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Description of key information

Subchronic Oral (diet): NOEL: 1000 ppm, (77.0 mg/kg bw/day / 81.6 mg/kg bw/day), male/female rat, EPA OPP 82-7, Classen 1996

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
77 mg/kg bw/day
Study duration:
Quality of whole database:
Both available studies were conducted under GLP and in accordance with standardised guidelines. Both studies were assigned a reliability score of 1 according to the criteria of Klimisch (1997) and were considered to be suitable as an accurate reflection of the test material. The quality of the database is high.

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 subchronic neurotoxic potential of the test material was determined in a study conducted according to GLP and in line with the standardised guideline EPA OPP 82 -7 (Neurotoxicity Screening Battery). During the study groups of 10 male and 10 female rats were administered test material in the diet, for 90 consecutive days, at concentrations of 0, 100, 300 and 1000 ppm. Mortality, clinical signs, body weight and food consumption were monitored throughout the study. A Functional Observational Battery (FOB) was performed and motor activity was measured pre-test and at test weeks 4, 8 and 13. At necropsy, animals were sacrificed. The brain, spinal cord, peripheral nerves and eyes, as well as the liver (all animals) were collected, prepared for histopathological evaluation and examined microscopically. Neuropathological examination was limited to 5 animals per sex and group. The concentrations of test material in the diet resulted in mean daily test material intakes of 7.8, 23.4 and 77.0 mg/kg in males and 8.7, 26.0 and 81.6 mg/kg in females.

Under the conditions of the study all animals survived and no clinical signs were recorded. Food consumption and body weight development were not affected by treatment. In the absence of altered liver weights, microscopic examination of the liver showed inflammatory cell infiltration, cholangiofibrosis of intrahepatic bile ducts, pigments with Kupffer cells, necrosis of single hepatocytes, cytoplasmic vacuolation, hypertrophy of centrilobular hepatocytes and increased mitotic activity of hepatocytes of males dosed at 1000 ppm with single, minimal findings seen also in one animal each of 300 ppm males and 1000 ppm females. Observation and functional tests conducted during the FOB did not show any effect of toxicological significance and no treatment-related effects on the different motor activity parameters were seen. Macroscopical and microscopical examination of the eyes, optic nerves, and multiple areas of the central and peripheral nervous system of the males and female, control and high dose animals subject to neuropathological examination, did not reveal any treatment-related neuropathic changes. Based on this data, it was concluded that the test material, when administered to rats in the diet at a concentration of 1000 ppm for 90 consecutive days, induced liver toxicity with beginning effects seen in one male at 300 ppm. There were no effects indicative of a potential neurotoxicity. A dietary concentration of 1000 ppm, resulting in a daily intake of 77.0 and 81.6 mg/kg in males and females, respectively, was thus considered to represent the NOEL for neurotoxicity. The NOEL for systemic toxicity was determined to be 100 ppm (equivalent to 7.82 and 8.69 mg/kg for males and females, respectively).

The acute and delayed neurotoxic potential of the test material, when administered to rats as a single oral dose, was determined in a study conducted according to GLP and in line with the standardsed guideline EPA OPP 81-8 (Neurotoxicity Screening Battery). During the study the test material was administered in a single oral dose, by gavage, to ten male and ten female rats. Animals were exposed in a limit test at a nominal concentration of 2000 mg/kg, a vehicle control was run concurrently for comparison. The nominal concentration was analytically confirmed by HPLC to be within 1% of the nominal.


Under the conditions of the test, the test material did not induce any changes in clinical signs, observations and functional tests conducted as part of the Functional Observational Battery and did not affect motor activity neither at the time of peak plasma concentrations nor at later time points throughout the 8 days post-dose. Neuropathological examination did not reveal any morphological changes in the central or peripheral nervous system. The test material was therefore considered not to induce acute or delayed neurotoxicity in rats when given as a single oral dose of 2000 mg/kg.

Justification for selection of effect on neurotoxicity via oral route endpoint:
Classen (1996) was selected as the key study on the basis that this was a reliable 90-day guideline study. The acute Classen (1998) study was entered as supporting information.

Justification for classification or non-classification

In the absense of any neurotoxicological effects in either the repeated dose or acute studies, no classification for this endpoint is required under Directive 67/548/EEC or Regulation (EC) No. 1272/2008.

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