Registration Dossier

Administrative data

Description of key information

similar to OECD 424, oral, rat, 90 -days: NOAEL = 996 mg/kg bw/day (highest dose tested)

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
996 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 1) and consistent study, and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, of Regulation (EC) No 1907/2006.

Effect on neurotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on neurotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The study was designed to investigate the possible neurotoxicity of the test material and was conducted similar to OECD TG 424. The test material was administered by dietary admixture to three groups, each with ten male and ten female Sprague-Dawley Crl:CD® (SD) IGS BR strain rats, for up to 90 consecutive days (13 weeks), at dietary concentrations of 150, 1500 and 12000 ppm (equivalent to a mean achieved dosage for males and females of 12, 117 and 996 mg/kg/day, respectively). A further group of ten males and ten females was exposed to basal laboratory diet to serve as a control.

There were three unscheduled deaths during the study but these were not attributed to neurotoxicity. The three interim deaths of male rats at 12000 ppm were attributed to physical injury (an open wound to the tail, broken teeth and tongue injury). Normally, such injuries would not have resulted in death, however, the blood was reported as thin and pale for one of these animals, suggesting an adverse effect on clotting potential. However, this was a systemic effect of treatment and was not indicative of neurotoxicity. Clinically observable signs were confined to opacity of the eyes and varying degrees of fur loss. A treatment-related reduction in bodyweight for animals of either sex treated with 12000 ppm was considered to be attributable to the effects of administration, due to a reduction in food efficiency in the same group. Temporary reduction in bodyweight gain at the early stages for groups treated with 1500 ppm was probably attributable to the unpalatable nature of the dietary admixture and was not a direct effect of toxicity. Ophthalmoscopic examination revealed opacity and neovascularisation of the cornea, throughout the treatment groups, with effects more severe at 150 and 1500 ppm. This was considered to be attributable to the effects of administration of the dietary admixture. Diet residue may have been accidentally deposited in and around the eyes, causing irritation. Neovascularisation is a mechanism which promotes corneal healing and is a common pathological response following corneal insult. A reduction in absolute brain weight was detected at all treatment levels. This was most probably due to the lower bodyweight gains seen during the first week of the study and not a neurotoxic effect of treatment. In addition, necropsy findings from 12000 ppm animals showed thickening of the glandular gastric epithelium. Histopathological examination showed no evidence of neurotoxicologically significant ocular or gastric change and neural tissue of 12000 ppm animals was similar to that of controls. No toxicologically significant microscopic changes were detected.

Conclusion: Since no neurotoxic effects were observed up to the highest dose level, a 'No Observed Adverse Effect Level' (NOAEL) of 12000 ppm (equivalent to a mean achieved dosage of 996 mg/kg bw/day) for neurotoxicity was derived.

Justification for classification or non-classification

The available data on neurotoxicity with 2-{2-chloro-4-mesyl-3-[(tetrahydrofuran-2-ylmethoxy)methyl]benzoyl}cyclohexane-1,3-dione (CAS 473278-76-1) does not meet the criteria for classification according to Regulation (EC) No 1272/2008, and is therefore conclusive but not sufficient for classification.