Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The effects of Amber core (P#620) on reproductive function and pre-natal and post­natal developments were assessed according to OECD guideline 415. The test material was administered by gavage to three groups of 24 male and 24 female Wistar rats each, at dose levels of 20, 100 and 500 mg/kg bw/day. A control group of 24 males and 24 females was dosed with vehicle alone (0.5% sodium carboxymethyl cellulose/0.5% Tween 80).

Clinical signs, bodyweight, dietary intake and water consumption were monitored. After ten weeks of treatment for males and two weeks of treatment for females, pairing of animals within each dose group was undertaken on a one male: one female basis, to produce litters. During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size. Litter weights and individual offspring weights were also recorded on specific days post partum. All surviving females and offspring were terminated on Day 21 post partum with the males being terminated after the majority of the females and litters had been killed. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues from high dose and control animals was performed.

There was no unscheduled death, no relevant clinical sign, no effect on bodyweight and food consumption. Increased water intake was observed for both sexes at 500 mg/kg bw/day and males at 100 mg/kg bw/day (likely to reflect unpalatable, or slightly irritant, test material formulation). Mating performance, fertility and gestation length were considered to have been unaffected by treatment. No treatment-related macroscopic abnormalities were detected for adults or offspring.

Histopathological examinations of adult tissues revealed centrilobular hepatocyte enlargement for both sexes at 500 mg/kg bw/day and a greater incidence and severity of globular accumulations of eosinophilic material in the tubular epithelium of male rats at 500 mg/kg bw/day, with an associated greater incidence and severity of groups of basophilic tubules also being present. Additionally tubular necrosis and affected isolated tubules in the outer medulla immediately adjacent to the renal cortex was observed for 10 males at this dosage level.

It is assumed that the centrilobular hepatocyte enlargement observed, occurs as an induction of the microsomal drug metabolizing enzyme systems caused by the treatment of several compounds and is considered to be cellular adaptation phenomena. In the case of Amber core, the adaptative response is important as it was already demonstrated in the 28 -day repeated oral dose toxicity study described in this dossier (see § 7.5.1).

Moreover, the changes of both the renal tubular epithelium and basophilic tubules are lesions known to be spontaneous in male rats only and are not observed in other species. Therefore, this effect is specific to male rat, and is not relevant for the risk assessment in human.

There was no obvious adverse effect of treatment of the corpora lutea and implantation counts, litter size at birth and subsequent survival and bodyweight of the offspring to weaning or on sex ratio.

Therefore, it can be assumed that no test substance related effect was observed in the highest dose group of adult animals considering that the changes observed in the liver and in the kidney resulted from cellular adaptation phenomena and species specificity, respectively.

Hence, histopathological examinations of liver and kidneys at 20 or 100 mg/kg bw/day were not performed even if increased absolute and relative liver weights in males were recorded assuming that in the absence of any other effect, the liver weight changes was likely related to cellular adaptation phenomena. Therefore, it is assumed that the highest dose (500 mg/kg bw/d) is a NOAEL for systemic effect in the adult animals.

Moreover, there were no effects observed for reproductive parameters and a clear NOEL for reproductive toxicity including the survival, growth and development of the offspring was established at 500 mg/kg bw/day.


Short description of key information:
Toxicity to reproduction by oral route: no effects, NOEL= 500 mg/kg bw /day (Key study, OECD 415, Kr.2)

Effects on developmental toxicity

Description of key information
Developmental toxicity: no data

Justification for classification or non-classification

Harmonized classification:

The test item has no harmonized classification for human health according to the Regulation (EC) No. 1272/2008 including the ATP2 draft.

Self classification:

Based on the available data, no additional classification is proposed for the fertility, the development and the lactation.