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4 -week oral toxicity

The subacute effects of 1,4 -cyclohexanedicarboxylic acid (CHDA) were evaluated in rats that were given diet containing the material for four weeks. Diets were prepared to contain 1.0% corn oil and either 0.0, 0.1, 0.3, or 1.0% of CHDA, and the test diets were fed seven days per week to male and female rats (n=5/sex/group) that were group-housed. At the end of a 4-week feeding period, rats were anesthetized with CO2inhalation and exsanguinated. Blood was collected for hematology and clinical chemistry assessments and organs were collected, weighed, and processed for histopathological evaluations. Mean values were calculated for body weight, feed consumption, organ weights, hematology, and clinical chemistries. All mean data were evaluated using Bartlett's test (p<0.01), a one-way ANOVA (p<0.05), or duncan's multiple range test (p<0.05), to indicate statistical significance. Data indicate that treatment with CHDA did not produce mortality or adverse clinical signs at any dose level, and no changes in body weight gain, feed consumption, hematology, serum clinical chemistries, or organ weights were observed. The no-observed-effect-level (NOEL) for male and female rats was determined to be 871 and 894 mg/kg/day, respectively.

13 -week oral toxicity

Test article administration by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 100, 300 and 1000 mg/kg body weight/day for a period of at least 90 days. A control group was treated similarly with the vehicle, PEG 300, only. The groups comprised 1 0 animals per sex, which were sacrificed after at least 90 days of treatment. Additional 5 rats per sex and group were used at 0 and 1000 mg/kg. These animals were treated for 90 days and then allowed a 28-day treatment-free recovery period after which they were sacrificed. Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during the acclimatization, treatment and recovery periods. Ophthalmoscopic examinations were performed at acclimatization, the end of the treatment and recovery periods. Functional observational battery, locomotor activity and grip strength were performed during week 13 and during week 17 (treatment and recovery, respectively). At the end of the dosing and the treatment-free recovery period, blood samples were withdrawn for hematology and plasma chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals, as well as selected organs from low- and mid-dose animals.

There were no test item-related deaths that occurred during the course of this study. There were no test article-related changes in behavioral indicies (functional observational battery; locomotor activity), and food consumption and ophthalmoscopic examinations were similarly unaffected. The mean body weights and mean body weight gain of the rats treated with 100 mg/kg/day or 300 mg/kg/day were considered to be unaffected by treatment. Reduced mean body weights noted in rats treated with 1000 mg/kg/day were considered to be a slight test item-related effect. These changes were more distinct in the females. The lower mean body weights and mean body weight gain were noted during treatment in males treated with 1000 mg/kg/day improved slightly during the recovery period, whereas lower mean body weights and lower mean body weight gain persisted during the recovery period in females. There were no test item-related differences in the hematological or biochemical parameters were noted during treatment and recovery in males or females at any dose level. Following necropsy, there were test article-related changes observed in male rats treated with 1000 mg/kg/day which included reduced mean spleen-to-brain weight ratios accompanied by reduced mean absolute thymus weights, reduced thymus-to-body weight ratio and reduced thymus-to-brain weight ratio. The differences noted in the latter organ correlated with lymphoid depletion seen microscopically. Test article-related changes in female rats treated with 1000 mg/kg/day included slightly reduced mean absolute ovary weights as well as reduced ovary-to-body weight ratios and ovary-to-brain weight ratios, together with reduced mean absolute uterus weights, reduced uterus-to-body weight and reduced uterus-to-brain weights. An elevated liver-to-body weight ratio that also was noted in these females was considered to be a test item-related adaptive change. After 13 weeks of treatment at 300 mg/kg/day, no test item-related changes in mean absolute or relative organ weights were ascertained in males. Females had reduced mean absolute uterus weights, reduced uterus-to-body weight ratios and reduced uterus-to-brain weight ratios which were considered to be test item-related. The elevated liver-to-body weight ratio noted in these females was considered to be test item-related adaptive change. At 100 mg/kg/day, no test item-related changes of toxicological relevance were ascertained. All other differences in the mean absolute and relative organ weights were considered to be incidental. In rats treated previously with 1000 mg/kg/day and allowed to recover for 4 weeks, test item-related differences noted in the spleen and thymus of males were reversible after the recovery period. In females, the test item-related reduction of mean uterus weights persisted after the recovery period in females. Test item-related adaptive differences in the liver of females were reversible after the recovery period. Microscopic findings observed at necropsy after the 13-week treatment period was limited to minimal or slight centrilobular hypertrophy of the hepatocytes in all female rats treated with 1000 mg/kg/day, and lymphoid depletion in the thymus of male rats treated with 300 or 1000 mg/kg/day with dose-related incidence and severity. After 4 weeks of recovery, the liver and the thymus morphology returned to normal.

Justification for classification or non-classification

In a 4-week repeat dose oral toxicity study, 1,4-cyclohexanedicarboxylic acid (CHDA) produced a no observed effect level (NOEL) for male and female rats was determined to be 871 and 894 mg/kg, respectively. According to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, compounds with a 28-day NOEL above 300 mg/kg are not classified as a specific target organ toxicant upon repeat exposure.

Similarly, in a 13-week repeat dose oral toxicity study, CHDA produced a NOAEL of 300 mg/kg, and the regulations stipulate that compounds with a 90-day NOAEL above 100 mg/kg are not classified as a specific target organ toxicant upon repeat exposure.