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EC number: 213-944-5 | CAS number: 1068-27-5
The oral administration of Di-Tert-Butyl 1,1,4,4-Tetramethyl Tetramethylene Diperoxide (read-across substance), CAS 78-63-7 to rats by gavage, for 90 days, at dose levels of 15, 50 and 150 mg/kgbw/day, did not result in any toxicologically significant adverse effects. The ‘No Observed Adverse Effect Level’ (NOAEL) was, therefore, considered to be 150 mg/kgbw/day.
The oral administration of Di-Tert-Butyl 1,1,4,4-Tetramethyl Tetramethylene Diperoxide, CAS# 78-63-7 to rats by gavage, at dose levels of 15, 50 and 150 mg/kg bw/day, did not result in any adverse effects of treatment.
Clinical observations were confined to increased salivation observed for both sexes at 50 and 150 mg/kg bw/day. At 150 mg/kg bw/day all animals were affected but at 50 mg/kg bw/day the overall number of animals and incidence tended to be lower. Observations of this nature are commonly observed following the oral administration of an unpalatable or slightly irritant test item formulation and in isolation are considered not to be related to systemic toxicity. There were considered to be no effects of treatment on behavioral or functional assessments, body weight, food consumption or food conversion efficiency for either sex throughout the study. Hematological and blood chemistry investigations at 150 mg/kg bw/day did not reveal any adverse effect of treatment for either sex.
For both sexes at 150 mg/kg bw/day, there was an increase in absolute and body weight relative organ weights for the liver, suggestive of an adaptive change, although this was not accompanied by any evidence of microscopic change and was considered not to represent an adverse effect of treatment. In the thyroid glands for both sexes there was a greater incidence of minimal or mild diffuse hypertrophy of the follicular epithelium than in controls at all dosage levels. The underlying mechanism for this treatment-related change was not apparent but the most likely explanation for its development is a perturbation of thyroid hormone synthesis, transport or metabolism. Since the rat thyroid gland has been shown to be markedly more sensitive than humans in its response to xenobiotics it seems reasonable to conclude that the minor difference seen in this study would not carry significant risk to humans.
Microscopic examination of kidney sections revealed a dosage-related increase of intra-epithelial hyaline droplets in males that affected all the treated groups. In males given 150 mg/kg bw/day the presence of an increase in hyaline droplets was associated with granular cast formation, an increase in basophilic tubules and single cell necrosis of cortical tubules. These findings were consistent with an etiological diagnosis of alpha-2µ-microglobulin nephropathy using immunohistochemistry, in which there was a clear increase in staining intensity at the highest dosage. It was, therefore, concluded that all the treatment-related renal changes were a consequence of alpha-2µ-microglobulin nephropathy and, since this condition is species specific, of no relevance to human exposure. The increased levels of hyaline droplets and the other changes observed in males at the highest dosage were considered responsible for the increased absolute and body weight-relative kidney weights observed for these animals.
The study was designed to investigate the systemic toxicity of the test item and is compatible with the following regulatory guidelines:
i) The OECD Guidelines for Testing of Chemicals No. 408 "Subchronic Oral Toxicity - Rodent: 90 Day Study (Adopted 21 September 1998).
ii) This study was also designed to be compatible with Commission Regulation (EC) No. 440/2008 of 30 May 2008, laying down test methods pursuant to Regulation (EC) No. 1907/2006 of the European Parliament and of the Council on the Registrarion, Evaluation, Authorisation and Restriction of Chemicals (REACH)
The test item was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for ninety consecutive days, at dose levels of 15, 50 and 150 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (corn oil).
Clinical signs, functional observations, body weight change, dietary intake and water consumption were monitored during the study. Estrous cycle assessment was performed during the final three weeks of the study. Hematology and blood chemistry were evaluated for all animals at the end of the study. Urinalytical investigations were performed during the final week of the study. Ophthalmoscopic examination was also performed on control group and high dose animals prior to the start of treatment and during Week 12 of the study.
All animals were subjected to gross necropsy examination, which included male sperm assessments, and histopathological evaluation of selected tissues from high dose and control animals was performed.
There were no unscheduled deaths on the study.
Neither the type, incidence nor distribution of clinical sign observed during the study indicated any effect of treatment at dosages up to 150 mg/kg bw/day.
There were no treatment-related changes in behavioral parameters measured.
Functional Performance Tests
There were no treatment-related changes in functional performance.
Sensory Reactivity Assessments
Sensory reactivity to different stimuli (auditory, visual and proprioceptive) appeared unaffected by treatment at 15, 50 or 150 mg/kg bw/day.
There were no adverse effects of treatment on body weight gain for either sex at 15, 50 or 150 mg/kg bw/day.
There were no effects of treatment on food consumption or food conversion efficiency for either sex at 15, 50 or 150 mg/kg bw/day.
Estrous Cycle Assessment
There were no treatment-related effects on female estrous cycles.
There were no treatment-related effects detected in water consumption.
Ophthalmic examination of animals receiving 150 mg/kg bw/day at the end of the study did not indicate any effect of treatment.
There were no toxicologically significant effects detected in the hematological parameters examined.
There were no toxicologically significant effects detected in the blood chemical parameters examined.
Assessment of urine parameters at the end of the study did not indicate any obvious effect of treatment at 15, 50 or 150 mg/kg bw/day.
Neither the type, incidence nor distribution of macroscopic abnormalities detected at terminal necropsy indicated any adverse effect of treatment.
Males treated with 150 mg/kg bw/day showed a statistically significant increase in absolute and body weight-relative kidney weight.
No toxicologically significant effects were detected in females treated with 150 mg/kg bw/day or animals of either sex treated with 50 or 15 mg/kg bw/day.
There were no toxicologically significant effects on the concentration, motility or morphology of samples of epididymal sperm. There were no treatment-related effects on the concentration of homogenisation resistant epididymal or testicular spermatid counts.
The following treatment related microscopic abnormalities were detected:
Kidneys: increased incidence of intra-epithelial hyaline droplets in all treated male groups. In males given 150 mg/kg bw/day, associated granular cast formation, an increase in basophilic tubules and single cell necrosis of cortical tubules was also evident.
Thyroids: The incidence of minimal or mild diffuse hypertrophy of the follicular epithelium was increased in animals of either sex from all treatment groups.
The oral administration of Di-Tert-Butyl 1,1,4,4-Tetramethyl Tetramethylene Diperoxide, CAS# 78-63-7 to rats by gavage, at dose levels of 15, 50 and 150 mg/kg bw/day, did not result in any toxicologically significant adverse effects. The ‘No Observed Adverse Effect Level’ (NOAEL) was therefore considered to be 150 mg/kg bw/day.
Key study (OECD 408, read-across)
A repeated-dose study via oral route is not available. Consequently, read-across was applied using study results obtained from Di-Tert-Butyl 1,1,4,4-Tetramethyl Tetramethylene Diperoxide (CAS 78 -63 -7), a structure analogue of the substance to be registered.
The oral administration of Di-Tert-Butyl 1,1,4,4-Tetramethyl Tetramethylene Diperoxide, CAS 78-63-7 to rats by gavage, at dose levels of 15, 50 and 150 mg/kg bw/day, did not result in any adverse effects of treatment.
Overall it was considered that the No Observed Adverse Effect Level (NOAEL) for this study was 150 mg/kg bw/day.
The 90-day NOAEL is 150 mg/kg bw/day, the highest dose tested. The increase in liver weight was not considered adverse and the effect on the kidney, observed in the males, is species specific. These types of effects and this dose level do not warrant classification for STOT-RE. Bases on the data available, the test substance was not classified and labelled according to Regulation (EC) No 1272/2008 (CLP).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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