Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
An in vitro metabolism study in hepatocytes, comparing rat to human, rabbit and mouse, showed clear differences in metabolism between the rat and other species. it was proposed that the adverse effects observed in rat studies were misleading due to the observed differences in metabolism of the test substance. and thus the test substance should not be classified.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
the study has been performed to to recognised standards (GLP, OECD 415) however the results were determined to be due to a matabolite of this parent molecule, and not of the molecule itself by further studiesdescribed below.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

With regard to previous data acquired in the rat, the sponsor had classified the test substance as CMR2 (GHS) as a self-classification and also structurally related materials due to male reproductive organ effects seen following oral gavage studies in rats.

The effects previously seen with Cyclamen aldehyde in rats were thought not to be relevant to human metabolism and exposure.

An in vitro metabolism study in hepatocytes, comparing rat to human, rabbit and mouse, showed clear differences in metabolism between the rat and other species. The study was conducted at 3 doses (1, 10 and 100μm) and 3 timepoints (0, 1 and 4 hours treatment). The toxic metabolite thought to be responsible for the reproductive organ effects seen in rats (4-isopropyl benzoic acid) is found as a metabolite in rat hepatocytes but is not found in human, rabbit or mouse.

The overall data indicate that the rabbit (or mouse) would provide a better model for human toxicity of Cyclamen aldehyde. Confirmation of the presence of the toxic metabolite (4-isopropyl benzoic acid) in rats in vivo had also been previously detected in rat urine during a gavage study.

Conclusions on toxicity and classification

Overall the data can be summarised as follows:

• The toxic metabolite of Cyclamen aldehyde (4-isopropyl benzoic acid) has been confirmed.

• This metabolite is found in rats in vitro and in vivo but is not found in rabbits, mice and humans in a metabolism study.

• Cyclamen aldehyde does not cause reproductive organ effects in a more relevant species (rabbit).

• Therefore, the effects seen in rats are unlikely to be relevant to the human route and levels of exposure.

• The hazardous property will not be expressed in humans and classification is not warranted.


Short description of key information:
the results found in the study performed in the rat indicate the potential for teratogenicity. However, furhter work performed regarding the metabolites of the test substance in different species indicate that this risk could be

Justification for selection of Effect on fertility via oral route:
see below

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Toxicity to reproduction: other studies

Additional information

With regard to previous data acquired in the rat, the sponsor had classified the test substance as CMR2 (GHS) as a self-classification and also structurally related materials due to male reproductive organ effects seen following oral gavage studies in rats.

The effects previously seen with Cyclamen aldehyde in rats were thought not to be relevant to human metabolism and exposure.

An in vitro metabolism study in hepatocytes, comparing rat to human, rabbit and mouse, showed clear differences in metabolism between the rat and other species. The study was conducted at 3 doses (1, 10 and 100μm) and 3 timepoints (0, 1 and 4 hours treatment). The toxic metabolite thought to be responsible for the reproductive organ effects seen in rats (4-isopropyl benzoic acid) is found as a metabolite in rat hepatocytes but is not found in human, rabbit or mouse.

The overall data indicate that the rabbit (or mouse) would provide a better model for human toxicity of Cyclamen aldehyde. Confirmation of the presence of the toxic metabolite (4-isopropyl benzoic acid) in rats in vivo had also been previously detected in rat urine during a gavage study.

Conclusions on toxicity and classification

Overall the data can be summarised as follows:

• The toxic metabolite of Cyclamen aldehyde (4-isopropyl benzoic acid) has been confirmed.

• This metabolite is found in rats in vitro and in vivo but is not found in rabbits, mice and humans in a metabolism study.

• Cyclamen aldehyde does not cause reproductive organ effects in a more relevant species (rabbit).

• Therefore, the effects seen in rats are unlikely to be relevant to the human route and levels of exposure.

• The hazardous property will not be expressed in humans and classification is not warranted.

Justification for classification or non-classification

Overall the data can be summarised as follows:

• The toxic metabolite of Cyclamen aldehyde (4-isopropyl benzoic acid) has been confirmed.

• This metabolite is found in rats in vitro and in vivo but is not found in rabbits, mice and humans in a metabolism study.

• Cyclamen aldehyde does not cause reproductive organ effects in a more relevant species (rabbit).

• Therefore, the effects seen in rats are unlikely to be relevant to the human route and levels of exposure.

• The hazardous property will not be expressed in humans and classification is not warranted.