Tributyl benzene-1,2,4-tricarboxylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Gene expression associated with developmental toxicity: No repression of genes in the testicular mal-development pathway

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

346 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a repeat-dose toxicity combined with a screening study of reproductive toxicity on a structurally similar trimellitate, the linear alcohol ester side chains of the molecule being C8 rather than C4 of the registered substance, no significant effect on reproductive ability, organ weight or histopathology of the ovary, delivery or maternal behaviour was apparent. The NOEL for reproductive / developmental toxicity was considered to be 500 mg/kg/day (346 mg/kg/day when differences in molecular weight are accounted for) for both parents and offspring, the highest dose examined. An OECD screening study of reproductive toxicity on another trimellitate, this with C8 branched alcohol ester side chains, revealed no functional changes in fertility or reproductive performance although histopathological examination revealed reduced spermatocytes & spermatids in the testes of males given the substance at doses of 300 and 1000 mg/kg/day. The NOELs for systemic toxicity were considered to be 100 & 1000 mg/kg/day (69 & 690 mg/kg/day when differences in molecular weight are accounted for) for males & females respectively. The NOEL for reproductive / developmental toxicity is considered to be 1000 mg/kg/day (690 mg/kg/day when differences in molecular weight are accounted for) for offspring.It is noted that, in a repeat dose toxicity study of 90 -days duration, approximately double that of the screening study, the testicular effects described above were not seen.

A two-generation reproductive toxicity study is required in accordance with Section 8.7.3 of Column 1, Annex IX. It is proposed to waive the need to conduct this study on the basis of the fact that well-conducted OECD 421 reproductive/developmental toxicity screening studies and data from subchronic repeat dose toxicity studies show no functional effect on the reproductive performance of both male and female rats. These studies provide adequate data to demonstrate the potential toxicity to reproduction of the substance to humans and to derive relevant DNELs for oral exposure. Furthermore, it is well known that, for this class of substance, the principle reproductive toxicity potential is towards the developing male testes. This aspect of the toxicological profile has been studied adequately using RNA transcriptional profiling in an assay that subscribes to the principle of the 3R’s.

Short description of key information:
Reproductive toxicity - Rat: NO(A)EL - 346 mg/kg/day

Justification for selection of Effect on fertility via oral route:
Studies are available on two structural analogues of the registered substance, the selected study being that on the closest structural analogue to the registered substance.

Effects on developmental toxicity

Description of key information

Developmental toxicity - Rat: NO(A)EL 658 mg/kg/day

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEL

658 mg/kg bw/day

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, conducted on a structurally similar trimellitate, the linear alcohol ester side chains of the molecule being C8 to C10 rather than C4 of the registered substance, found no exposure related developmental toxic effects, findings being limited to indicators of maternal toxicity.On the basis of the results obtained, 300 mg/kg/day (198 mg/kg/day when differences in molecular weight are accounted for) was considered the NOAEL for maternal toxicity and 1000 mg/kg/day (658 mg/kg/day when differences in molecular weight are accounted for) the NOAEL for embryo-foetal effects.

In a study on another trimellitate, this with C8 branched alcohol ester side chains, no treatment-related effects indicative of maternal toxicity and no effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment. No effects levels were:

NOEL maternal toxicity: 1050 mg/kg/day (726 mg/kg/day when differences in molecular weight are accounted for)

NOEL pre-natal developmental toxicity: 1050 mg/kg/day (726 mg/kg/day when differences in molecular weight are accounted for)

NOEL post-natal evaluation of offspring: 500 mg/kg/day (346 mg/kg/day when differences in molecular weight are accounted for); LOAEL: 1050 mg/kg/day (726 mg/kg/day when differences in molecular weight are accounted for) based on a slight increase in retained areolar region in males treated at 1050 mg/kg/day post-natal Day 13, no longer present post-natal day 18 and slightly higher increase in displaced testes compared to controls although the observed incidence was within the range of historical control data).

It is considered that for this class of substance, by association with phthalate esters, the principle concern regarding developmental toxicity is towards the developing male testes. This aspect of the toxicological profile has been studied in detail using RNA transcriptional profiling in an assay that subscribes to the principle of the 3R’s.

Justification for selection of Effect on developmental toxicity: via oral route:
Studies are available on two structural analogues of the registered substance, the selected study being that on the closest structural analogue to the registered substance.

Toxicity to reproduction: other studies

Additional information

Studies on structurally similar trimellitates, one with the linear alcohol ester side chains of the molecule being C8 to C10 rather than C4 of the registered substance and another with C8 branched alcohol ester side chains, examined the effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling. The outcome of these studies indicate that the substances do not cause repression of genes in the testicular mal-development pathway indicating that they are unlikely to cause testicular dysgenesis in rats as is seen with some phthalate esters.

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Justification for classification or non-classification

Studies of reproductive have revealed no functional changes in fertility or reproductive performance other than, in a screening study of reproductive toxicity, reduced spermatocytes & spermatids in the testes of males given a trimellitate with C8 branched alcohol ester side chains at doses of 300 or 1000 mg/kg/day. Such effects were not apparent with this substance at dose levels as high as 1000 mg/kg/day in a sub-chronic study of 90 days duration, the duration of exposure being approximately double that of the screening study. Studies of effects on gene expression associated with developmental toxicity in male rat foetal testes by transcriptional profiling indicate that the substances do not cause repression of genes in the testicular mal-development pathway, indicating that the substances are unlikely to cause testicular dysgenesis in rats.

A pre- and post-natal developmental toxicity study with a trimellitate containing C8 branched alcohol ester side chains revealed no effects on developmental toxicity at a dose level of 500 mg/kg/day. At the higher dose level of 1050 mg/kg/day a slight increase in retained areolar region was observed in males on post-natal Day 13 which was no longer present post-natal day 18. A slightly higher increase in displaced testes compared to controls was also seen although the observed incidence was within the range of historical control data. A similar study with a trimellitate containing linear alcohol ester side chains of C8 to C10 length (rather than C9 of the registered substance), found no exposure related developmental toxic effects, findings being limited to indicators of maternal toxicity. In this study the NOAEL for embryo-foetal effects was regarded as being 1000 mg/kg/day.

In accordance with Regulation (EC) No. 1272/2008 effects such as small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments are considered to be of low or minimal toxicological significance insufficient to warrant classification.