Calcium sulphidoacetate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP Guideline

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report Date:

1998

Materials and methods

Test guideline

Qualifier:

according to

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Test material

Reference

Name:

Unnamed

Type:

Constituent

Details on test material:

Test substance: Ammonium thioglycolate (71%)
Source: Merck KGaA
Batch: U1499277
Content of active ingredient: 71.5%

Test animals

Species:

rat

Strain:

Wistar

Details on test animals and environmental conditions:

Strain of rats: Hsd/Cpb: WU
Source: Fa. Harlan Winkelmann GmbH, 33178 Borchert
Age: 9-10 weeks old
Acclimatization period: 6 days
Weight range at study initiation: 177-213 g Diet: Altromin Standard Diet TPF N 1234, ad libitum
Water: Tap water, ad libitum

Husbandry:
Housing: Makrolon type III cages
Illumination: artificial lighting from 6.00 a.m. - 6.00 p.m.
Temperature: 21-23.5°C
Relative humidity: 51-66%Vehicle: demineralized water

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: demineralized water

Details on exposure:

- Rate of solution preparation: daily
- Amount of vehicle: 10 ml/kg (base on weight on GD6)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration and homogeneity of ammonium thioglycolate in preparations administred were determined once during the study, on the second day of treatment. The results showed values ranging from 96.5 % to 100 % of the nominal concentrations

Details on mating procedure:

- Groups of four sexually matures, virgin females were left over night with one stock stud.
- Proof of pregnancy: sperm in vaginal smear (GD 0)

Duration of treatment / exposure:

gestation days 6 - 19

Frequency of treatment:

daily

Duration of test:

Duration of test: 15 days - dosing GD 6 -19, animals were killed on day 20

Doses / concentrations

Remarks:

Doses / Concentrations:
3, 15, and 75 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Clinical signs including mortality and evidence of abortion were checked daily.
Body weight was determined on GD0, 6 and daily until GD20.
Food and water consumption were recorded at designated intervals during pregnancy.
On day 20 of pregnancy, females were killed. The terminal body weights of the dams were recorded. Females were examined macroscopically.

Litter parameters were recorded: number of corpora lutea, implantation sites, early and late resorptions, and dead and live foetuses.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes / No / No data
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:

Foetuses were weighed, sexed, and submittedto external examination. About 1/2 of them were examined for skeletal malformations and 1/2 for organ malformations.The foetus sex was determined on the base of measurment of anogenital indice and by inspection of gonads.

Statistics:

yes: Dunnett test or Fischer-Pitman permutation test

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 rats in the high dose group. Two animals in the high dose group died on GD 20, one day after the last administration of the test material. These deaths are regarded to be treatment related.
18 to 24 rats out of 25 per group proved to be pregnant.
The body weight development, food and water consumption were not affected by treatment. The terminal body weights were similar in all groups.
The uterus weights in the high dose group were slightly, but not significantly lower than in the control or the other groups. This finding is regarded to be accidental. The numbers of corpora lutea, implantations and live foetuses were not affected.
The numbers of dead foetuses, complete, early and late resorptions were not increased. The sex distribution was not affected in any of the groups.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

15 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

75 mg/kg bw/day

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The weights of the foetuses in the low, mid, and high dose groups were similar to the control and not affected by treatment. The frequency of all malformations was in a normal range and not increased.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The doses of 3 and 15 mg ammonium thioglycolate/kg were systemically tolerated by the rats.
At dose level of 75 mg/kg, two dams died on GD 20. Rooting in the bedding material had been seen, but no maternotoxic
effects.
The no observed effect level (NOEL) for embryo-fetal toxicity was 75 mg/kg.
No teratogenic effects were observed.

Executive summary:

The potential of ammonium mercaptoacetate to induce developmental toxicity after maternal exposure during the critical period of organogenesis was evaluated in rat according to OECD Guideline N° 414 (22nd January 2001) and in compliance with Good Laboratory Practices.

Ammonium mercaptoacetate was administered orally by gavage to four groups of 25 bred female Sprague-Dawley rats once daily from gestation days 6 through 19. Dosage levels were 0, 3, 15, and 75 mg/kg/d.

The fetuses were delivered by caesarean section on GD 20 and examined for macroscopic malformations. About 1/2 of them were examined for skeletal malformations and 1/2 for organ malformations. Clinical signs including mortality and evidence of abortion were checked daily. Body weight was determined on GD0, 6 and the daily until GD20. Food and water consumption was recorded at designated intervals during pregnancy. On day 20 of pregnancy, females were killed. The terminal body weights of the dams were recorded. The gravid uterus was weighed and foetuses removed by hysterectormy. Females were examined macroscopically.

The doses of 3 and 15 mg ammonium thioglycolate/kg were systemically tolerated by the rats. All animals in the low and medium level dose group survived to the scheduled necropsy. At the dose level of 75 mg/kg, two dams died on GD20, one day after the last administration of test material. These death were considered treatment related. At this dose level, rooting in the bedding material had been seen in all rats, but no maternotoxic effects. No treatment related internal findings were observed at any dose level. No clinical signs that could be attributed to ammonium mercaptoacetate were observed in the treated groups. Body weight and food consumption were not affected by treatment. Intrauterine growth and survival were unaffected by ammonium mercaptoacetate administration at all dose levels. Any significant or relevant foetal external, soft tissue and skeletal malformations were observed at any dose level. The developmental variations expressed in the treated groups were generally similar to those present in the control group or occurred in a manner that was not dose related. No teratogenic effects were observed

Under these experimental conditions, the No-Observed-Adverse-Effect-Level (NOAEL) was 15 mg/kg/d for maternal toxicity. A NOAEL has been determined at 75 mg/kg/d for embryo-foetal toxicity.