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EC number: 205-087-0
CAS number: 133-06-2
Short description of key information: Toxicity to fertility, three generation reproduction study, subacute study, oral (gavage), rat (COBS CD strain rats) m/f, in-house-method, NOEL: 500 mg/kg/bw/day
General observations: No treatment-related effects were seen in the
general behaviour or appearance of the treated parental rats or pups.
Survival of parental rats was unaffected by treatment.
Parental body weights: Diet analysis indicated that captan levels ranged
from 90 to 100% of the nominal levels. Throughout all generations, a
dose-dependent decrease in male and female body weights in 100, 250 and
500 mg/kg bw/day treatment groups was observed. This was statistically
significant in 250 and 500 mg/kg bw/day treatment groups at all times
and occasionally significant at 100 mg/kg/day. Although a reduction in
the 25 mg/kg bw/day parental weight of males was evident during the F0
and F2 generations, there was no statistical significance. F2 generation
male body weight at sexual maturity was similar to the control Parental
food consumption: Slight to moderate decreases in parental food
consumption (g food/rat/day) were observed in males and females of all
treatment groups in all three generations ( Table
7.8.1 -1). Exceptions were slight increases over the control in
25 mg/kg bw/day F1 males and 100 mg/kg bw/day F2 females and similar
food consumption in 25 mg/kg bw/day F2 females compared to the control.
Pup body weights: In general, dose-related reductions in pup body
weights were seen in all litters throughout lactation at 100, 250 and
500 mg/kg/day. These reductions were statistically significant in all
six matings in the 250 and 500 mg/kg/day dose groups throughout
lactation to weaning and at most body weight intervals in the 100
mg/kg/day litters. The body weight of pups at lactation day 21 was
significantly lower than the control in males and females. Mean pup body
weights were slightly lower than the controls in the 25 mg/kg/day dose
group with occasional statistical significance. At lactation day 21,
mean pup body weights were slightly lower than the controls in all six
matings with statistical significance noted for F1b litters only.
Foetal body weights: The mean foetal body weights in the 500 mg/kg
bw/day dose group were significantly lower than the control (Table
Reproductive parameters: No consistent treatment-related effects on male
and female fertility or length of gestation were observed. Two females
at 500 mg/kg bw/day showed high incidences of peri-natal pup losses at
the F1b mating, but as these were isolated incidences in this generation
and were not seen in other matings or other generations, no association
with treatment is made. Pup survival during lactation was unaffected in
the 25 and 100 mg/kg bw/day dose groups. At 250 mg/kg bw/day a reduction
in survival was noted through lactation day 4 of the F1a, F2a and F3a
litters and in 500 mg/kg bw/day in the litters of all three generations
7.8.1 -2). Litter size was reduced in F1a and F1b litters in all
treatment groups (except at 100 mg/kg bw/day for F1b) compared to the
controls. The 250 and 500 mg/kg bw/day dose group F2a and F2b litter
sizes were reduced compared to the controls.
Teratology: No treatment-related or statistically significant
differences were noted in male and female fertility, mean numbers of
nonviable foetuses, early and late resorptions and postimplantation loss
per dam or foetal sex distribution in any of the captan treated groups
compared to the control. There were no biologically meaningful or
statistically significant differences in the number of foetuses or
litters with malformations in the captan treated groups compared to the
Gross Pathology: There were no treatment-related abnormalities in any of
the pups examined after weaning or in any of the parental rats that died
during the study.
In a three generation reproduction study in Charles River COBS CD strain rats, Captan was administered in the diet at dosage levels of 0, 25, 100, 250 and 500 mg/kg/day. The first (F0) and third (F2) generations were mated twice and the second (F1) generation three times. Offspring from the second mating of the F0 and F2 generations were selected after weaning to comprise the next generations. Offspring from the generation's third mating (F2c) were delivered by Cesarean section on gestation day 19.
Throughout the duration of the study, the parental rats and pups were observed for signs of toxicity, changes in general behavior and appearance, and survival. Parental body weights and food consumption were recorded weekly. Litter and pup weights were recorded at specific intervals during lactation. Male and female fertility, length of gestation, pup viability and litter size were evaluated.
No changes considered to be related to Captan treatment were seen for the parental rats with respect, to general behavior and appearance, survival, male and female fertility or length of gestation.
Mean body weights of the parental females at the 25 mg/kg/day treatment level were comparable to the control during all generations.
Mean body weights of the 25 mg/kg/day parental males were slightly lower than the control during the F0 and F2 generations. The F2 generation male weights were reduced as a result of lower weight at initiation of the generation. At the 100, 250 and 500 mg/kg/day treatment levels, significant reductions in male and female body weights as compared to the control group were evident throughout all three generations following a dose-related trend. Food consumption values at all Captan levels were slightly to moderately decreased from the control values, paralleling the reduction observed in body weights.
The general behavior and appearance of the Captan treated pups were similar to the control. Pup survival during lactation at the 25 and 100 mg/kg/day treatment levels was not affected by treatment.
At the 250 mg/kg/day treatment level, decreased survival was noted through lactation day 4 of the F1a, F2a and F3a litters, while at the 500 mg/kg/day treatment level, consistent reductions were apparent in the litters of all three generations, primarily through lactation day 4.
Reduced litter sizes occurred in all Captan treatment groups in the first generation, and in the 250 and 500 mg/kg/day treatment groups F2a and F2b litters.
treatment-related reductions in mean pup body weights during lactation were evident in the litters of all three generations at the 100, 250 and 500 cg/kg/day treatment levels and most litters at the 25 mg/kg/day treatment level.
At Cesarean section of the F2c litters, no biologically meaningful or treatment-related differences in the mean numbers of nonviable fetuses, resorptions, postimplantation loss, fetuses or litters with malformations or fetal sex distribution were noted as compared co the control. A very slight reduction in the mean number of viable fetuses and total implantations was evident in the 250 and 500 mg/kg/day groups.
Mean numbers of corpora lutea at the 500 mg/kg/day treatment level was also decreased. The F2c fetal body weights were comparable to the control at Captan levels of 250 mg/kg/day or less. At 500 mg/kg/day, fetal body weights were significantly lower than the control.
At the gross necropsy examinations of the pups after weaning or of parental rats dying on study, no abnormality indicative of a compound related effect was observed.
From the results evaluated in the present study, doses of 25 mg/kg/day and above could not be considered no-effect levels.
Developmental Toxicity: Subacute (30 days) oral gavage, rabbit (f), NOEL (maternal and foetal) = 10 mg/kg/day, USEPA Guideline 83-3 equivalent to OECD 414 equivalent to EU 88/302/EEC, B31.
Levels of captan in dosing solutions: Achieved concentrations of captan in dosing preparations were ± 4% of nominal levels. Homogeneity and stability of captan in solution were satisfactory.
General observations: Treated dams had an increased incidence of few or no faeces compared to the control. Increased incidences of diarrhoea in all treated groups and mucus in the faeces in 100 mg/kg bw/day dams were observed. One 100 mg/kg bw/day female was killed intercurrently following signs of abortion. There was a dose-related reduction in maternal body weight gain in 30 and 100 mg/kg bw/day dams, which was most marked during days 7 to 10. Compensatory body weight gain was evident during the post-dosing period in the 100 mg/kg bw/day dams (Table 7.8.2-2). A dose-related reduction in food consumption was also seen in the 30 and 100 mg/kg bw/day females, followed by a compensatory increase in food consumption by 100 mg/kg bw/day dams, particularly on days 26 to 30. The low dose group was unaffected.
Table 7.8.2-2 Developmental toxicity study in the rabbit: body weight of dams
Body weight gain (g) at dose (mg/kg bw/day)
1 – 7
7 – 19
7 – 10
10 – 13
13 – 16
16 – 19
19 – 30
19 – 22
22 – 26
26 – 30
1 – 30
Significantly different from the control, * (p < 0.05), ** (p < 0.01)
Pregnancy and litter data: There was no treatment-related effect on pregnancy rate. The incidence of pre-implantation loss in 100 mg/kg bw/day dams was not significantly affected. Post-implantation loss in 100 mg/kg bw/day dams was significantly increased compared to the control and reflected the increased incidences of intra-uterine deaths (early and late). Mean total implantation loss was not affected by captan treatment and as a result there was no adverse effect on the mean number of live foetuses compared to the controls. Mean foetal weight in the 100 mg/kg bw/day dose group was significantly lower than the control, with a consequent reduction (not statistically significant) in mean gravid uterine weight. A summary of litter data is given in Table 7.8.2-3.
Table 7.8.2-3. Developmental toxicity study in the rabbit: litter data
Litter data parameter
Dose (mg/kg bw/day)
Corpora lutea (mean)
Pre-implantation loss (transformed mean)
Post-implantation loss (transformed mean)
Intra-uterine deaths (mean % early)
Intra-uterine deaths (mean % late)
Live foetuses (mean)
Mean gravid uterine weight (g)
Mean litter weight (g)
Mean foetal weight (g)
Foetal assessment (major defects): The incidence of foetuses with major defects was significantly increased in the 100 mg/kg bw/day dose group compared to the control. Eight foetuses from five litters had at least one major abnormality compared to one in the control. Four of the eight foetuses affected in the 100 mg/kg bw/day dose group were from one litter. There was no compound-related effect on the incidence of defects involving the cardiac blood vessels but there was an increased incidence of foetuses with major defects of the head in both the 30 and 100 mg/kg bw/day groups. In the latter group, two of the three affected foetuses were litter mates. Of the remaining types of major defects all but one occurred in the 100 mg/kg bw/day group. The possibility of the major defects being treatment-related cannot be dismissed though the small numbers involved and type of specific minor defects and the fact that several foetuses were litter mates, provides no strong evidence for a compound relationship.
Foetal assessment (minor defects): The incidence of minor external/visceral defects was increased in the 30 and 100 mg/kg bw/day dose groups compared to the control and was mainly due to an increase in the incidence of cysts on the liver. The overall incidence of minor skeletal defects was unaffected by treatment, although the incidence of unossified 6thand 7thlumbar transverse processes and asymmetric alignment of the pelvic girdle was increased in the 100 mg/kg bw/day dose group.
Foetal assessment (variants): There were no external or visceral variants. Each foetus had at least one skeletal variant. Treatment-related effects were seen in the incidence of the following variants in the 100 mg/kg bw/day dose group; odontoid partially ossified (increase); normal length extra 13th ribs (increase); 27 pre-sacral vertebrae (increase): asymmetric development of 1st and 2nd sacral vertebrae (increase); 4th, 5th, 6th and 7th lumbar transverse processes partially ossified; 2nd lumbar transverse processes partially ossified; 3rdlumbar transverse processes fully ossified. The effects on ossification of the lumbar transverse processes reflect reduced ossification which may be associated with reduced foetal weight. The majority of these variants were also seen in the 30 mg/kg bw/day dose group.
The overall incidence of foetuses with extra 13th rib was increased in 30 and 100 mg/kg bw/day dose groups compared to the control (60.8, 52.1, 77.3 and 77.6% affected in the control, 10, 30 and 100 mg/kg bw/day dose groups).
Foetal assessment (manus and pes assessment): An increase in manus scores, reflecting the decrease in ossification was observed in the 100 mg/kg bw/day dose group (mean score 2.56, p <0.01) compared to the control (mean score 2.24). The mean pes score was 2.0 for all dose groups. A summary of the incidence of defects and variants is given in Table 7.8.2-4.
Table 7.8.2-4 Developmental toxicity study in the rabbit: summary of foetal defects and variants
Incidence of foetal defects and variants
Number of litters examined
External and visceral:
Number of foetuses examined
Number of foetuses with major defects
Number of foetuses with minor defects only
Number of foetuses showing variants
Significantly different from the control, * (p < 0.05), ** (p < 0.01)
Gross pathology dams: There was no evidence of treatment-related effects on the incidence of macroscopic findings
The purpose of this study
was to investigate the effects of captan on the embryonic and foetal
development of the rabbit when administered by gavage during
The rabbit is one of the
species generally recommended for assessment of teratogenicity and the
New Zealand White strain was used because of its known susceptibility to
a number of teratogens and because of the substantial background data
within this laboratory relating to studies of this type. The oral route
was chosen for administration of captan as this represents a possible
route of human exposure.
Groups of 20 female New
Zealand White rabbits were dosed by gavage with 0, 10, 30 or 100 mg
captan/kg/day in corn oil from Days 7-19 (inclusive) of gestation which
thus included the period of major organogenesis. A control group of
animals received corn oil alone.
The day of insemination was
designated Day 1 of gestation. On Day 30 of gestation the females were
killed and their uteri examined for live foetuses and intra-uterine
deaths. The foetuses were weighed, examined for external and visceral
abnormalities, sexed, eviscerated and stained for skeletal examination.
Administration of captan at
dose levels of 30 and 100 mg/kg/day was associated with maternal
toxicity and developmental toxicity.
An increase in major defects
at these dose levels provided no consistent evidence of a compound
relationship due to the diverse nature of the abnormalties seen. The
overall no-effect level was 10 mg captan/kg/day.
No negative effects on reproduction and developmental toxicity were discovered. Captan is not classified as being toxic for reproduction.
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