Disulfiram

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

23.05.89-21.06.91

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

GLP - Guideline study, tested with the source substance tetramethylthiuram disulfide (CAS No. 137-26-8). In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance. (For detailed information on the justification of read-across, please refer to the analogue justification document attached in IUCLID section 13).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report Date:

1991

Materials and methods

Test guideline

Qualifier:

according to

Guideline:

EPA OPP 83-1 (Chronic Toxicity)

Deviations:

yes

Remarks:

On several occasions there was only one observation per day for mortality and moribundity. Due to mistakes food consumption values for week 10 reflect 6-day consumption. Blood sampling prior to treatment (week -2) was done on non-fastened animals. Before

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

- Name of test material (as cited in study report): Thiram
- Physical state: off-white powder
- Analytical purity: 97.5 %
- Purity test date: 06/89 and 07/90
- Lot/batch No.: 117
- Stability under test conditions: stability was assured through analysis by the sponsor
- Storage condition of test material: room temperature

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

52 weeks

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
0, 0.84, 2.61, 7.35 mg/kg bw/day for males
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
0, 0.90, 2.54, 7.23 mg/kg bw/day for females
Basis:
actual ingested

No. of animals per sex per dose:

6

Control animals:

yes, plain diet

Results and discussion

Effect levels

1

Dose descriptor:

NOEL

Effect level:

ca. 0.84 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: No effects were observed at the lowest dose level.

2

Dose descriptor:

NOEL

Effect level:

ca. 2.54 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: No effects were observed at the mid-dose level.

3

Dose descriptor:

LOEL

Effect level:

ca. 2.61 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: Findings on hematology and clinical chemistry

4

Dose descriptor:

LOEL

Effect level:

ca. 7.23 mg/kg bw/day (actual dose received)

Sex:

female

Basis for effect level:

other: Findings on clinical chemistry

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Clinical signs: No treatment-related effects were noted in any of the dogs surviving until termination.

Mortality: One female at 90 ppm was sacrificed during week 25, due to clonic convulsions with pulmonary congestion. Pathology examinations revealed meningoencephalitis. One female at 250 ppm was sacrificed during week 26 due to clonic seizures with opisthotonos. Pathology examinations revealed hydrocephalus. Both conditions of these dogs were not considered treatment-related.

Body weight: There were no statistically significant differences in body weights of males and females at any dose level. At week 52 mean body weights of males at 30, 90, and 250 ppm were 93%, 105%, and 87%, respectively of the control values. For females mean body weights in the 30, 90, and 250 ppm groups were 108%, 94%, and 98% of the control values, respectively.

Food consumption: Food consumption of females at 250 ppm was significantly lower than controls during week 20. However, there were no consistent effects on food consumptions in both sexes throughout the study.

Ophthalmoscopic examination: No ophthalmic lesions were observed for any animals.

Blood analysis: Haematology: 30 ppm: No effects. 90 ppm: No effects. 250 ppm: Reduced RBC values in males in weeks 13, 26, and 52. None of this effects was considered adverse. Thiram may have also caused higher MCV and MCH values. Since there were similar differences noted before initiation, no conclusion could be drawn from these findings.

Clinical Chemistry: 30 ppm: No effects. 90 ppm: In males, total protein was decreased in week 26 and 52. Also in males, increased total cholesterol values in week 13, 26, and 52. 250 ppm: Decreased total protein and albumin, as well as increased cholesterol values in males and females in weeks 13, 26, and 52. None of these effects was considered adverse.

Urinalysis: No effects.

Sacrifice and pathology:

Organ Weights: 30 ppm: Significant increased relative liver weights in males, due to a slight increase in absolute liver weight and a slight decrease in body weight. However, the increase in the relative liver weights was not considered test substance-related. 90 ppm: Significant increased absolute and relative liver weights in males. 250 ppm: Significant increased absolute liver weights in males, and significant increased relative liver weights in males and females. In males, liver-to-brain-weight ratios were also increased.

Gross and histopathology: Macroscopic Findings: No treatment-related effects.

Microscopic Findings: No treatment-related effects.