5. What daily exposure levels to phthalates are considered safe?
The SCHER opinion states:
3.4.2 Phthalate toxicity
The critical toxic effects of DEHP relate to reproduction. A 3-generation reproductive study in which DEHP was administered to rats in the diet gave a NOAEL of 4.8 mg/kg bw/day for testicular and developmental toxicity. A TDI of 0.05 mg/kg bw/day, based on this NOAEL, and the default uncertainty factor of 100, was established for DEHP by EFSA and is supported by SCHER.
Recent studies show that peroxisome proliferation may not represent a relevant mode-of- action for DEHP induced liver tumours, since peroxisome proliferator-activated receptor (PPAR) knockout mice also showed tumour induction after lifetime administration of DEHP. Alternative mechanisms for liver tumour induction have been outlined in the MAK- justification for DEHP with the conclusion that genotoxic events very unlikely are involved in the tumourigenicity of DEHP (MAK, 2002). At the DEHP-doses observed in humans, DEHP-exposure therefore does not represent a relevant cancer risk to humans. Therefore, the tumour induction by high doses of DEHP in rodents is not considered as an endpoint relevant for risk characterisation (MAK, 2002).
Di-isononyl phthalate (DINP) is a mixture of esters of o-phthalic acid with C8-C10 (C9 rich) alkyl alcohols. These alcohols can be obtained by different processes, yielding different ratios of chain length and branching distribution, which result in different DINP types. Presently, 2 different DINP types are used (CAS 68515-48-0 and CAS 28553-12-0). These DINP mixtures are considered together. Previously, a group TDI of 0.15 mg/kg bw/day (with di-isodecyl phthalate – (DINP + DIDP), was based on peroxisome proliferation in rodent liver, but peroxisome proliferation in rodents is not relevant for human risk assessment. In a 2-generation reproductive toxicity study with DINP, NOAELs of 500 mg/kg bw/day and 622 mg/kg bw/day were established for minor developmental effects and decreases in live birth and survival indices, respectively. The pivotal toxicological effects for DINP are hepatic changes. Using the NOAEL of 15 mg/kg bw/day for non-peroxisome proliferation-related chronic hepatic and renal effects and an uncertainty factor of 100, a TDI of 0.15 mg/kg bw/day was derived.
There also are two different di-isodecyl phthalate (DIDP) products with different CAS numbers (68515-49-1 and 26761-40-0). The two phthalates are considered fully interchangeable and are considered together. There is no indication of reproductive organ effects for DIDP evidenced in repeated dose toxicity studies. In a 13-week oral study in dogs, a NOAEL of 15 mg/kg bw/day could be derived. Based on the liver effects in dogs (considered as a non-sensitive species to peroxisome proliferation) with a NOAEL of 15 mg/kg bw/day, a lowest overall NOAEL of 15 mg/kg bw/day could be considered. No TDI for DIDP is available, but low concern can be derived when exposures are below 0.15 mg/kg bw/day (MOE > 100).
The results of several acute- and intermediate-duration oral studies in rodents indicate that the potential of di-n-octyl phthalate (DNOP) to cause adverse reproductive and developmental effects is low. Unlike other phthalate esters such as DEHP, DNOP does not appear to affect testicular function or morphology (Hardin et al. 1987; Heindel et al. 1989). Observed hepatic effects in intermediate duration studies consisted of a statistically significant increase in hepatic ethoxyresorufin-0-deethylase activity andhistological changes in hepatic architecture. Thyroid toxicity was also noted at this concentration. No chronic oral TDI is available for DNOP.
A NOAEL of benzylbutyl phthalate (BBP) of 20 mg/kg bw/day for developmental effects was observed in a 2-generation study in rats (Nagao et al., 2000) based on a decreased body weight in offspring at the LOAEL of 100 mg/kg bw/day. The NOAEL for effects on reproductive organs was 100 mg/kg bw/day. A NOAEL of 50 mg/kg bw/day for developmental effects was also observed in a second 2-generation study (Tyl et al., 2004). Therefore, a TDI of 0.5 mg/kg bw/day based on a reduction of anogenital distance in the F1 and F2 generation with a LOAEL of 250 mg/kg bw/day was derived for BBP.
The male reproductive system is also a main target of di-n-butyl phthalate (DNBP) toxicity with a NOAEL (50 mg/kg) and a LOAEL (100 mg/kg) for DNBP-effects on male reproductive development in the F1 generation (Mylchreest et al. 2000). In a 2- generation rat study, a LOAEL of 52 mg/kg for embryotoxicity in the F2-generation was observed.
A developmental toxicity study in the rat (Lee et al., 2004), with dietary exposure to DNBP during the period from late gestation (gestational day 15) to the end of lactation (Postnatal day 21), showed effects on the development of male and female offspring at lower doses than when examining the development of reproductive tissues at various postnatal ages in detail. Reduction of testicular spermatocyte development and mammary gland changes in both sexes of offspring were seen at PND 21 at doses of app. 1.5-3.0 mg/kg bw/day and above, with dose-dependent increased incidence and/or severity. Loss of germ cell development was no longer present at 1.5 to 3 mg/kg bw/day at postnatal week 11, but showed a dose-dependent increase in a dose range from 14-28 mg/kg bw/day to 712-1372 mg/kg bw/day. Based on loss of germ cell development and mammary gland changes at 1.5 to 3 mg/kg bw/day in the diet (the lowest tested dose), a NOAEL could not be established. EFSA has derived a TDI of 0.01 mg/kg bw/day using a high safety factor.
DIBP, after giving rats high doses of 600 mg/kg bw/day day from gestational day (GD) 7 to either GD 19 or GD 20/21, induced testicular and developmental effects similar to DBP and DEHP. However, since no dose response was assessed, further developmental and postnatal studies are needed to characterize the reproductive effects of DIBP and derive a NOAEL for risk assessment (Borch et al. 2006). A TDI therefore has not been defined.