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Description of key information

No repeated dose toxicity data for the submission substance is available. However adequate and reliable data for a structural anologue (i.e. C8TM, for read-across justification please see read-across report in section 13) are reported here. In this Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening (OECD 422, GLP conform, subacute exposure duration) a NOAEL of 125 mg/kg bw/day was identified.

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
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
For details on endpoint specific justification please see read-across report in section 13 or find a link in cross-reference “assessment report”.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Gross pathological findings:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
134.6 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: effects in clinical chemistry at 500 mg/kg bw/day
Remarks on result:
other: effect level corrected for molecular weight
Dose descriptor:
NOEL
Effect level:
134.6 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Hepatocellular hypertrophy in centrilobular region of liver observed in males treated at 500 mg/kg.
Remarks on result:
other: effect level corrected for molecular weight
Dose descriptor:
NOEL
Effect level:
32.3 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Increased liver weight and reduced red blood cell count observed in females treated at 125 and 500 mg/kg/day
Remarks on result:
other: effect level corrected for molecular weight
Critical effects observed:
not specified
Conclusions:
In this Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening according to OECD testing guideline 422 and performed according to GLP rats were treated via oral gavage with 0, 30, 125 or 500 mg 1,2,4 benzenetricarboxylic acid, trioctyl ester (C8TM)/kg bw/day for at least 42 days (males) up to 54 days (females). Some changes in hematological aparameters, clinical chemical parameters and on liver weights and pathology were observed (partially not dose -realted and only single parameters concerned). In a conservative approach changes in clinical chemistry observed in both sexes at the highest dose group were used to establish the the no-observed-adverse-effect level (NOAEL). Thus the NOAEL of this study is judged to be 125 mg/kg bw/day.
Executive summary:
A the study used as source was a Combined repeated dose toxicity study with reproduction/developmental toxicity screening (OECD TG 422, GLP conform). The test was conducted for 1,2, 4 benzenetricarboxlyic acid, trioctyl ester (C8TM) at 0 (carrier), 30, 125 and 500 mg/kg for both female and male animals, with repeated administration in Sprague Dawley female and male rats (13 animals each/group) from 2 weeks before mating up until mating, then for 42 days for males and for pregnant females throughout gestation until day 4 of lactation.

Other than 1 female death in the 500 mg/kg group at 23 days gestation, no deaths were recorded. In terms of changes in general condition, salivation was observed in both males and females directly following administration in the 500 mg/kg group. In females in the 500 mg/kg group, body weight increase values were low at 7-14 days gestation, but there was no influence of the test substance on male body weight or male and female food intake. In females, there was a reduction in red blood cell count and an increase in liver weight in the 125 mg/kg group, and decreased plasma protein concentration and increased glucose concentration in the 500 mg/kg group. Males in the 500 mg/kg group showed decreased serum protein and elevated alkaline phosphatase activity. Histological findings showed centrilobular liver hypertrophy in males in the 500 mg/kg group, but no reproductive system abnormalities thought to be caused by administration of the test substance were noted.

From the above test results and under the test conditions in this study, the no-effect dose of 1,2, 4 benzenetricarboxlyic acid, trioctyl ester for repeat dose toxicity was determined at 125 mg/kg day for males, 30 mg/kg day for females and the no-effect dose for reproduction/developmental toxicity was determined at 500 mg/kg day for parent animals and pups. In a conservative approach changes in clinical chemistry observed in both sexes at the highest dose group were used to establish the the no-observed-adverse-effect level (NOAEL). Thus the NOAEL of this study is judged to be 125 mg/kg bw/day (corresponding to 134.6 mg submission substance/kg bw/day).

The results of the source compound were considered applicable to the target compound. Justification and applicability of the read-across approach (structural analogue) is outlined in the read-across report in section 13 or find a link in cross-reference “assessment report”.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
134.6 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP study of high reliability (Klimisch score 1), which was performed with a structural anologue of the submission substance. The quality of the data is high

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

Mode of Action Analysis / Human Relevance Framework

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
reliable study for the oral exposure route available, also due to physical chemical properties (i.e. very low vapour pressure) no relevant inhalation exposure is expected

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
due to physical chemical properties (i.e. very low vapour pressure) no relevant inhalation exposure is expected and no local irritating effects were observed in animal studies investigating irritating properties on the skin and the eyes


Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
reliable study for the oral exposure route available, due to molecular weight (above 500 Da) and physical chemical properties (i.e. very low water solubility and the high log Po/w) the dermal exposure route is of low relevance and no effects in acute dermal toxicity study identified

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
no local irritating effects were observed in animal studies investigating irritating properties on the skin

Additional information

No repated dose toxicity data for the submission substance is available. However adequate and reliable data for a structural anologue (i.e. C8TM, for read-across justification please see read-across report in section 13) are reported here.

In this Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening according to OECD testing guideline 422 and performed according to GLP rats were treated via oral gavage with 0, 30, 125 or 500 mg 1,2,4 benzenetricarboxylic acid, trioctyl ester (C8TM)/kg bw/day for at least 42 days (males) up to 54 days (females). Mild anaemia and increased liver weight were observed in females treated at levels of 125 mg/kg bw/day or greater. However, for the above noted effects no increase of response could be observed between the 125 and 500 mg/kg bw/day groups. Centrilobular hypertrophy of hepatocytes in the liver was observed in males treated at 500 mg/kg/day. Moreover at the 500 mg/kg bw/day group some clinical chemical parameters were significantly different from control groups. In males increased ALP and reduced total protein was observed. In females, also reduced total protein levels were found and in addition a decrease in creatinine concentration and increase in glucose concentration. Overall the no-observed-effect level (NOEL) for repeated-dose toxicity under the conditions of this study was therefore 30 mg/kg bw/day in females and 125 mg/kg bw/day in males. In a conservative approach changes in clinical chemistry observed in both sexes at the highest dose group were used to establish the the no-observed-adverse-effect level (NOAEL). Thus the NOAEL of this study is judged to be 125 mg/kg bw/day (corresponding to 134.6 mg submission substance/kg bw/day; MoHLW, 2001, RL1).

Justification for classification or non-classification

Based on the results of a structural analogue in a combined repeated dose toxicity study with reproduction/developmental toxicity screening the submission substance is not classified for repeated dose toxicity according to criteria in Regulation (EC) No 1272/2008.

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