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Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Mode of Action Analysis / Human Relevance Framework

Additional information

 The potential for 2,2,4,4-tetramethyl-1,3-cyclobutanediol to cause target organ toxicity following repeated exposure is well understood and is based on the results of two studies that followed OECD guidelines 407 and 408, and were conducted under GLP assurances GLP. The first one was a 28-day exposure study whose primary purpose was to determine dose levels to conduct the second key study which consisted of three treatment groups (20 rats/sex/dose) administered test article BID at dose levels of 25, 80, and 240/200 mg/kg (50, 160 and 480/400 mg/kg/day) for 90 days. Controls received distilled water vehicle. The 240 mg/kg/dose BID dose level was lowered to 200 mg/kg BID on Day 43 due to increased mortality. In this study, no test article-related adverse effects were seen on body weight, hematology, coagulation, clinical chemistries, urinalysis, or in macroscopic evaluations at necropsy. There were 11 male and 13 female early deaths in 240/200 mg/kg group and 1 female given 80 mg/kg BID. Cause of death was undetermined in all females and most males. One male from the 240/200 dose group appeared to have died from aspiration of foreign material and another from urogenital/inflammation/obstruction/calculi. Test article-related clinical observations were noted in the 80 and 240/200 mg/kg dose groups. At 80 mg/kg BID clonic convulsions were seen in 1 male in Week 11, 2 males in Week 13, and 1 female in Week 10. Females were hypersensitive to touch and stereotypic behavior was seen in both genders at 80 mg/kg BID. At 240/200 mg/kg BID in addition to clonic convulsions (noted in Weeks 2, 3, 6, and 7), hypersensitive to touch was seen in both genders as well as stereotypic behavior. The stereotypy was most frequently characterized as jumping and rigidity; the rigidity could have also been another convulsion. The highest incidences of convulsions and stereotypy were seen in the first few weeks. The subsequent lower incidence was attributed to lowering the dose level on Day 43. At the end of the 13 -week study, there were no test article-related effects seen in the functional observational battery of tests or motor activity. In the weekly neurobehavioral observations 1 to 2 hours post-dose, the convulsions described above were seen in a few 240/200 mg/kg BID animals. In addition, at 240/200 mg/kg BID the grid activity count data for the males showed increased activity. However, at the end of the 13-week study there was no test article-related effect on motor activity. The possible differences that were noted were sporadic with no relationship to dose. There was a transient test article-related decrease in food consumption for the first week in both the males and females at 240/200 mg/kg BID. All groups consumed a similar amount of food each week after that. Statistically significantly increased mean kidney weights were present in males at 25, 80, and 240/200 mg/kg/dose BID when compared to controls. Mean absolute kidney weights were increased 7%, 12%, and 18% in males at 25, 80, and 240/200 mg/kg/dose BID, respectively. There was no microscopic correlate for the increased weights in kidneys examined and the percent of weight increase was considered not to be biologically significant. Test article-related organ weight changes were also present in adrenal glands. Statistically significantly increased adrenal gland weights were present in males and females at 240/200 mg/kg BID and in males at 80 mg/kg BID (absolute and relative to brain weight) when compared to controls. Mean absolute adrenal gland weights were increased 19% and 41% in males at 80 and 240/200 mg/kg BID, respectively and 33% in females at 240/200 mg/kg BID. The increased adrenal gland weights correlatedmicroscopically to diffuse cortical hypertrophy/hyperplasia. Diffuse cortical hypertrophy/hyperplasia was present in 5 and 8 males at 80 and 240/200 mg/kg BID, respectively and in 2 females at 240/200 mg/kg/dose BID. Diffuse cortical hypertrophy/hyperplasia was characterized by a minimal to mild increase in the size and number of cells in the zonas fasciculata and reticularis of the adrenal cortex. This was the only microscopic finding in the study despite the neurobehavioral changes. Test article-related sperm effect was limited to the significant reduction in total sperm concentration per cauda epididymis and sperm concentration per gram cauda epididymis at 240/200 mg/kg/dose. This was likely a stress related response.In conclusion, under the conditions of this study, where rats were dosed orally for 13-weeks at 25, 80, 240/200 mg/kg/dose BID, the NOAEL was 25 mg/kg BID (50 mg/kg/day). 


Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: behaviour

Justification for classification or non-classification

Based on the toxicological profile of TMCD and weight of evidence no classification for specific Target Organ Toxicity – Repeated Exposure according to GHS is warranted despite the NOAEL being <100 mg/kg. The major effect of behaviour changes was very transient in nature and their was no morphological changes or alterations in the functional operational battery.