Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Study initiation: 16 Jun 1989, test diet administration initated: 20 Jul 1989, last F1 necrospy performed: 02 Dec 1990
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 83-4 (Reproduction and Fertility Effects)
Deviations:
yes
Remarks:
Food intake dring mating period was not measured
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: White powder
- Analytical purity: 97.84 %
- Lot/batch No.: 117
- Stability under test conditions: Stable

Test animals

Species:
rat
Strain:
other: Charles River Crl:CD® VAF/Plus®
Sex:
male/female
Details on test animals and environmental conditions:
Age at study initiation: 49 days
Body weight at study initiation: males 268 - 310 g, females 176 - 205 g

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: up to 21 days
- Proof of pregnancy: daily check, copulatory plug referred to as day 1 of pregnancy
- Due to poor conception rates in the F1b litter, the F0 parents were mated altogether three times. F1c litter was used to select the F1 parents, which were mated twice to produce the F2a and F2b litters.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Duration of exposure before mating: F0 / F1 parents: 81/84 days
Duration of exposure in general F0, F1, F2 males, females: Continuously throughout the study
Frequency of treatment:
Daily (food consumption)
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 30, 60 and 180 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 1.52, 2.94 and 8.88 mg/kg/day
Basis:
actual ingested
F0 males
Remarks:
Doses / Concentrations:
0, 2.27, 4.61 and 13.89 mg/kg/day
Basis:
actual ingested
F0 females
Remarks:
Doses / Concentrations:
0, 1.83, 3.82 and 11.37 mg/kg/day
Basis:
actual ingested
F1 males
Remarks:
Doses / Concentrations:
0, 2.39, 5.12 and 16.21 mg/kg/day
Basis:
actual ingested
F1 females
No. of animals per sex per dose:
26
Control animals:
yes, concurrent no treatment

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
fertility
Effect level:
> 9 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: corresponds to 11.1 mg disulfiram/kg bw/day
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
ca. 1.5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: corresponds to 1.85 mg disulfiram/kg bw/day

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
Developmental toxicity
Generation:
F1
Effect level:
3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Remarks:
corresponds to 3.7 mg disulfiram/kg bw/day
Sex:
male/female
Basis for effect level:
other: Mean offspring body weights were consistently reduced to a significant degree in all litters across both generations at the 180 ppm level.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Mortalities and clinical signs:

Two deaths occurred in the F0 and F1 generation each but all four deaths were not regarded as treatment-related. Treated F0 females showed an increased incidence of hair loss in a non-dose-related pattern. In F1 animals no clinical signs of toxicity were observed.

Body weight:

Statistically significant and treatment-related reductions in body weight in F0 females were observed during the F1a gestation period in the mid- and high-dose group. During the F1b and F1c gestation periods, reductions in body weight were observed in the high-dose group only. Decreases in the mean weekly body weight were observed in the F1 generation at the high dose level during the initial 10 weeks (males) or 13 weeks (females). These decreases were consistent with a reduced growth observed in these animals. Statistically significant reductions were additionally noted for high-dose females during the F2a and F2b gestation period.

Food consumption:

Reductions were noted for the F0 males at the high-dose level for three weeks and at the mid-dose level for two weeks. Food consumption of F0 females in the mid-dose group was reduced for one week and for several weeks in the high-dose group. Dose-related reductions were additionally noted for F0 females in the mid- and high-dose group throughout the F1a gestation period. This treatment-related reduction continued throughout the F1b and, without reaching statistically significance, in the F1c gestation period in the high-dose group. During the lactation periods in the high-dose group, food consumption was decreased in all three breeding periods. During the F2a and F2b gestation and lactation period food consumption was significantly and treatment-related reduced in the high-dose group.

Organ weight: There was no treatment-related effect on testes weight in the F0 and F1 generation males.

Necropsy: All macroscopic and microscopic changes seen in the rats were considered to be spontaneous or agonal.

Reproductive preformance: No treatment-related differences in the male and female copulatory and fertility indices, the gestation index, the mean copulatory interval or the mean gestation length were observed. Sperm were present, motile and morphologically normal.

Litter data

The mean number of stillborn and live pups in the treated groups was comparable with the one of the control litters at all dose levels and in both generations.

Pup body weight: Mean offspring body weights were consistently reduced to a significant degree in all litters across both generations at the 180 ppm level.

Clinical observations: No dose-related trends were observed in the type and incidence of clinical observations in treated F1 and F2 offspring when compared to the untreated controls.

Necropsy: No dose-related trends were observed in the type and incidence of clinical observations in treated F1 and F2 offspring when compared to the untreated controls.

Applicant's summary and conclusion