Commission Regulation (EC) No 429/2008Show full title

3.2.2.5. Reproduction toxicity studies (including prenatal developmental toxicity)

To identify possible impairment of male or female reproductive function or harmful effects on progeny resulting from the administration of the active substance, studies of reproductive function must be carried out by:

(1)

two generation reproduction toxicity study; and

(2)

prenatal developmental toxicity study (teratogenicity study).

For new trials validated alternative methods reducing the use of animals can be used.

3.2.2.5.1. Two generation reproduction toxicity study

Studies of reproductive function must be carried out and extend over at least two filial generations (F1, F2) in at least one species, usually a rodent, and may be combined with a teratogenicity study. The substance under investigation shall be administered orally to males and females at an appropriate time prior to mating. Administration shall continue until the weaning of the F2 generation.

All relevant fertility, gestation, parturition, maternal behaviour, suckling, growth and development of the F1 offspring from fertilisation to maturity and the development of the F2 offspring to weaning must be carefully observed and reported. Protocols for the reproduction toxicity study should be in line with OECD Guideline 416.

3.2.2.5.2. Prenatal developmental toxicity study (teratogenicity study)

The objective is to detect any adverse effects on the pregnant female and the development of the embryo and foetus as a result of exposure from implantation through the entire gestation period. Such effects include enhanced toxicity in the pregnant females, embryo-foetal death, altered foetal growth and structural abnormalities and anomalies in the foetus.

The rat is usually the species of choice for the first study. If a negative or an equivocal result for teratogenicity is observed, another developmental toxicity study shall be conducted in a second species, preferably the rabbit. If the rat study is positive for teratogenicity, a study in a second species is not necessary except where a review of all the core studies indicates that the ADI would be based on the rat teratogenicity. In this case a study in a second species would be required to determine the most sensitive species for this endpoint. Protocols should be in line with OECD Guideline 414.