Registration Dossier

Administrative data

Description of key information

Four repeat dose studies have been reported.  One was performed unequivocally with the racemic mixture and the 2nd (004) was assumed to use racemic material, the other two used the L(+)isomer specifically.  

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

A common feature of all the feeding studies has been neurotoxicity. This was manifest as clinical signs of varying severity but also of cellular necrosis in specific areas of the brain. This is therefore assumed to be non-reversible. A further common feature has been reduced testes weights and histologically reduced / absent sperm production in treated rats. Where rats age can be ascertained, these were exposed during the maturation phase and bodyweights were substantially affected. Thus, it is possible/ likely that this represents delayed maturation rather than a specific effect on the testis.

 

It is evident, from the studies with the L (+) isomer that the toxicity mainly resides with this isomer in that similar dose levels to those established for the racemic product produce the same range of effects. In the most reliable study, neurotoxicity defined the endpoint which was determined to be 750 ppm in the diet (approx. 80 mg/kg/day in these rats). As females are less affected this endpoint is suitable for both sexes. A consistent observation of neurotoxicity indicates a requirement for classification.

Justification for classification or non-classification

Due to the neurotoxic effects observed and the dose received, the substance should be classified as follows:

For specific target organ toxicity resulting from repeated exposure, category 2; STOT-RE Category 2; H373 May cause damage to organs through prolonged or repeated exposure (by ingestion) (CLP Regulation (EC) 1272/2008 )

Xn; R48/22 Danger of serious damage to health by prolonged exposure (DSD 67/548/EEC).

It should be noted that the testicular effects, although probably related to delayed maturation, may also be considered for the purposes of classification. However, as the neurotoxicity defines the no effect level, and the study is considered sufficiently reliable to be included in the evaluation, this requirement need not be applied. Precautions which will protect against neurotoxicity will also be sufficient to protect against testicular effect.