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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Sep-Oct 1988
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:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Food consumption was not recorded.
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: 99.82 %
- Impurities (identity and concentrations): Tetramethylthiuram monosulfide 0.005 %, sodium sulfate 0.01 %, water 0.1 %
- Purity test date: 18 Apr 1988
- Lot/batch No.: 860410/L
- Stability under test conditions: stable
- Storage condition of test material: Room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: aqueous 0.5 % carboxymethylcellulose containing 0.5 % (w/v) Tween 80
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: not reported. Virgin female rats were mated overnight individually with males. Each morning following pairing, the trays beneath the cages were checked for ejected copulation plugs and a vaginal smear was prepared from each female and examined for the presence of spermatozoa. The day on which a sperm positive vaginal smear or at least 3 vaginal plugs were found was designated as being day 0 of gestation.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: The day on which a sperm positive vaginal smear or at least 3 vaginal plugs were found was designated as being day 0 of gestation.
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
day 20 of gastation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 7.5, 15, and 30 mg/kg bw (1 mL/100 g bw)
Basis:
nominal conc.
Concentration in vehicle: 0, 0.75, 1.5 and 3.0 mg/ml
No. of animals per sex per dose:
25 female animals per dose
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
7.5 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Maternal toxic effects:

Clinical signs: The only treatment-related finding was a dose-related incidence in the number of dams.

Mortality: No deaths occurred.

Body weight:

7.5 mg/kg/d: Body weight gain was marginally reduced during treatment period (up to day 8 of gestation), but was unaffected thereafter. This effect was of no biological relevance for the progress and outcome of pregnancy.

15 mg /kg/d: Significant reduced body weight during treatment period only.

30 mg/kg/d: Marked transient body weight loss during treatment.

Necropsy: No gross treatment-related macroscopic abnormalities.

Teratogenic/embryo toxic effects (see table below):

No effects were noted on the implantations, resorptions, number of live foetuses, pre- and post-implantation losses.

7.5 mg/kg/d: Placental weight was slightly lower than concurrent control values, but remained within the historical control range. Foetal weight was unaffected and there was no evidence of foetal toxicity.

15 mg/kg/d: Mean foetal weight was slightly below that of the concurrent control group (p = 0.0507) and the incidence of small foetuses was slightly elevated, but both values were within the historical control range. Placental weights were slightly lower as compared to controls, but remained within the historical control range. There was an increased incidence of foetuses with reduced 13th ribs.

30 mg/kg/d: Mean foetal and placenta weights were significantly reduced (p 0.001), and there was a high incidence of small foetuses with weights of less than 2.7 g. There was an associated retardation of foetal development and slightly increased incidences of subcutaneous oedema and reduced 13th ribs.

Teratogenic/embryo toxic effects

Dose/endpoints Historical control data Recorded range  0 mg/kg bw/d  7.5 mg/kg bw/d  15 mg/kg bw/d  30 mg/kg bw/d
number pregnant females     25 25  25  25 
corpora lutea count [mean/dam]  16  13.9 -19  15 15.6  15  14.8 
implantations [mean/dam] 14.6  12 -16.7  13.9  14  13.6  13.5 
viable young (total)  13.7  11.1 -15.3  13.6  13.3  13.2  12.9 
resorptions (total)  0.86  0.25 -1.65  0.3  0.8  0.4  0.6 
Pre-implantation loss [%]  8.8  1.6 -16.5  8.4  10.0  9.6  9.7 
Post-implantation loss [%]  5.9  1.7 -12.7  5.4 3.2  4.2 
foetal weight [mean in g]  3.31  3 -3.55  3.24  3.26  3.13  2.89* 
placental weight [mean in g]  0.5  0.43 -0.57  0.50  0.47*  0.46*  0.41* 
Subcutaneus oedema [% incidence]  19.35 0 -63.2  9.9  5.1  11.3 20.4 
Reduced 13th ribs [% incidence] 1.77  0 -8.9  3.2  6.1  13.1  9.5 
Small foetuses (<2.7 g) [% incidence] 3.69   0 -16.9 1.8  1.8  8.2  23.8 

* significantly different from control: p<0.05 (nested analysis of variance and weighed t-test)

Diaphragmatic hernia was noted in two foetuses (of different litters) of the low-dose group, and in one foetus of the high-dose group. The occurrence of three affected foetuses from three different litters in the treated groups was higher than might be expected for this strain of rat. However, there was no indication of any dose-related response and group mean values were within historical control ranges. Thus, the possibility that this abnormality is test substance-related was considered equivocal.

Applicant's summary and conclusion