Captan

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 January to 20 February 1987

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

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, N-(trichloromethylthio)cyclohex-4-ene-1,2-dicarboximide
- Molecular formula: C9H8Cl3NO2S
- Molecular mass: 300.59
- Physical state: white powder
- Purity: 90.5 %
- Batch number: SX-1086
- Date of arrival: 8 January 1987
- Storage conditions: room temperature

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on species / strain selection:

New Zealand White rabbits; Hazleton Dutchland, Denver, Pennsylvania; approximately 3 1/2 month old at initiation.

Sex:

male/female

Administration / exposure

Type of coverage:

occlusive

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

21 days

Frequency of treatment:

five days per week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

110 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

12.5 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5/sex/dose group

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

Parameters evaluated were clinical signs (daily), general appearance, behaviour and pharmacotoxic signs and dermal irritation (pretest and days 2, 4, 8, 11, 15, 18 and 21), body weight (pretest and twice weekly), food intake (weekly), haematology and clinical chemistry (day 21)

Sacrifice and pathology:

Organ weights (adrenal, brain, kidney, liver, ovary, testis), gross pathology and histopathology (adrenal, brain, kidney, liver, lung, ovary, testis, skin, spleen and gross lesions).

Results and discussion

Results of examinations

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

There were no signs of dermal irritation at the application sites in the control animals. Animals in the 12.5 mg/kg bw and 110 mg/kg bw were also normal apart from very slight desquamation in one 12.5 mg/kg bw female on day 21 and slight erythema observed in two 110 mg/kg bw females on day 21. Slight erythema, oedema and desquamation were observed starting at day 4 in some animals in the 1,000 mg/kg bw group.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One 110 mg/kg bw female was found dead on day 9 of the test, but the death was considered to be unrelated to exposure of captan.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain and food consumption in 12.5 and 110 mg/kg bw animals were comparable to the control animals and no signs of overt toxicity were noted. The body weight of 1,000 mg/kg females was significantly lower than the control on day 22.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Significant differences in food consumption were noted between the 1,000 mg/kg bw dose group and the control in weeks 2 and/or 3.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Treatment-related changes noted at autopsy were observed at the application sites and were limited to mild desquamation in one 12.5 mg/kg bw female and in one male and three females from the 1,000 mg/kg bw dose group.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Whereas microscopic changes to the site of application occurred in all dose groups there was no apparent dose-relationship.

Effect levels

1

Key result

Dose descriptor:

NOEL

Effect level:

110 mg/kg bw (total dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

2

Key result

Dose descriptor:

NOEL

Effect level:

12.5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

dermal irritation

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

General observations: Body weight gain and food consumption in 12.5 and 110 mg/kg bw animals were comparable to the control animals and no signs of overt toxicity were noted. One 110 mg/kg bw female was found dead on day 9 of the test, but the death was considered to be unrelated to exposure of captan. The body weight of 1000 mg/kg females was significantly lower than the control on day 22. Significant differences in food consumption were noted between the 1000 mg/kg bw dose group and the control in weeks 2 and/or 3.

Local findings: There were no signs of dermal irritation at the application sites in the control animals. Animals in the 12.5 mg/kg bw and 110 mg/kg bw were also normal apart from very slight desquamation in one 12.5 mg/kg bw female on day 21 and slight erythema observed in two 110 mg/kg bw females on day 21. Slight erythema, oedema and desquamation were observed starting at day 4 in some animals in the 1000 mg/kg bw group. Haematology and clinical chemistry: There were no treatment-related effects on haematological or clinical chemistry parameters.

Gross pathology, organ weights and histopatholgy: Treatment-related changes noted at autopsy were observed at the application sites and were limited to mild desquamation in one 12.5 mg/kg bw female and in one male and three females from the 1000 mg/kg bw dose group. Whereas microscopic changes to the site of application occurred in all dose groups there was no apparent dose-relationship.

7.5.3-1 Subacute dermal study on rabbits: summary of female body weights (mean ± sd)

Day	Body weight (g)
	0 mg/kg bw	12.5 mg/kg bw	110 mg/kg bw	1000 mg/kg bw
0	2422 ± 113.1	2441 ± 135.8	2414 ± 175.4	2407 ± 175.3
3	2430 ± 137.9	2450 ± 140.4	2429 ± 199.7	2302 ± 158.2
7	2433 ± 281.2	2534 ± 140.1	2522 ± 250.0	2290 ± 215.3
10	2588 ± 126.8	2585 ± 143.1	2664 ± 264.0	2336 ± 167.5
14	2680 ± 156.4	2684 ± 170.7	2742 ± 304.2	2387 ± 220.1
17	2745 ± 156.6	2736 ± 179.4	2830 ± 324.7	2387 ± 201.9
22	2793 ± 125.6	2819 ± 171.4	2893 ± 333.8	2429 ± 163.0*

* Significantly different from the control (p < 0.05).

7.5.3-2 Subacute dermal study on rabbits: summary of food consumption (mean ± sd)

week	Food consumption (g/animal/day)
	0 mg/kg bw	12.5 mg/kg bw	110 mg/kg bw	1000 mg/kg bw
males
1	127.9 ± 59.57	163.8 ± 85.35	144.4 ± 20.99	81.1 ± 13.93
2	170.7 ± 35.82	159.2 ± 33.12	161.3 ± 11.05	110.3 ± 26.10^*
3	132.3 ± 23.58	129.9 ± 41.78	134.9 ± 11.34	110.9 ± 12.18
females
1	124.0 ± 52.41	150.3 ± 17.75	128.7 ± 41.98	76.5 ± 35.90
2	159.7 ± 27.28	161.3 ± 18.86	160.0 ± 23.14	107.4 ± 15.84^**
3	137.4 ± 15.75	137.1 ± 16.33	135.0 ± 14.96	92.3 ± 22.23^**

* Significantly different from the control (p < 0.05);

** significantly different from the control (p < 0.01).

7.5.3-3 Subacute dermal study on rabbits: summary of dermal findings in 1000 mg/kg bw dose group animals

Dermal Sign		Days
		2		4		8		11		15		18		21
		m	f	m	f	m	f	m	f	m	f	m	f	m	f
Erythema	None	5	5	5	3	5	4	5	5	5	4	2	2	2	2
	Very slight	0	0	0	2	0	1	0	0	0	1	3	3	3	3
	Well defined	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Moderate to severe	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Severe	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Oedema	None	5	5	5	5	5	5	5	5	5	5	2	3	2	3
	Very slight	0	0	0	0	0	0	0	0	0	0	3	2	3	2
	Slight	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Moderate	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Severe	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Atonia	Normal	5	5	5	5	5	5	5	5	5	5	5	4	5	5
	Slight	0	0	0	0	0	0	0	0	0	0	0	1	0	0
	Moderate	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	Marked	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Desquamation	None	5	5	5	5	5	5	5	5	5	3	1	1	1	1
	Slight	0	0	0	0	0	0	0	0	0	2	4	4	4	3
	Moderate	0	0	0	0	0	0	0	0	0	0	0	0	0	1
	Marked	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Number of animals		5	5	5	5	5	5	5	5	5	5	5	5	5	5

m=males, f=females

Applicant's summary and conclusion

Conclusions:

The NOEL for systemic effects was 110 mg/kg bw in both males and females, based on reduced food consumption (males and females) and body weight (females). The NOEL for local effects was less than 12.5 mg/kg bw in both males and females, based on dermal irritation changes to the skin observed at the macroscopic and microscopic level in the lowest dose group tested.

Executive summary:

Dermal effects on New Zealand White rabbits were studied according to EPA OPP 83-1. Five animals per sex an dose were chosen for examination. 12.5, 110 and 1000 mg/kg bw were used. 

Animals in the 12.5 mg/kg groups were similar to the control animals in body weight gain and food consumption and there were no signs of test article related overt toxicity noted in these groups during the course of the study. At 1000 mg/kg, however, animals had decreased body weight gains and decreased food consumption (g/animal/day and g/kg/day) in both sexes achieved statistical significance as compared to control values at one or more intervals during the study. The 1000 mg/kg animals also exhibited a higher degree of dermal irritation at the application site than animals in the other groups. Overall, the irritation produced by the test article was minimal.

Other than the body weight and food consumption decrement in the 1000 mg/kg animals, there was no evidence of the test article related systemic toxicity in any animal. Results of clinical pathology determinations in treated animals were similar control values, with minor differences attributed to animal variation. Organ weight differences that occurred were due to normal animal variation and/or body weight differences in the high dose females.

One female from the 110 mg/kg group was found dead on the study day 9. The salient lesion in this animal was severe hemorrhagic ileitis, which was considered to be spontaneous and unrelated to administration of the test article.

There were microscopic test article related dermal findings that occurred in animals from all treated groups with no apparent dose response. In males, the changes consisted of acanthosis and hyperkeratosis. In females, the findings included acanthosis, hyperkeratosis and subacute dermatitis. All other microscopic findings were judged to be spontaneous and/or incidental in nature.

In summary the NOEL for systemic effects was 110 mg/kg bw in both males and females, based on reduced food consumption (males and females) and body weight (females). The NOEL for local effects was less than 12.5 mg/kg bw in both males and females, based on dermal irritation changes to the skin observed at the macroscopic and microscopic level in the lowest dose group tested.