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Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
600 mg/kg bw/day
Additional 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 to 0.8% (or approximately 15 to 600 mg/kg/day). 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 (Table 14, Hushka et al., 2001). 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/day). 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. Up to the highest dose tested no overt signs of reproductive toxicity were reported, and no effects were observed on fertility parameters. In the P2 generation liver and kidney changes were observed in the P2 males. A NOAEL of approximately 33 to 76 mg/kg bw/d (0.06%) was derived with the range being due to the fact received doses differed depend...

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:
NOAEL
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

The T criterion includes substances known to impair fertility in humans or cause developmental toxicity in humans (Category 1), substances regarded as if they impair fertility in humans or cause developmental toxicity to humans (Category 2), or substances which cause concern for human fertility or for humans owing to possible developmental toxic effects (Category 3). In each case appropriate animal or other relevant studies are needed to clearly show or support toxic effects. 

Fertility: A 2-generation reproductive toxicity test of DIDP conducted in rats showed there were no changes in reproductive indices (Exxon Biomedical Sciences, 1997 and 2000; key data published in Hushka et al., 2001). Up to the highest dose tested, no overt signs of reproductive toxicity were reported and no effects were observed on fertility parameters.  Additionally, there were no effects on the testis weights from male rats fed DIDP for 21 days and the testicular histology was normal (BIBRA, 1986). Accordingly, the overall conclusion from these studies was that DIDP has no effect on fertility and does not meet the criterion for T. 

Developmental toxicity: DIDP did produce a developmental effect in the 2-generation reproductive toxicity studies (Exxon Biomedical Sciences, 1997 and 2000; key data published in Hushka et al., 2001) as evidenced by the decrease in postnatal survival indices which was observed in both two-generation studies leading to the NOAEL of 0.06% (33-76 mg/kg/d). Results from the cross-fostering and switched diet satellite groups indicate that lactation exposure may contribute to the toxicity of DIDP (EU RAR on DIDP, 2006). The results of a developmental toxicity study in rats (Waterman et al., 1999) indicate that DIDP did not induce severe developmental effects. Skeletal variations were observed at 1,000 mg/kg/d concurrently with slight signs of maternal toxicity which led to a NOAEL of 500 mg/kg/d (EU RAR on DIDP, 2006).

See section 5.9 for additional details from reproductive and developmental toxicity studies.

The decreases 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 severe enough to justify a classification (EU RAR on DIDP (2006)) indicating that DIDP does not meet the criterion for T based on reproductive toxicity. This opinion was concluded during the May 2000 meeting of the EU CMR and Pesticides Working Groups on Classification and Labeling for adverse effects on development (ECBI/56/02 Add. 12, Rev. 6, Table 1c).