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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
preliminary study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report Date:
1998

Materials and methods

Principles of method if other than guideline:
range finding study
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Source of test compound: Merck KGaA
Batch: U1499277
Content of active ingredient: 71.5%

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann
- Age at study initiation: 11-13 weeks
- Weight at study initiation:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23
- Humidity (%): 51-73
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The preparations were produced daily at the central dispensary. There were stable for at least 4 hours.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Groups of four sexually matures, virgin females were left over night with one stock stud.
On the day following, vaginal smear were taken and checked for the presence of sperm. The day were sperm was founded was considered as GD0
Duration of treatment / exposure:
gestation days 6 - 19
Frequency of treatment:
daily
Duration of test:
Duration of test: 15 days - dosing GD 6 -19, rats were killed on day 20
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
The rats were killed on GD 20.

Examinations

Maternal examinations:
BODY WEIGHT: Yes (on GD0, GD6 and until the animals were killed)

FOOD CONSUMPTION: Yes on GD6, 10, 15, 20
WATER CONSUMPTION: on GD 3, 6, 9, 12, 15, 18

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: organs (macroscopally)

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
The foetuses were removed, weighed, and examined for macroscopic malformations. The sex was evaluated by measurment of anogenital distance and inspection of the gonads.
Statistics:
not appropriate. only mean values and standard deviations were calculated

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Rooting in the bedding material was seen in all animals and salivation in one animal of the 100 and 150 mg/kg groups.
Reduced spontaneous activity and piloerection were seen in single animals at 100 and in most animals at 150 mg/kg.
All animals at 150 mg/kg felt cold to the touch. Tonic-clonic convulsions, disturbed coordination of movement, stretched-out gait, and protruding eyeballs in both eyes were seen in one animal at 150 mg/kg.
Three animals treated with 100 mg/kg and all animals treated with 150 mg/kg died between GD 10 and 20.
At 50 mg/kg, the body weight development was very slightly and at 100 and 150 mg/kg it was clearly affected. The food consumption was reduced at 100 and 150 mg/kg, and the water consumption was slightly reduced at 50, 100, and 150 mg/kg.
In the rats treated with 100 mg/kg, the terminal body weight was lower, indicating maternal toxicity.
The numbers of corpora lutea, implantations and live foetuses per dam were not affected at the doses up to 50 mg/kg. In the 2 surviving rats at 100 mg /kg, the number of corpora lutea and implantations was unaffected, but the foetal loss was increased. The sex distribution was not affected in any of the groups.

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
The foetuses in the 100 mg/kg dose group were lighter, but not malformed.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

The following numbers of rats died and/or proved to be pregnant:

Group

Dose (mg/kg)

Died

Pregnant/total

1

0

0

5/5

2

1

0

5/5

3

10

0

5/5

4

50

0

5/5

5

100

3

5/5

6

150

5

3/5

Applicant's summary and conclusion

Conclusions:
Since the animals at 50 mg/kg showed no signs of intoxication and only very slightly reduced body weight gain during pregnancy, the high dose for the main study should be higher than 50 mg/kg. Since the animals at 100 mg/ kg showed signs of intoxication and 3/5 animals died, the high dose for the main study should be lower than 100 mg/kg.
Executive summary:

A preliminary study has been conducted for evaluating the potential reprotoxic effects of ammonium thioglycolate in rats and for evaluating the correct dose to administrate to rats in the core study (Reproductive Toxicity study with oral adminstration of ammonium thioglycolate to rats, according to OCDE guideline n°414).

Ammonium thioglycolate was administered by gavage to groups of 5 pregnant Wistar rats from gestation days (GD) 6 to 19 at daily doses of 1, 10, 50, 100, and 150 mg/kg. The control rats group were treated with the vehicle, demineralized water. The rats were killed on GD 20. The foetuses were removed, weighed, and examined for macroscopic malformations.

The numbers of corpora lutea, implantations and live foetuses per dam were not affected at the doses up to 50 mg/kg. At 50 mg/kg, the animals showed no signs of intoxication and only very slightly reduced body weight gain during pregnancy.

At 100 mg/kg, the animals showed signs of intoxication and 3/5 animals died. In the 2 surviving rats at 100 mg /kg, the number of corpora lutea and implantations was unaffected, but the foetal loss was increased. The foetuses in the 100 mg/kg dose group were lighter, but not malformed. Then the high dose for the main study should be lower than 100 mg/kg. At 150 mg/kg, all animals died.

In conclusion, the high dose for the main study should be higher than 50 mg/kg and lower thant 100 mg/kg.