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EC number: 202-676-4 | CAS number: 98-52-2
28 days, subacute, oral, rat (OECD 407): NOAEL = 150 mg/kg bw/day
In a GLP study performed according to OECD Guideline 407 (adopted in 1995) the subacute toxicity of 4-tert-butylcyclohexanol was assessed in an oral 28-day study in rats followed by a 14-day recovery period (98-184-DGT). 5 rats per sex per dose were daily treated per gavage with 50, 150 and 300 mg/kg bw/day of 4-tert-butylcyclohexanol in corn oil. A control group received the vehicle only. An additional satellite group of 10 animals (5 per sex) in the control and high dose group for observation of reversibility, persistence or delayed occurrence of toxic effects were included for 14-day post-treatment. The test concentrations applied in this 28-day study were based on the results of a previously conducted range-finding study.
Apart from 2 animals of the high dose group (males) that died because of gavage application failure (verified by necropsy), no animal died during the study. Moderate to severe clinical signs were observed in the mid and high dose groups and included convulsions, prone and squatting position, straub tails, vocalisation and walking on tiptoes (individual animals). The peak period of clinical effects was approx. 15 min after dosing. Individual animals predominantly of the high dose group still showed mild clinical symptoms in the afternoon. No clinical signs were noticed in the control and low dose group or during the recovery period.
During home cage and (extended) open field observation ataxia, fasciculation, paddling movement, defence against touching, aggressiveness, hunchback/squatting position, reduced respiration, hyperactivity, straub tail, piloerection and slight convulsions were noticed only in individual animals, predominantly in the high dose group. Furthermore, individual animals of the high dose groups showed minimal or high sensitivity of pain. The additional functional observations which were protocolled as rearing, landing foot splay and grip strength showed no changes of toxicological importance. An increase in motoractivity was observed in the high dose groups, especially in high dose females when compared to control. However the increase was statistically not significant in the high dose male and female groups as well as in the high dose male recovery group. Animals of the control, low and medium dose groups showed a normal response to different stimuli. No significant findings were observed during the recovery period.
The statistically significant reduction in body weight and body weight change in the high dose male (recovery) group compared to control animals at the end of the treatment period might be substance-related. Evidence of reversibility was found at the end of the recovery period. In contrast, the high dose females (recovery) showed a statistically significant increase of group mean weekly body weight change at the beginning of the study. The male and female low, medium and high dose groups as well as the high dose female recovery group showed no differences of toxicological importance concerning body weight and body weight changes compared to control at the end of the treatment period.
Examinations of food and water consumption, clinical chemistry, haematology and urine analysis did not reveal differences of toxicological importance in the treated animals compared to control animals or historical background data.
A statistically significant increase in relative adrenal weight (% to body weight) was observed in high dose males which is explained by an increased activity of the adrenals due to the stress in connection with the application of the test substance. At the end of the recovery period the relative epididymides weight of the male high dose group was increased statistically significant compared to controls. The absolute weight of adrenals in high dose males and the absolute weight of epididymides in the high dose males recovery group showed no statistically significant increase and there were no corresponding histopathological findings. The microscopic examination of the kidneys revealed an alpha-2 micro globulin nephropathy syndrome in male rats. However, this is of no concern to man as it is specific to the male rat.
Therefore, the NOAEL is considered to be 150 mg/kg bw/day based on the partly severe clinical signs and the effects on motoractivity and body weight, which have been observed in the high dose groups (300 mg/kg bw/day; LOAEL). No target organ could be identified.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: There is only one study available.
The available data on repeated dose toxicity of 4-tert-butylcyclohexanol do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.
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