Captan

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 October 1986 to 3 December 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 83-1 (Chronic Toxicity)

Deviations:

no

GLP compliance:

yes

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Captan

EC Number:

205-087-0

EC Name:

Captan

Cas Number:

133-06-2

Molecular formula:

C9H8Cl3NO2S

IUPAC Name:

2-[(trichloromethyl)sulfanyl]-2,3,3a,4,7,7a-hexahydro-1H-isoindole-1,3-dione

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material: Captan Technical, N-(trichloromethylthio)cyclohex-4-ene-1,2-dicarboximide
- Molecular formula: C9H8Cl3NO2S
- Molecular mass: 300.59
- Physical state: white powder
- Analytical purity: 90.4 % (w/w)
- Batch number: WRC 4921-26-15
- Date of arrival: 7 July 1986
- Storage conditions: room temperature
This sample of Captan Technical was assayed before the study began and was found to contain 90.4 wt. % captan. Retain samples analyzed 35-months later assayed at 89.0 and 88.8 wt.% captan, thus demonstrating the stability of the test material through the duration of the 12-month chronic toxicity study.

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

52 weeks (one year)

Frequency of treatment:

once/day

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

12.5 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

60 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

300 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Three groups: 12.5, 60 and 300 mg/kg bw/day (5/sex/dose). Control group: empty gelatine capsules (5/sex).

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
HAEMATOLOGY: Yes
CLINICAL CHEMISTRY: Yes
URINALYSIS: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Effect levels

Key result

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Sex:

male/female

Basis for effect level:

other: Captan Technical was well tolerated by dogs when administered orally in gelatin capsules at dose levels up to 300 mg/kg/day for 52 weeks.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

 

Captan Technical was administered orally by capsule to beagle dogs at dosage levels of 12.5, 60.0 and 300.0 mg/kg/day for 52 weeks. Control dogs received empty gelatin capsules. Five male and five female animals were initiated on study in each of the four groups.

All animals survived until the termination of the study. The 300 mg/kg/day dosage level had a higher incidence of emesis and soft/mucoid stool compared to those of the control group. These observations were considered to be related to administration of the test substance.

One female at the 60 mg/kg/day dosage was noted with observation "appears to have convulsed" on three days during the study. Convulsions have been observed spontaneously in dogs at IRDC although at a low incidence. Microscopically all tissues for this animal were within normal limits. Since the finding was observed rarely, and only in one mid-dose animal, it was not considered to be related to administration of the test article.

General observations: There were no mortalities during the study. A higher incidence of emesis and soft/mucoid stool was sporadically noted in 300 mg/kg bw/day animals compared to the control, although these were also noted in other groups including controls. This was probably a treatment-related effect but was not considered as a toxicological effect.

There were no significant differences in group mean body weight at any interval. Food consumption values for females administered test substance appeared lower than control females. However, food consumption in the control group females was considered higher than normal and therefore no toxicological significance is attached to the relatively low food consumption in the 60 and 300 mg/kg bw/day animals. No treatment-related

ophthalmological abnormalities were detected. Physical examination findings revealed no significant findings.

 

Haematology, clinical chemistry and urinalysis: There were no treatment-related effects on haematological or clinical chemistry parameters and urinalysis was considered normal.

 

Gross pathology, organ weights and histopathology: No treatment-related gross pathological changes were observed. Absolute organ weights were unaffected by treatment. A significant increase in the liver weight was observed in 300 mg/kg bw/day males compared to the control. This was considered to be related to the lower body weight observed in this group compared to the control and not treatment-related. No treatment-related histopathological changes were observed.

 

 

Table 7.5.1-1: Group mean body weight at study week 52 and the percent differences from the pretest

Dosage Level (mg/kg/day)	Mean Body Weights, kg, Week 52 (percent difference from pretest)
	Male			Female
	Pretest	Week 52	% difference	Pretest	Week 52	% difference
0.0	12.2	13.3	+9.0	9.0	9.4	+4.4
12.5	11.7	12.9	+10.3	9.3	10.1	+8.6
60.0	11.1	11.8	+6.3	9.3	10.8	+16.1
300	11.7	12.6	+7.7	9.4	10.00	+6.4

 

Table 7.5.1-2: Average group mean food consumption g/animal/day for study weeks 1 through 52 and the percent difference from the control group

Dosage Level (mg/kg/day)	Average Group Mean Food Consumption, g/animal/day (percent difference from control)
	Male		Female
		% difference		% difference
0.0	389		408
12.5	417	+7.2	311	-23.8
60.0	441	+13.4	316	-22.5
300.0	413	+6.2	351	-14.0

 

Table 7.5.1-3-: Average group mean food consumption g/kg/day for study weeks 1 through 52 and the percent difference from the control group

Dosage Level (mg/kg/day)	Average Group Mean Food Consumption, g/kg/day (percent difference from control)
	Male		Female
		% difference		% difference
0.0	30.1		44.4
12.5	33.8	+ 12.3	31.5	-29.1
60.0	38.0	+26.2	32.1	-27.7
300.0	34.5	+14.6	36.5	-17.8

Applicant's summary and conclusion

Conclusions:

The NOEL was 300 mg/kg bw/day in both male and female dogs.

Executive summary:

Captan Technical was administered orally by capsule to beagle dogs at dosage levels of 12.5, 60.0 and 300.0 mg/kg/day for 52 weeks; control dogs received empty gelatin capsules. The dose levels for this study were selected on the basis of a preliminary four week range finding study in dogs in which dose levels of 300 mg/kg/day and above produced emesis, in appetence and a reduction in body weight.

Computerized random selection in a block design based on body weights. Animals with large absolute differences from the quarantine population body weight mean eliminated prior to randomization and homogeneity of group body weight variances used as the criteria for acceptance. Body weights, food consumption values, clinical pathology parameters and organ weight values analyzed using analysis of variance and Bartlett's test. Treatment groups compared to the control group, by sex, using the appropriate t-statistic (equal or unequal variance). Nonparametric analysis, when appropriate, by rank transformation.

Observations noted for dogs in the 12.5 mg/kg/day group were similar to those recorded for the control group. Body weight gains were similar in all groups. Food consumption values in male groups were comparable through the study. Food consumption values in female dogs administered the test substance appeared to be less than those for control females. However, food consumption values for the female control group were higher than normal. Food consumption for all female dogs exposed to the test substance was considered normal at around 300 to 350 g/dog/day. Consequently no toxicological significance was attributed to the apparent reduction in food consumption in test substance treated animals.

Other observations and examinations performed during the in-life phase of the study were unremarkable. No test substance related abnormalities were detected during the ophthalmoscopic examinations, detailed physical examinations, and the clinical pathology evaluations.

No test article related macroscopic changes were observed in any of the male or female dogs that were terminally sacrificed after a one year period of study. Occasional changes that were seen at necropsy in these dogs were considered incidental in nature and unrelated to the administration of the test article.

At terminal sacrifice, no test article related organ weight changes were observed in any of the treatment groups.

There were no test article related microscopic changes in any of the male or female dogs that were sacrificed after a one year period of study. Occasional changes were seen in a variety of organs, but these were considered spontaneous in nature and usual for dogs of this age and breed.

In conclusion Captan Technical was well tolerated by dogs when administered orally in gelatin capsules at dosage levels up to 300 mg/kg/day for 52 weeks. There was some emesis and soft/mucoid stool at the 300 mg/kg/day level. However, these signs were regarded as a response to the taste and physical nature of the test substance rather than a toxicological effect. The no toxic effect dose level in this study was 300 mg of Captan Technical/kg/day to both male and female dogs. Daily dosage of higher than 300 mg/kg was considered likely to result in significant toxicity and potentially lead to deaths in a one year study.

The NOEL for oral administration of captan is set to 300 mg/kg bw/day in both male and female dogs.