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Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproduction 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.
No effects on reproductive performance were observed in a Combined Repeated Dose Toxicity Study with Reproduction/Developmental Toxicity Screening of oral administration of 1,2,4 benzenetricarboxylic acid, trioctyl ester (C8TM) in Rats (highest exposure concentration: 500 mg/kg bw/day).

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
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
Key result
Dose descriptor:
NOAEL
Effect level:
538.5 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on reproductive performance or sex organs
Remarks on result:
other: effect level corrected for molecular weight
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
538.5 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on pup weight, sex ratio, survival index, viability index and no abnormalities found in visual examination of live pups or necropsy of pups at the end of the study
Remarks on result:
other: effect level corrected for molecular weight
Reproductive effects observed:
not specified
Conclusions:
Combined repeated dose toxicity study with reproduction/developmental toxicity screening was conducted for 1,2, 4 benzenetricarboxlyic acid, trioctyl ester (C8TM). This GLP conform study was performed according to OECD testing guideline 422. Sprague-Dawley rats (13 animals each/group) were treated with 0, 30, 125 and 500 mg/kg for 42 days for males and for pregnant females throughout gestation until day 4 of lactation. No adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 500 mg/kg/day for both parent animals and offspring, this being the highest dose level investigated.
Executive summary:

The study used as source was a Combined repeated dose toxicity study with reproduction/developmental toxicity screening conducted for the structural analogue 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. This GLP conform study was performed according to OECD testing guideline 422.

Effects on parental animals concerning repeated dose toxicity are presented in detail in the respective endpoint study record and will not be discussed further. The NOAEL for systemic effects after repeated substance administration is judged to be 125 mg/kg bw/day (corresponding to 134.6 mg subsmission substance/kg bw/day), based on changes in clinical chemistry in both sexes.

For reproduction and developmental toxicity screening, no changes suggestive of effect from the test substance were noted in female estrous cycle, male and female copulation index, or fertility index, delivery and lactation conditions in dams. Furthermore, no effect from the test substance was noted in the birth index, gestation period, numbers of corpora lutea, number of implantation sites and implantation index. In addition, no changes caused by the test substance were noted for viability, sex ratio and body weight of pups. Thus the NOAEL reproduction/fertility/developmental for parental animals and offspring is judged to be 500 mg/kg bw/day (highest dose tested, corresponding to 538.5 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”   

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
538.5 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
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No reproduction 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.

A combined repeated dose toxicity study with reproduction/developmental toxicity screening was conducted for 1,2, 4 benzenetricarboxlyic acid, trioctyl ester (C8TM). This GLP conform study was performed according to OECD testing guideline 422. Sprague-Dawley rats (13 animals each/group) were treated via oral gavage with 0, 30, 125 and 500 mg/kg (42 days for males, females approx. 54 days (throughout gestation until day 4 of lactation). No adverse effects on oestrous cycle, copulation, fertility, delivery or lactation and no changes related to gestation index, gestation length, numbers of corpora lutea, implantation sites or implantation index. There were no changes in sex ratio, body weight, viability or morphology of pups. The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 500 mg/kg/day for both parent animals and offspring (corresponding to 538.5 mg subsmission substance/kg bw/day), this being the highest dose level investigated (MoHLW, 2001, RL1).


Justification for selection of Effect on fertility via inhalation route:
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 Effect on fertility via dermal route:
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

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 reproductive toxicity according to criteria in Regulation (EC) No 1272/2008.

Additional information

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