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Dipentylphthalat
(CAS-Nr.: 131-18-0)

Ausgabe: März 2003
Stand: Oktober 2002

Di-(npentyl)phthalate (DnPP) is a linear phthalic acid ester of medium chain length. Certain products also contain the isopentyl isomer in major amounts and some of the studies described below are based on this mixture. Major toxicological differences are not assumed for the isopentylisomer (diisopentylphthalate; CAS No.: 42925- 80-4) nor for the closely related di-nbutylphthalate (DBP) and di-nhexylphthalate. Where data gaps exist, study results from either compounds may be crossread to DnPP and considered for the assessment of this substance.

Mutagenicity:

No data are available for DnPP itself or its isomers.

On the basis of the structural characteristics and in analogy to the very extensive data base relating to di-nbutylphthalate (DBP; BUa 1987/1993), with regard to this end point, there are no suspicions of DnPP having a genotoxic effect.

Carcinogenicity:

Longterm studies on DnPP are not available.

An increase in liver weights was determined within the framework of a prenatal toxicity study conducted with a mixture of 40% DnPP and DIPP (see below). DnPP is presumably a peroxisome proliferator in the rodent in the same way as DBP (BUa 1987/1993). This type of enzyme induction is associated with a general enlargement of the liver and - at least initially - increased DNa synthesis. In the rat and the mouse, this potentially represents a metabolism situation in which there is a disposition to develop hepatic tumours.

However, there is a great difference in the actual carcinogenicity of the individual peroxisome proliferators. The level of the effect threshold and the extent of liver enlargement, rather than the maximum peroxisome density and enzyme activity in the highdose range, are prognostically meaningful. Various lipidreducing pharmaceutical agents as well as the phthalic acid ester DBP have been examined for this in detail. The phthalic acid esters belong to the weak peroxisome proliferators which means that relatively high doses are required to trigger this effect and carcinogenicity does not show up unless at a low rate and at the end of the animals life span.

Nonrodents are largely resistant to the phenomenon of peroxisome proliferation and its associated effects such as enzyme induction, hepatomegaly and tumour induction (see below). Hamsters exhibit weak effects (Lake et al., 1984). On current view, the species differences are largely attributable to the density and functionality of the peroxisomestimulating (PPARα) receptor, which in the rat and the mouse is expressed to a particularly high degree and in a complete and functionally active form (Ashby et al., 1994; Bentley et al., 1993; Lee et al., 1995; Cattley et al., 1998; Maloney and Waxman, 1999). In these species, stimulation of the receptors leads to a large number of transcriptions or gene expressions and, morphologically, to proliferation of certain cellular organelles (peroxisomes, mitochondria, endoplasmatic reticulum), suppression of apoptosis (Roberts et al., 1998) and an initial (with some substances also continuous) increase in DNa synthesis (Marsman et al., 1988) and mitosis rate after activation of the Kupffer cells (Rose et al., 1997). At all effective doses, the liver is enlarged for a longer period.

Transgenic mice lacking the peroxisomestimulating receptor (PPARα) do not exhibit peroxisome proliferation, hepatomegaly or increased DNa synthesis with di(-2-ethylhexyl)phthalate (DEHP; Ward et al., 1998). Testicular and renal damage was less marked in PPARa deficient mice than in the wild type; this indicates that the species difference was not solely a matter of bioavailability. Furthermore, a highly effective peroxisome proliferator and strong hepatocarcinogen in rats (Wy - 14, 643) did not cause effects in PPARα knockout mice (Peters et al., 1997).

The human liver exhibits 1 - 10 % of the functional PPARα receptor density of mice (Palmer et al., 1998). This is probably the reason for man's lower toxicodynamic sensitivity, which is also expressed in vitro in liver cell cultures (see below). Experience with fibrate therapies over many years has so far not shown a tumorigenic effect in man.

On the basis of experimental and clinical experience, peroxisome proliferators are currently not classified by IARC as being carcinogenic for man (IARC, 1995/1996). This estimation is mainly shared in more recent publications though in a more differentiated manner and the sense of pronounced quantitative differences (Cattley et al., 1998; Doull et al., 1999; Maloney and Waxman, loc. cit.).

In hepatic cell cultures from the rabbit, guinea pig, marmoset and man, no effects could be observed with DEHP or DINP and other peroxisome proliferators or their active metabolites; the activity of the enzymes palmitoyl-CoA-oxidase and carnitine acetyl transferase remained unchanged, there was no influence on spontaneous or TRGF²1- induced apoptosis, on DNa synthesis,²-oxidation or the formation of hydroxylauric acid (Elcombe et al., 1997; Ashby et al., 1994; Butterworth et al., 1989; Dirven et al., 1993; Goll et al., 1999; Hasmall et al., 1999).

Reproductive Toxicity:

Developmental effects:

After oral administration of a mixture of 40% DnPP with 60% diisopentylphthalate to Wistar rats in doses of 40, 200 and 1,000 mg/kg from the 6th - 15th day of pregnancy (8 - 10 animals per group; preparation in olive oil) the following results were obtained:

In the top dose all fetuses were resorbed (100% postimplantation loss). The dams showed on day 20 of pregnancy - i.e. 5 days after the end of the application period - ca. 15 and, resp. 12% increases in relative kidney and liver weights. bodyweight gain, when corrected for uterine weights, was normal, so that all reduction in weight gain was due to fetal losses. Relating the only slight maternal to the severe fetal effects, the fetal toxicity is regarded as specific and selective.

No effects were observed at 200 and 40 mg/kg (Hellwig et al., 1997).

Within the frame of a multigeneration study in CD-1 mice following the "continuous breeding protocol" female animals at concentrations of 2.5% DnPP in the diet (~ 4,790 mg/kg/ day) did not give birth when mated to untreated males. This appears to reflect prenatal toxicity at high doses, since the female sexual organs were histologically not affected (Heindel et al., 1989). Since fertility was already mostly impaired at the lowest dose tested in the main study, i.e. 0.5 % in the diet (ca. 760 mg/kg bw d), it can be assumed that prenatal toxicity was also present in this dose group.

Structurally related materials like di-nbutylphthalate (BUa 1987/1993) and di-nhexylphthalate (Lamb et al., 1987) also show a selective fetal toxicity.

Fertilityreducing effect: