Amantadine hydrochloride

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

In a reproduction study weanling rats (Wistar-derived Food and Drug Research Laboratories' rats, males and females), (3 litters, 20 animals/sex/dose) were treated continuously for 9 weeks preceding the first mating with a diet providing 10 mg/kg bw of the test item (purity unknown). 3 weeks before the third mating (week 30 of test) the dosage of the drug-treated group was raised to 32 mg/kg bw daily. Fertility, gestation, viability, and lactation indices were determined.

Fertility index was reduced in the third litter when the test substance was administered in a dosage of 32 mg/kg bw daily (estimated human equivalent dosage of 45 mg/kg bw daily) to both males and females. Fertility was not affected when the test item was given in a dosage of 10 mg/kg daily (estimated human equivalent dosage of 1.4 mg/kg daily).

Conclusion: Under the conditions of the study there is a possible risk of impaired fertility in rats.

In a second reproduction study Virgin Holtzman rats were dosed orally with the test substance (50, 100 mg/kg bw) from 5 days prior to mating until day 6 of pregnancy (Lamar et al., 1970).

Autopsies were performed on day 14 of gestation. Fertilization, cleavage, implantation, resorption and development of mammalian ova in vivo were investigated.

Significant decreases in the number of implantations and increases in the number of resorptions at 100 mg/kg bw were observed.

Conclusion: Under the conditions of the study there is a possible risk of impaired fertility in rats.

In a further reproduction study New Zealand white rabbits were dosed orally with the test substance (50, 100 mg/kg bw) from 5 days prior to mating until day 6 of pregnancy (Lamar et al., 1970).

Autopsies were performed on day 14 of gestation. Fertilization, cleavage, implantation, resorption and development of mammalian ova in vivo were investigated.

No significant decreases in the number of implantations and no increases in the number of resorptions were observed in all dose groups.

Conclusion: Under the conditions of the study no impaired fertility was observed in rabbits.

Short description of key information:
Fertility, oral, rats, non-GLP, non-Guideline: possible risk of impaired fertility (Vernier et al., 1969).
Fertility, oral, rats, non-GLP, non-Guideline: the test substance seems to impair fertility (Lamar et al., 1970).
Fertility, oral, rabbits, non-GLP, non-Guideline: the test substance seems not to impair fertility (Lamar et al., 1970).

Effects on developmental toxicity

Description of key information

Teratogenesis assay, oral, rats, non-GLP, non-Guideline: the test substance seems to be teratogenic (Lamar et al., 1970).
Teratogenesis assay, oral, rats, non-GLP, non-Guideline: the test substance seems not to be teratogenic (Lamar et al., 1970).

Additional information

In a teratogenicity study in Virgin Holtzman rats the test item was administered orally (37, 50, and 100 mg/kg bw) on days 7-14 of gestation (Lamer et al., 1970). Autopsy was done just before expected parturition. Resorption and number of pups per litter were determined. Gross examination of rat pups were performed and malformations were recorded.

At the dose levels of 50 and 100 mg/kg bw increases in resorption and decreases in the number of pups per litter were noted. Gross examination of rat pups revealed no malformations at 37 mg/kg bw, whereas at 50 and 100 mg/kg bw malformations such as edema, malrotated hindlimbs, missing tail, stunting, and brachygnatha were observed. Examination of skeletal preparations of fetuses revealed cases of absent ribs and absence of the lumbar and sacral portions of the spinal colunn in the 50 and 100 mg/kg bw groups.

Conclusion: In rats the test substance seems to be teratogenic, and teratogenicity occured at 50 mg/kg bw/day (about 12 times the usual human dose).

In a teratogenicity study in New Zealand White rabbits the test item was administered orally at a dose level of 100 mg/kg bw on days 7-14 of gestation (Lamar et al., 1970). Autopsy was done just before expected parturition. Resorption and number of pups per litter were determined. Gross examination of rat pups were performed and malformations were recorded.

At the dose level of 100 mg/kg bw no gross malformations were observed in rabbit pups per litter were noted.

Conclusion: In rabbits the test substance seems not to be teratogenic.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available experimental test data for toxicity to reproduction and developmental toxicity are reliable and suitable for the purpose of classification under Directive 67/548/EEC. As a result the substance is considered to be classified for toxicity to reproduction and developmental toxicity (R62 - Possible risk of impaired fertility and R63 - Possible risk of harm to the unborn child) under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

 

Classification, Labeling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data for toxicity to reproduction and developmental toxicity are reliable and suitable for the purpose of classification under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No.1272/2008. As a result the substance is classified for toxicity to reproduction and developmental toxicity (Cat 2, H316: Suspected of damaging fertility or the unborn child), under Regulation (EC) No.1272/2008, as amended for the 2nd time in Commission Regulation (EU) No. 286/2011.