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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Study completed on 29 Jun 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - 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 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Food consumption was not measured.
Principles of method if other than guideline:
Protocol not fully in compliance with method B of the Directive 87/302/EEC
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Thiram
EC Number:
205-286-2
EC Name:
Thiram
Cas Number:
137-26-8
Molecular formula:
C6H12N2S4
IUPAC Name:
thiram
Details on test material:
- Name of test material (as cited in study report): Thiram
- Purity test date: 99.5 %
- Lot/batch No.: 860410/L
- Physical state: white powder
- Stability: no data

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Suspension of 0.5 % w/v aqueous CMC containing 0.5 % w/v Tween 80
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No mating period. Females were artificially inseminated.
Duration of treatment / exposure:
Day 6-19 post insemination
Frequency of treatment:
Daily from day 6 at day 19 post insemination
Duration of test:
Sacrificed on day 29 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 2.5 and 5 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
15-20 pregnant females
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 2.5 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
ca. 5 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
ca. 5 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
> 5 mg/kg bw/day
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Findings:

Motrtality: A total of 8 females died or were killed in extremis: Control 1, low dose 1, mid dose 2 and high dose 4. Necropsy findings for the 8 decendents revealed evidence of respiratory or gastro-intestinal tract disorder, or accidential tracheal intubation

Clinical signs: No abnormal clinical symptoms were detected.

Body weight: Control group exhibited unusually poor pattern of body weight gain, therefore supplementary from a second group (1A) was provided. Body weight gain in low- and mid-dose group was superior to control group but essentially similar to supplementary control group. In the high-dose group, body weight gain was similar to control but inferior to supplementary control group. Hence, the possibility of an adverse effect on body weight gain due to treatment cannot be entirely excluded.

Necrospy: No treatment-related macroscopic changes were observed.

Caesarean data: One female in each of control and high-dose group aborted. In addition, one female in each of mid- and high-dose group exhibited total litter resorption. Considering the low incidence of pregnancy loss and the absence of any confirmatory increased incidence of post-implantation loss, involvement of Thiram seemed unlikely.

Teratogenic/embryo toxic effects: An apparent marginal increase in the incidence of small foetuses was observed at necropsy for females in group 1 and 5 mg/kg bw/d, compared with the concurrent controls, but the values were within the laboratory background control range (mean 13.6 % incidence, range 0 -32.3 %).

Following freehand serial sectioning, a slight reduction was seen, in group 5 mg/kg bw/d, in the incidence of foetuses with both incisors erupted, and a corresponding increase in the incidence of foetuses with only the lower incisors erupted.

Results of dams, foetuses no effect:

 Parameter/Dose  Control  1 mg/kg bw  2.5 mg/kg bw  5 mg/kg bw
 Body weight gain       reduced 
 Total no. inseminated 18  15  18  20 
 Mortality  1 1
 Not pregnant  5 2
 Abortion
 No. gravid females/group 13  14  15  18 
 Total litter loss
 Pregnant at term with viable young 11  13  12  12 
 Small foetuses (< 32 g) [% incidence] 17.3  23.8  14.1  28.3 

Comments: Dams: It seemed unlikely that maternal toxicity was due to administration of thiram. Foetuses: The apparent marginal increase in small foetuses was considered to be unrelated to treatment in view of the absence of dose- effect relationship or any corresponding reduction in group mean foetal weight. With regard to the eruption of the scissors, any treatment related effect was unlikely because of absence of correlation with foetal weight and because of the background control data.

Applicant's summary and conclusion