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EC number: 615-086-0 | CAS number: 70225-05-7
Repeated Dose Oral, read-across, 1 key study and 3 supporting study- (equivalent or similar to OECD TG 407)Repeated Dose Dermal-Testing not required based on Column 2 Annex IXRepeated Dose Inhalation-Testing not required based on Column 2 Annex IX
Male and female Crj: CD (SD) rats were exposed to 0(vehicle), 100, 300 and 1,000 mg/kg/day of the test material, tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate in corn oil. The test material was given once daily for 28 days. Two separate groups (0 and 1000 mg/kg bw/day) were allowed to recover for 2 weeks before examination. At the end of the 28 day period, the test animals were sacrificed and body weight, food/water consumption, haematology, organ weights, serum analysis, liver biochemistry, and histopathology were performed on all animal. There were no changes noted by the investigators attributed to the test material.
The NOAEL for the test material was determined to be >1000 mg/kg bw/day for male and female rats.
Classification as a repeat oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/548/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Repeat dose toxicity studies were not located for the submission substance (CASRN 70225-05-7). However, data from the chemical category Trimellitates are available and was used as read-across in this hazard assessment.
The submission substance is expected to have a low order of repeated dose toxicity by the oral route of exposure based on read-across data. Four studies were located for the read-across substance, TOTM. These studies were performed in a manner similar or equivalent to currently established OECD guidelines.
A 28 day feeding study with rats (Chemicals Manufacturers Association, 1984) showed a decrease of hemoglobin and an increase of leucocyte counts and serum cholesterol as well as an increased liver weight in the mid and high dose groups (0.67 and 2.0 %). Liver biochemistry revealed increases in palmitoyl CoA oxidation (increased in both sexes at 2.0% and males at all dose levels) and catalase activity (increased in males at 2.0%), suggesting the induction of peroxisome proliferation. Further analysis by an electron microscope indicated slight increased number of peroxisomes in hepatocytes at the high dose. It is generally accepted that the induction of peroxisome proliferation occurs specifically in rodents but much less in other species including humans. There were no dose-related histopathological changes in any treated groups. The NOAEL in this study was considered to be 0.2 % (184 mg/kg bw/day). Although these limited effects are not indicative of significant toxicity and occur at doses above the guidance values for classification, a DNEL was derived based on these findings.
In a second 28d feeding study in rats, no test substance related changes were noted in terms of clinical signs, body weight, food consumption, hematology, blood examination, urinalysis and pathological findings. The NOAEL in this study was 1000 mg/kg/day (Ministry of Health and,, 1996b).
In a 28d oral gavage study assessing hepatotoxicity, there were no test substance related effects on absolute or relative liver weights. The NOAEL in this study was 1000mg/kg/d (Biosearch, 1981).
Finally, in a 21d oral gavage study assessing hepatotoxicity, (BIBRA, 1987), there were no treatment-related effects on absolute or relative liver weights up to 2000 mg/kg/d in males, however there was evidence of peroxisome proliferation at the high dose by electron microscopy. In contrast, in females, there were significant but not dose-responsive increases in relative and absolute liver weights at all dose levels. There were also changes in serum chemistry. There was no NOAEL identified.
Taken together, the limited effects observed in the 28 day repeat dose toxicity tests were not indicative of significant toxicity and occurred at doses above the guidance values for classification.
Justification for Read-Across
The Trimellitate Category-as defined in the US Environmental Protection Agency’s (EPA) High Production Volume (HPV) Challenge Program and the Organization for Economic Cooperation and Development’s (OECD) Screening Initial Data Set (SIDS)-, includes four chemicals containing individual trimellitate triesters or mixed trimellitate esters, which are defined as esters of 1,2,4,-benzenetricarboxylic acids that have branched or branched and linear alkyl groups. The members are: 1,2,4-benzenetricarboxylic acid, tris (2-ethylhexyl) ester (CASRN 3319-31-1 [TOTM]); 1.2.4-benzenetricarboxylic acid, triisooctyl ester (CASRN 27251-75-8 [TIOTM]); 1,2,4-benzenetricarboxylic acid, triisononyl ester (CASRN 53894-238 [TINTM]); and 1,2,4-benzenetricarboxylic acid, decyl octyl ester (CASRN 67989-23-5 [DOTM]). The Trimellitate Category was formed on the principle that substances of similar structure have similar toxicological properties and the premise that a narrow range of ester carbon numbers will produce trends in physicochemical, environmental and toxicological properties.
The submission substance (CASRN 70225-05-7) fits the Trimellitate Category definition of an ester of 1,2,4-benzenetricarboxylic acid with branched and linear alkyl groups, with the distinction of having side chains of slightly longer length (C10, and C13). Because of the similarity in structure and physicochemical properties, it is reasonable to rely on theavailable data on the HPV Trimellitate substances to characterize the human health effects of CSRN 70225-05-7 (see read-across justification in section 13 of IUCLID dossier for more information).
Based on the available data, the submission substances is not expected to produce significant systemic toxicity following repeated exposure. Therefore, these findings do not warrant classification of the test material for target organ toxicity (repeated exposure) under the new Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP), under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations, or under the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).
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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