Ester reaction products of 1,4-Benzenedicarboxylic acid with C11-14 iso-alcohols, C13-rich

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No other concerns identified

Additional information

Reproductive toxicity studies (OECD 421 or 422) are not required based on Annex IX standard information requirements. Taking into account the results of the available test data provided in this dossier and the physicochemical properties of the submission substance, it is expected that this material does not present a reproductive toxicity hazard. The available data are adequate for risk assessment and therefore no further testing are proposed.

Short description of key information:

No studies required based on REACH Annex XIII and IV column 2. Not expected to cause reproductive toxicity based on available data.

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study, read-across, 1 key study, two species- NOAEL= 747 mg/kg/day in rats and 1382 mg/kg/day in mice.  These were the highest dose tested in both species (according to OECD 414).  

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Additional information

Reproductive and developmental toxicity studies were not located for the submission substance. However, data from the structurally related analogue, DEHT, are available and were used as read-across for the purposes of hazard assessment. 

 

The potential for adverse effects following DEHT exposure on reproduction and in utero development in mice and rats was evaluated according to the methods described in OECD guideline 414 (Faber et al., 2007). In these studies, diet containing DEHT was fed to four groups of mated female Crl:CD(SD)IGS BR rats (25/group) from gestation day (GD) 0–20 or Crl:CD1(ICR) mice (25/group) from GD 0–18. Concentrations within the feed were 0, 0.3, 0.6, and 1.0% for the rats and 0, 0.1, 0.3, and 0.7% for the mice. The dose rate from dietary DEHT exposure was 0, 226, 458, and 747 mg/kg/day in the rats and 197, 592, and 1382 mg/kg/day in the mice for the control, low, mid, and high-exposure groups, respectively. DEHT exposure did not affect clinical observations. A slight reduction in body weight gain was noted in the high-dose rat group (1.0%); the remaining groups were unaffected. At necropsy, increased liver weights were noted in the high-dose rat group (1.0%) and the mid- and high-dose mouse groups (0.3 and 0.7%). Mean numbers of implantation sites and viable fetuses, mean fetal weights, and mean litter proportions of preimplantation loss, early resorptions, late resorptions, and fetal sex ratios were unaffected by DEHT exposures. No treatment-related malformations or variations were observed at any concentration level in the rat and mouse developmental toxicity studies. The NOAEL for developmental toxicity in rats was 747 mg/kg/day and 1382 mg/kg/day in mice. The NOAEL for maternal toxicity was 458 mg/kg/day in rats and 197 mg/kg/day in mice.

 

In this same study, a uterotrophic assay for estrogenic activity was conducted in sexually immature rats (Faber et al., 2007). Sexually immature female rats received oral gavage doses of 20, 200, or 2000mg DEHT/kg bw/day from postnatal day (PND) 19–21. A slight reduction in rate of body weight gain was noted on the first day of dosing in the high dose group, but no other indications of toxicity were evident. DEHT exposure did not affect wet or blotted uterine weight parameters in any of these dose groups. The NOAEL for estrogenic activity was 2000mg/kg/day.

 

These data together with the likely limited bioavailability of the parent material (as described in the toxicokinetic assessment, IUCLID section 7.1) are considered adequate to conclude the submission substance has a low potential for developmental/reproductive toxicity. The available data are adequate for risk assessment and therefore no further testing are proposed.

Justification for Read-Across

For the purpose of this assessment, data for a lower molecular weight terephthalate, di(2-ethylhexyl) terephthalate (DEHT), was used as read-across. This read-across approach is based 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. Both the submission substance and DEHT are composed of a1,4-benzenedicarboxylic acid moiety with a branched alkyl alcohol attached to the acid units via an ester linkage (referred to as the alkyl side chains).The distinguishing feature between DEHT and the submission substance is in the alkyl side chains. DEHT has alkyl side chains with a 2-ethylhexyl moiety (carbon number of 8) whereas the submission substance has mixed alkyl side chains ranging in carbon backbone length from C11-C13. Because of the similarity in structure and physicochemical properties, it is reasonable to rely on available data on DEHT to characterize the human health effects of the submission substance.

 

Due to its higher molecular weight and bulkier side chains, the submission substance is expected to demonstrate a lower order of toxicity than DEHT. This is supported by similar structural activity relationships observed with ortho-phthalate ester compounds, i.e. the higher molecular weight phthalates (ester side chains >C7) are less active than the transitional phthalates (ester side chains C4-C6). Thus the use of DEHT to represent the potential hazards of the substance to be registered is considered a conservative estimate of toxicity.

 

The chemical structures of terephthalates (e.g. DEHT and MCP1440) are isomeric to theortho-phthalates (e.g. DEHP, DINP, and DIDP). That is terephthalates are derived from a 1,4-benzenedicarboxylic acid whereas ortho-phthalates are derived from 1,2-benzenedicarboxylic acid. This structural difference is thought to be very important as it provides the basis for the different metabolic profiles and therefore different toxicity outcomes following exposure to these phthalate esters (Barber, 1994a). Current data suggest that the mono-phthalate (MEHP) is the metabolite responsible for several of the toxicological effects following exposure to DEHP as well as other ortho-phthalates (Ruddick et al., 1981; Mitchell et al., 1985; Price et al., 1991). The distinct decrease in the amount of mono-phthalate formation following exposure to DEHT (and other terephthalates) is believed to account for the decreased toxicity associated with exposure in laboratory animals.

Justification for classification or non-classification

There is adequate information available from which to assess the potential of the submission substance to induce reproductive or developmental effects and to conclude that classification under 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) is not warranted.