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EC number: 603-837-5
CAS number: 134605-64-4
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
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.
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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