Benzene-1,2,4-tricarboxylic acid 1,2-anhydride, oligomeric reaction products with ethane- l,2-diol

Endpoint summary

Description of key information

Local respiratory sensitisation, but no systemic toxicity, is observed in rats after subchronic or chronic exposure of various cyclic acid anhydrides.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

294 µg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

3 µg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

adequate

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

This endpoint is being filled using data from category members of the Selected Cyclic Acid Anhydrides category, of which BECKOPOX(TM) EH 694 is a member.

5-Isobenzofurancarboxylic acid, 1,3-dihydro-1,3-dioxo-, reaction products with 1,2-propanediol (ZAN 573) was investigated in a repeated dose toxicity dose-range finding study. There were no adverse effects observed after 7 days at the limit dose of 1000 mg/kg bw/d in rats. ZAN 573 is structurally similar to BECKOPOX(TM) EH 694. This favorable preliminary result supported the general knowledge that cyclic acid anhydrides, as a category, are not systemically toxic after repeated dosing in mammals. Expert groups at the WHO, 2009, reviewed the available repeated dose toxicity studies of several cyclic acid anhydrides, and concluded that systemic toxicity is not observed. Toxicokinetic behaviour favors rapid conversion of anhydrides to the acid form and subsequent urinary excretion. Repeated dose toxicity is not one of the critical health effects of exposure to cyclic acid anhydrides. Phthalic anhydride was studied in a two-year bioassay by the U. S. National Cancer Institute (NCI, 1979) with the finding that it was not carcinogenic, nor associated with systemic toxicity in an 8-week preliminary toxicity study at doses up to 500 mg/kg bw/d. Furthermore, detailed review of the major repeated dose toxicity studies of trimellitic anhydride (oral gavage route, Estep and Teske, 1969, Hill Top Research) and trimellitic acid (inhalation route, Hatoum and Fenters, 1989, IITRI) support this conclusion.

Local respiratory sensitization reactions occur after exposure to cyclic acid anhydrides. This is identified as a critical health effect by the expert groups at the WHO, 2009. The review of Human Health Effects of Cyclic Acid Anhdyrides (WHO, 2009) provides discussions of toxicokinetics, immunologic studies, and human workplace experiences which support the proposal that these substances are sensitisers to the respiratory tract. A detailed review of the repeated dose inhalation toxicity study of trimellitic anhydride (Leach, Hatoum and Derrick, 1988, IITRI) provide a compelling argument for immune-mediated lung injury (increased lung weight, hemorrhagic foci, inflammation and bronchoalveolar pneumonia. Rats were exposed to aerosolized trimellitic anhydride for up to 13 weeks, with periods of recovery and challenge. Multifocal lobular bronchopneumonia was observed at all concentrations; the LOAEC was 3 µg/m³. Anti-TMA antibodies were measured in the serum of exposed animals, increasing in the first 6 weeks and fluctuating at later time points until they diminished after 50 weeks. There were no instances where pulmonary lesions occurred without the presence of antibodies. No lesions occurred in exposed immunosuppressed animals.

The registered substance is therefore considered a respiratory sensitiser and irritant.

A category approach is used for the assessment of this endpoint. The hypothesis for the category of cyclic acid anhydrides is the similar chemical behaviour and analogous breakdown products in environmental and biological systems. The common functional group is a 1,3-dioxo-1,3-dihydro-2-furan ring (i. e., a cyclic acid anhydride) directly attached to an aromatic ring. The cyclic anhydride moiety is quickly hydrolysed to form a dioic acid. The cyclic acid anhydride moiety and its dioic acid derivatives are the principal loci of toxicity, rather than the remainder of the molecule. Within the category, oligomeric forms of the cyclic acid anhydrides are less likely to be absorbed across biological membranes than the simple, monomeric forms, so that this read-across represents the worst case scenario. The read-across information to acceptable to fulfil the information requirements of the REACH Annexes VII-X, to be the basis for classification and labelling decisions, and for risk assessment.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
experimental result on a member of the Selected Cyclic Acid Anhydrides category

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
experimental result on a member of the Selected Cyclic Acid Anhydrides category

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
experimental result on a member of the Selected Cyclic Acid Anhydrides category

Justification for classification or non-classification

The registered substance is classified as a respiratory sensitiser and irritant, based on the behaviour of category members (trimellitic anhydride, phthalic anhydride). Furthermore, the UVCB includes trimellitic anhydride which is classified for STOT-SE. The classification is Respiratory Sensitiser, Category 1, H334, and STOT-SE Category 3, H335.