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Administrative data

Description of key information

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 IX
Repeated Dose Inhalation-Testing not required based on Column 2 Annex IX

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Conducted according to OECD TG 407. GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
other: Guidelines for 28-day Repeated Dose Toxicity Testing of Chemicals (Japan)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
Age at study initiation: 6 weeks old for males and females.
Weight at study initiation: 130-151g for male; 110-121g for female.
No. of animals per sex per dose: 5 Rats per sex per dose group
Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
Rats were fed 0(vehicle), 100, 300 and 1000 mg/kg bw/day of test material in corn oil once a day for 28 days. An additional recovery group for the 0 and 1000 mg/kg bw/day were allowed to recover for 2 weeks post exposure.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 days
Frequency of treatment:
once daily, 7 days/week
Remarks:
Doses / Concentrations:
0(vehicle), 100, 300 and 1000 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
5 Rats per sex per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Rats were fed 0(vehicle), 100, 300 and 1000 mg/kg bw/day of test material in corn oil once a day for 28 days. An additional recovery group for the 0 and 1000 mg/kg bw/day were allowed to recover for 2 weeks post exposure. Clinical observations performed and frequency: Body weights were recorded immediately prior to the first exposure and again for each animal every week.
Observations and examinations performed and frequency:
Clinical observations performed and frequency: Body weights were recorded immediately prior to the first exposure and again for each animal every week.
Sacrifice and pathology:
At the end of the 28th day treatment period the rats were sacrificed.

Haematologic parameters were evaluated for each animal. Blood samples for the haematologic determinations were taken from abdominal artery in rats after 16 hr fast.

Clinical chemistry analyses were performed on serum samples from each animal.

Urinalyses were performed for each rat. Urine samples were collected from each rat on the day prior to scheduled termination.
Statistics:
Bartlett's test, Dunnett's test or Kruskal-Wallis test depending on whether or not the data were nonhomogeneous or homogeneous. Fisher's test for the pathological result. Jonckheere's test for the correlation of dosage
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
Body weight: The mean body weight of treatment groups of rats for males and females had no significant differences from the controls during the course of the study.

Food/water consumption: There was no significant difference between control and treatment groups throughout treatment and recovery periods for both sexes.

Clinical signs: No abnormality was detected during the study.

Haematology:
At the end of dosing Males and Females: No dose-related significant changes were observed. In the examination of blood coagulating system, prothrombin time for males was slightly prolonged, but they were considered within the physiological fluctuation. For females, no significant changes in all test items.
After recovering period Males: Haemoglobin was slightly increased for males at 1000mg/kg group, but they were considered within the physiological fluctuation. In the examination of blood coagulation system, no significant changes were observed in all test items.
After recovering period Females: No significant change in all tests.

Biochemistry:
At the end of dosing Males: No dose-related significant adverse treatment-related effect in clinical chemistry.
At the end of dosing Females: At 300, and 1,000 mg/kg dosing, chlorine contents were low.
After recovering period Males: At 1,000 mg/kg dosing, potassium contents were slightly high.
After recovering period Females: At 1,000 mg/kg dosing, GOT were slightly high. But both changes were considered to be no meaning, because at the end of treatment these changes were not recognised.

Urinalysis:
At the end of dosing Males and Females: At 1,000 mg/kg dosing, some of rats (both sexes), amounts of urinary increased, but the mean urinary specific gravity values in the 1,000 mg/kg dosing group was not significant change from control group.
After recovering period Males and Females: No dose-related significant change in all tests.

Mortality and time to death: No deaths prior to scheduled termination.

Organ weight changes:
At the end of dosing Male: No dose-related change in all tested organs.
At the end of dosing Female: Relative liver weight were slightly increased at 100 mg/kg dosing, but no dose-related change. Other organs, no significant change.
After recovering period Males: At 1,000 mg/kg dosing, relative kidney weight were slightly low.
After recovering period Females: At 1,000 mg/kg dosing, absolute and relative adrenal weight were slightly high. But both changes were considered no related to dosing and recovering of this chemical.

Gross pathlogy and histopathlogy:
At the end of dosing Males: Coloured patch/zone of lungs were observed 1 of 100 mg/kg, 2 of 300 mg/kg and 3 animals of 1,000 mg/kg dosing group. Also hypertrophy of the kidney, hypertrophy of parathyroid, and etc. were observed. Amounts of eosinophilic body in the kidney were slightly increased in dosing group. But all these changes were considered no related the dosing and recovering of this chemical, because the degree and
rate of changes were same of all the group included control.

At the end of dosing Females: Red patch/zone of thymus dilated lumen of the uterus and etc. were observed. But all these changes were considered no related the dosing and recovering of this chemical, because the degree and rate of changes were same of all the group included control.

After recovering period Males and Females: No dose-related significant change in all tests.
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
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.
Executive summary:

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.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
184 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A decrease in hemoglobin and an increase of leucocyte counts and serum cholesterol as well as an incrased liver weight in the mid and high dose groups (0.67 and 2.0%) were noted.

Justification for classification or non-classification

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).