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EC number: 700-012-2 | CAS number: 950919-28-5
In a 14-day repeated dose toxicity range-finding study, groups of Wistar Han™:HsdRccHan™:WIST strain rats (3/sex/dose) were administered daily with test material at dose levels of 0 (vehicle control), 250, 500 and 1000 mg/kg bw/day in arachis oil BP by oral gavage. Animals were then observed for mortality, clinical condition, bodyweight, food consumption, water consumption and were all macroscopically necropsied after sacrifice.
- Mortality: Due to the severity of clinical signs observed, the 1000 mg/kg bw/day dose group was terminated following treatment on Day 3, together with one 500 mg/kg bw/day female. No further unscheduled deaths were observed.
- Clinical observations: Lethargy, moderate/severe ataxia, hunched posture, pilo-erection, and hypothermia were observed for animals of either sex treated with 1000 mg/kg bw/day and one female at this dose level was found comatosed. This dose level was considered excessive and all animals from this dose group were terminated following dosing on Day 3. Similar clinical signs were evident for one female treated with 500 mg/kg bw/day, which was also terminated on Day 3. Signs of lethargy and mild ataxia were observed for one male treated with 500 mg/kg bw/day and one male treated with 250 mg/kg bw/day. These signs were isolated and complete regression was evident thereafter.
- Bodyweight: Reduced bodyweight gains were observed in animals of either sex treated with 1000 mg/kg bw/day when compared to controls, prior to termination on Day 3. No adverse effect on bodyweight change was evident for animals of either sex treated with 500 or 250 mg/kg bw/day.
- Food consumption: Reduced dietary intake was evident for animals of either sex treated with 1000 mg/kg bw/day when compared to controls prior to termination on Day 3. No adverse effects on dietary intake were evident for animals of either sex treated with 500 and 250 mg/kg bw/day when compared to controls.
- Water consumption: Increased water consumption was evident for animals of either sex treated with 1000 mg/kg bw/day on Day 2 and Day 3 when compared to controls. No adverse effects on water intake were evident at 500 or 250 mg/kg bw/day.
- Necropsy: No macroscopic abnormalities were detected for both interim death and terminal kill animals.
Based on the results of this dose range-finding study, dose levels of 30, 300 and 600 mg/kg bw/day were selected for subsequent toxicity studies.
In a repeated dose toxicity study performed in accordance with OECD test guideline No. 407 and in compliance with GLP, test material solution in arachis oil was administered by gavage to three groups of Wistar Han™:HsdRccHan™:WIST strain rats (5/sex/dose) at dose levels of 30, 300 and 600 mg/kg bw/day for 28 consecutive days. Control rats were given the vehicle alone. The highest dose group was initially treated at a lower dose level (300 mg/kg bw/day) for the first two days of the treatment to allow animals in this dose group to acclimatise to the test material at a lower dosage before exposure to the full dosage of 600 mg/kg bw/day. This action was undertaken to reduce the risk of treatment-related deaths at the highest dose level following the effects observed in a previous study undertaken with this test material. Clinical signs, functional observations, bodyweight development, dietary intake and water consumption were monitored during the study. Haematology and blood chemistry were evaluated for all animals at the end of the study. All animals were subjected to gross necropsy examination and histopathological evaluation of selected tissues was performed.
Although no deaths were evident in this study, clinical signs were evident for one female from the highest dose group on the first day of treatment. Regression was evident on Day 2 and the dose level was increased to 600 mg/kg bw/day on Day 3. Clinical signs appeared in one male and two females on Day 4 (the second day of treatment at 600 mg/kg bw/day) and incidental clinical signs were evident during the treatment period. Incidents of hunched posture, and abnormal gait were also evident for two females treated with the intermediate dose on the first day of treatment however complete regression was evident thereafter. The clinical signs observed during the daily clinical observations were confirmed during the weekly arena observations. Furthermore, motor activity assessments revealed lower overall motor activity for animals of either sex treated with 600 mg/kg bw/day, extending into the male 300 mg/kg/day dose group. No significant reductions were evident during the final 20% of the assessment period, known as the asymptotic period, which would suggest that the reduced activity observed was most probably attributed to a slight decline in the physical health of the animals, and did not represent a neurotoxic effect of treatment. Remaining clinical signs consisted of increased salivation following dose, which was observed in both the high and intermediate dose groups. This observation is commonly observed following administration of a slightly unpalatable or irritant test material formulation. There were no toxicologically significant differences in dietary or water intake for treated animals when compared to control values and histopathological examinations did not reveal any effects of the gastro-intestinal tract which may be suggestive of irritancy. In the absence of any changes to suggest neurotoxicity the increased salivation detected in this study was not considered to represent an adverse effect of treatment and is most likely to be attributed to the poor taste of the test substance. A slight reduction in overall bodyweight change was observed for animals of either sex treated with the highest dose level in comparison to controls, with the effect extending into the intermediate male dose group. No adverse effects on dietary intake or food conversion efficiency were detected, therefore, the slightly reduced bodyweight gain was not considered to represent an adverse effect. Blood chemical analysis did not reveal any significant differences in the highest dose level, however, significantly elevated alanine aminotransferase levels were observed for males treated with 300 mg/kg bw/day, together with an increase in alkaline phosphate. Furthermore, liver weights were elevated for animals of either sex treated with 600 mg/kg bw/day with the effect extending into the intermediate male dose group. Finally, histopathological examination revealed centrilobular hepatocyte enlargement in the highest dose group, with the effect extending into the male 300 mg/kg bw/day dose group. The increases in enzyme activity, elevated liver weights and microscopic hepatic changes are commonly observed following the administration of a xenobiotics, resulting in induction of metabolising enzymes. In the absence of any inflammatory or degeneration changes, these findings were not considered to represent an adverse effect of treatment.
Due to the nature of the clinical signs observed at the highest dose level, consisting of ataxia, prostration and lethargy, together with the remaining treatment-related effects, a ‘No Observed Adverse Effect Level’ (NOAEL) could not be established at the highest dose level. The treatment-related effects detected at 300 mg/kg bw/day were not considered to represent an adverse health effect, therefore a NOAEL was established at 300 mg/kg bw/day. No treatment-related effects were detected at 30 mg/kg/day, therefore a No Observed Effect Level (NOEL) was established at 30 mg/kg bw/day.
Based on the results of this study, test material is not classified for damage to organs through 28 days oral repeated exposure according to the criteria of the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
This study is considered as acceptable and satisfies the requirement for sub-acute oral toxicity endpoint.
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