. Micronucleus test on mouse to evaluate FCR 1272
for mutagenic potential. Unpublished report no. 9435 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Herbold, B., 1980c. Dominant lethal test on male mouse to evaluate FCR
1272 for mutagenic potential. Unpublished report no. 9678 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Herbold, B., 1981. FCR 1272 Cyfluthrin. Pol Al-test on E. coil to
evaluate effects for DNA damage. Unpublished report no. 10450 from
Bayer Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Hixson, E.J., 1981. Investigative neurotoxicity studies in hens.
Unpublished report no. 165 from Mobay Chemical Corporation Corporate
Toxicology Dept., submitted to WHO by Bayer AG, Leverkusen, FRG.
Hoffmann, K., 1981. FCR 1272. Acute toxicity to sheep after oral
administration. Unpublished report no. 9750 from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Hoffmann, K. and Kaliner, G., 1981. FCR 1272. Chronic toxicity study
on dogs (six-month feeding experiment). Unpublished report no. 9991
from Bayer Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Hoffmann, K., and Schilde, B., 1983. FCR 1272 (Cyfluthrin) Chronic
toxicity to dogs on oral administration (12 months feeding study).
Unpublished report no. 11983 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Klein, O., Weber, H., and Suwelak, D., 1983. Biokinetic part of the
General metabolism studies in the rat. Unpublished report no. 11872
from Bayer Institute of Pharmacokinetics, submitted to WHO by
Bayer AG, Leverkusen, FRG.
Loser, E. and Schilde, B., 1980. FCR 1272. Subchronic toxicity study
on rats. Unpublished report no. 9386 from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Loser, E. and Eiben, R., 1983. FCR 1272 Multigeneration study on rats.
Unpublished report no. 11870 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Mihail, F., 1981a. FCR 1272. Test for sensitizing effect on guinea
pigs. Unpublished report no. 10267 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Mihail, F., 1981b. FCR 1272. Intracutaneous sensitization test on
guinea pigs (Draize test). Unpublished report no. 10222 from Bayer
Institute of Toxicology, submitted to WHO by Bayer AG, Leverkusen,
FRG.
Moriya, M. and Ohta, T., 1982. FCR 1272. Microbial mutagenicity study.
Unpublished report no. (unknown) from Department of Toxicology,
Institute of Environmental Toxicology, Japan, submitted to WHO by
Bayer AG, Leverkusen, FRG.
Nagane, M., Hatanaka, J., and Iyatomi, A., 1982. FCR 1272.
Mutagenicity test on bacterial system. Unpublished report no. 213 from
Nihon Tokushu Noyaku Seiko K.K. Agricultural Chemicals Institute,
Japan, submitted to WHO by Bayer AG, Leverkusen, FRG.
Oikawa, K., Iyatomi, A., and Watanabe, M., 1983a. FCR 1272. Special
toxicological study-morphological effects on the nervous system of
rats. Unpublished report no. R 3362 from Nihon Tokushu Noyaku Seiko
K.K. Agricultural Chemicals Institute and St. Marianna Medical
College, Dept. of Pathology, submitted to WHO by Bayer AG, Leverkusen,
FRG.
Oikawa, K. and Iyatomi, A., 1983b. Three-month toxicity study of FCR
1272 in rats. Unpublished report no. 264 from Nihon Tokushu Seiko K.K.
Agricultural Chemicals Institute and St. Marianna Medical College,
Dept. of Pathology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Pauluhn, J. and Kaliner, G., 1983. FCR 1272. Study for acute and
subacute inhalation toxicity on chickens. Unpublished report no. 11558
from Bayer Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Pauluhn, J. and Mohr, U., 1984. FCR 1272. Study for subchronic
inhalative toxicity to the rat for 13 weeks (63 exposures × 6 hours).
Unpublished report no. 12436 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Polacek, I., 1984. Study of FCR 1272 on neuromuscular dysfunction in
the tilting plane test on rats. Unpublished report no. R 2896 from the
Toxicological Institute of Regensberg, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Putnam, d., 1985. Sister Chromatid exchange assay in Chinese Hamster
Ovary (CHO) cells. Test article Baythroid (FCR 1272), technical
cyfluthrin. Unpublished report no. 693 (Mobay) from Microbiological
Associates, Bethesda, MD., submitted to WHO by Bayer AG,
Leverkusen, FRG.
Rabenold, C. & Brusick, D., 1982a. Evaluation of FCR 1272 in the
reverse mutation assay with Saccharomyces cerevisiae strains S138
and S211. Unpublished report no, R2248 from Litton Bionetics, Inc.,
Kensington, MD., submitted to WHO by Bayer AG, Leverkusen, FRG.
Rabenold, C. & Brusick, D., 1982b. Evaluation of FCR 1272 in the
induced mitotic crossing-over, reverse mutation, and gene conversion
assay with Saccharomyces cerevisiae strain D. Unpublished report
no. R2249 from Litton Bionetics, Inc., Kensington, MD., submitted to
WHO by Bayer AG, Leverkusen, FRG.
Roetz, R., 1983. FCR 1272 [Cyfluthrin]. Study for embryo-toxic effects
on rabbits after oral administration. Unpublished report no. 11855
from Bayer Institute of Toxicology, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Sacchse, K. & Zbinden, K., 1985. Acute oral toxicity study with FCR
1272 in the hen. Unpublished report no. R 3622 from Research and
Consulting Company AG, submitted to WHO by Bayer AG, Leverkusen, FRG.
Sacchse, K., 1986. Acute delayed neurotoxicity study with FCR 1272
(cyfluthrin) in the hen. Unpublished report no. R 3690 from Research
and Consulting Company AG, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Sasaki, Y., Imanishi, H., Watanabe, M. and Ohta, T., 1986. Cyfluthrin:
In vitro cytogenetics test. Unpublished report no. [unknown] from
Kodaira Labs., Institute of Environmental Toxicology, Japan, submitted
to WHO by Bayer AG, Leverkusen, FRG.
Schluter, G., 1982. FCR 1272 [Cyfluthrin]. Evaluation for embryotoxic
and teratogenic effects on orally dosed rats. Unpublished report
no. 10562 from Bayer Institute of Toxicology, submitted to WHO by
Bayer AG, Leverkusen, FRG.
Suberg, H. & Loser, E., 1983a. FCR 1272 (Cyfluthrin). Chronic toxicity
study on Mice (Feeding Study over 23 Months). Unpublished report
no. 12035 from Bayer Institute of Toxicology, submitted to WHO by
Bayer AG, Leverkusen, FRG.
Suberg, H. & Loser, E., 1983b. FCR 1272 (Cyfluthrin). Chronic toxicity
study on rats (2-year feeding experiment). Unpublished report
no. 11949 from Bayer Institute of Toxicology,'submitted to WHO by
Bayer AG, Leverkusen, FRG.
Thyssen, J. & Mohr, U., 1980. FCR 1272. Subacute inhalational toxicity
study on rats. Unpublished report no. 9373 from Bayer Institute of
Toxicology, submitted to WHO by Bayer AG, Leverkusen, FRG.
Thyssen, J., Kaliner, G. & Groning, P., 1981. FCR 1272. Neurotoxicity
study on chickens after cutaneous administration (cumulation tests).
Unpublished report no. 10768 from Bayer Institute of Toxicology,
submitted to WHO by Bayer AG, Leverkusen, FRG.
Thyssen, J. & Vogel, O., 1982. FCR 1272. Study for nerve damage effect
on the rat after 5-months oral application. Unpublished report
no. 10705 from Bayer Institute of Toxicology, submitted to WHO by
Bayer AG, Leverkusen, FRG.
Vijverberg, H. & Van den Bercken, J., 1982. Action of pyrethroid
insecticides on the vertebrate nervous system. Neuropathology and
Applied Neurobiology 8: 421-440. Submitted to WHO by Bayer AG,
Leverkusen, FRG.
Weber, H. & Suwelak, D., 1983. Fluorophenyl-UL-14C Cyfluthrin
(FCR 1272) biokinetic study on rats. Unpublished report no. 11575 from
Bayer Institute of Pharmakokinetics, submitted to WHO by Bayer AG,
Leverkusen, FRG.
Yang, L. & Louie, A., 1985. CHO/HGPRT mutation assay in the presence
and absence of exogenous metabolic activation. Test article Baythroid
(FCR 1272), technical cyfluthrin. Unpublished report no. 694 (Mobay)
from Microbiological Associates, Bethesda, MD., submitted to WHO by
Bayer AG, Leverkusen, FRG.
See Also:
Toxicological Abbreviations
Cyfluthrin (ICSC)
Cyfluthrin (WHO Food Additives Series 39)
CYFLUTHRIN (JECFA Evaluation)
Cyfluthrin (UKPID)