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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
600 mg/kg bw/day
Additional information

Justification for read-across:

The High Molecular Weight Phthalate Ester (HMWPE) Category consists of phthalate esters with an alkyl carbon backbone with 7 carbon (C7) atoms or greater. The category is formed on the principle that substances of similar structure have similar toxicological properties. The data available on high molecular weight phthalates demonstrate that members of this category have similar biological activities and toxicological properties; verifying the use of read-across data as an appropriate approach to characterize endpoints. Both substances named DTDP are high molecular weight phthalate esters (C13), diisotridecyl phthalate (CAS number 27253-26-5, EC number 248-368-3) and 1,2-Benzenedicarboxylic acid, di-C11-14-branched alkyl esters, C13-rich (CAS number 68515-47-9, EC number 271-089-3). Both are isomeric mixtures of C13 branched alkyl esters, the starting material being different but both starting materials consisting of various isomers of multibranched C13 alcohols. Where data maybe lacking for DTDP, DINP (C9) and DIDP (C10), which are also high molecular weight phthalate esters, are used as read-across substances to provide toxicological information.

In two 2-generation reproductive toxicity studies, there were no changes in reproductive indices and no effects on fertility. Additionally, there were no effects on reproductive organs in the repeated dose study. Accordingly, the overall conclusion from these studies was that DIDP has no effect on fertility. DIDP did produce a small, statistically significant decrease in postnatal survival indices which was observed in the second generation of both of the two-generation studies leading to the NOAEL of 0.06% (33-76 mg/kg/d). These effects were found in association with maternal toxicity: reduced body weight, instances of increased kidney weight, and /or liver enlargement. Therefore, the effects on post-natal survival could be secondary rather than a direct effect of DIDP on the rat pups. Cross fostering studies demonstrated that post natal body weight effects observed were reversible when post natal exposure to DIDP via the dams stopped. 

Short description of key information:
Reproductive toxicity of DIDP was evaluated in two 2-generation reproductive toxicity tests (Exxon Biomedical Sciences, 1997b and 2000; key data published in Hushka et al., 2001). Rats were exposed by dietary administration to levels of DIDP ranging from 0.0-0.8% (or approx. 15-600 mg/kg/d). There were no statistically significant differences in male mating, male fertility, female fertility, female fecundity, or female gestational indices between treated and control animals in the P1 or P2 generation. Mean days of gestation and mean litter size and of the treated and control groups were similar. There were no statistically significant differences in the mean sex ratio of the treated offspring compared with controls. It was concluded that fertility was unaffected by DIDP treatment at levels up to 600 mg/kg/day.
Parental toxicity:
In both studies, liver and kidney effects were observed in the P1 generation. Increased liver weights and associated hepatocellular hypertrophy were observed at dietary concentrations of 0.4% and greater in both studies. These dietary concentrations also produced kidney effects that were associated with alpha 2u microglobulin toxicity, a male rat specific effect and thus not relevant to humans. In the first study, minor effects on the liver were observed at 0.2% (103-203 mg/kg/d). In the second study, no hepatic effects were recorded at this concentration (114-225 mg/kg/day). As there is a range in intake levels, it is likely this dietary concentration results in ingestion of DIDP at or near the NOAEL for systemic effects from repeated dosing. In the P2 generation liver and kidney changes were observed in the P2 males. A NOAEL of approximately 33-76 mg/kg/d (0.06%) was derived with the range being due to the fact received doses differed depending on the period considered. Up to the highest dose tested no overt signs of reproductive toxicity were reported, and no effects were observed on fertility parameters.

Effects on developmental toxicity

Description of key information
Developmental toxicity studies of DIDP conducted at doses of 100, 500, and 1000 mg/kg provided evidence of slight and transient signs of maternal toxicity at 1,000 mg/kg/d (significant reversible decrease of body weight gain and food consumption) suggesting a conservative NOAEL of 500 mg/kg/d for maternal toxicity. The only statistically significant changes were skeletal variations (supernumerary cervical and rudimentary lumbar ribs) on a per litter basis at the high dose. Rudimentary ribs are a common finding in rat fetuses and should not be regarded as associated with malformations, but may only be related to transient maternal stress. It should be noted that supernumerary ribs were located in the cervical region which is less common (Waterman et al., 1999), but the biological significance of cervical supernumerary ribs remains uncertain. A NOAEL of 500 mg/kg/d may be assumed for skeletal variations.
Effect on developmental toxicity: via oral route
Dose descriptor:
500 mg/kg bw/day
Additional information

Skeletal variations were observed in the developmental studies at 1,000 mg/kg/d concurrently with slight signs of maternal toxicity and lead to a NOAEL of 500 mg/kg/d (European Commission, 2003). The decrease in survival indices mainly in F2 (day 1 and day 4) in the two-generation study as well as skeletal variations in developmental studies are not sufficient to justify classification for fertility, developmental or lactational effects (ECBI/51/00 - Rev.2 23.11.00). This opinion on fertility, developmental and lactational effects was concluded during the May 2000 meeting of the EU CMR and Pesticides Working Groups on Classification and Labelling (European Commission Working Group, 2000a; 2000b).

Justification for classification or non-classification

No classification as a repeated dose toxin is indicated according to the general classification and labeling requirements for dangerous substances and preparations (Directive 67-548-EEC) or the classification, labeling and packaging (CLP) regulation (EC) No 1272/2008.

Additional information