Division 5.6 Reproductive toxicity

Possible effects on reproductive physiology and the development of progeny shall be investigated and reported concerning the following aspects:

• Impairment of male and female reproductive functions or capacity, for example from effects on oestrus cycle, sexual behaviour, any aspect of spermatogenesis or oogenesis, or hormonal activity or physiological response which would interfere with the capacity to fertilise, fertilisation itself or development of the fertilised ovum up to and including implantation.

• Harmful effects on the progeny, for example any effect interfering with normal development, both before and after birth. This includes morphological malformations such as anogenital distance, nipple retention, and functional disturbances (such as reproductive and neurological effects).

Effects accentuated over generations shall be reported.

The active substance and its relevant metabolites shall be measured in milk as a second tier investigation where relevant effects are observed in the offspring or are expected (for example from a range-finding study).

Potential neurotoxic, immunotoxic effects and effects potentially related to changes in the hormonal system shall be carefully addressed and reported.

Investigations shall take account of all available and relevant data, including the results of general toxicity studies if relevant parameters (such as semen analysis, oestrous cyclicity, reproductive organ histopathology) are included, as well as knowledge concerning structural analogues to the active substance.

While the standard reference point for treatment responses shall be concurrent control data, historical control data may be helpful in the interpretation of particular reproductive studies. Where submitted, historical control data shall be from the same species and strain, maintained under similar conditions in the same laboratory and shall be from contemporaneous studies.

The information on historical control data provided shall include:

1. (a)

   identification of species and strain, name of the supplier, and specific colony identification, if the supplier has more than one geographical location;

2. (b)

   name of the laboratory and the dates when the study was performed;

3. (c)

   description of the general conditions under which animals were maintained, including the type or brand of diet and, where possible, the amount consumed;

4. (d)

   approximate age, in days, and weight of the control animals at the beginning of the study and at the time of killing or death;

5. (e)

   description of the control group mortality pattern observed during or at the end of the study, and other pertinent observations (such as diseases, infections);

6. (f)

   name of the laboratory and the examining scientists responsible for gathering and interpreting the pathological data from the study.

The historical control data shall be presented on a study by study basis giving absolute values plus percentage and relative or transformed values where these are helpful in the evaluation. If combined or summary data are submitted, these shall contain information on the range of values, the mean, median and, if applicable, standard deviation.

In order to provide useful information in the design and interpretation of developmental toxicity studies, information on blood concentration of the active substance in parents and foetus/offspring may be included in higher tier studies and reported.