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4-Nonylphenol, verzweigt
(CAS-NR.: 84852-15-3)
Nonylphenol
(CAS-NR.: 25154-52-3)

Ausgabe: Mai 2002 / geändert Oktober 2002
Stand: Mai 2002

The following data rely mostly on the EC Risk Assessment Report (EC-RAR) dating from August 1999. All references already cited there are not listed in this document. Only references not or not yet cited in the EC-RAR are listed here.

1 General Informations

"Nonylphenol" is a common name for several isomeric substances of the general chemical formula C₆H₄(OH)C₉H₁₉. Technical Nonylphenol consists mainly of a phenol which is substituted in paraposition with side chains of different degrees of branching. Moreover 4-NP contains 5 % (w/w) of each 2-NP and 2,4-Dinonylphenol. Due to the production process (synthesis of the side chain by polymerisation of propylene) unbranched nonylphenol is formed in small amounts only or even not at all.

Technical 4-NP is a clear or faint yellow viscous liquid with faint phenolic smell. Its physicochemical properties give no basis for safety concerns:

• low vapour pressure (ca. 0.3 Pa at 25°C )
• neither easily flammable nor explosive
• pKa value a little bit higher than for phenol (pKa / phenol 9.9; pKa / NP ca. 10.28).

Technical NP is mainly used for the synthesis of Alkylphenolpolyethoxylates (NPnEO). Unchanged NP is used in small amounts for some special purposes.

2 Classification and Labelling

In the EC-RAR the following classification of NP is proposed:

C; R 34       Xn; R 22

3 Mutagenicity

in vitro

Two Amestests with NP in Salmonella typhimurium Ta 1537, Ta 1538, Ta 98, Ta 100 and E.coli with and without addition of ratliver S9-mix (Hüls 1984; Shimizu et al, 1985) as well as a HPRT-assay in V79 cells (Hüls 1990) yielded negative results.

in vivo

There are two micronucleus assays with different routes of application available in mice, both with negative results:

• a rather new one (performed according to OECD Guideline) with i.p. application of different doses (50, 100 or 300 mg/kg bw; Hüls 1999);
• Another with p.o. application of a rather high dose (500 mg/kg bw; Hüls 1988).

4 Carcinogenicity

There are no carcinogenicity studies available with NP. Due to the negative outcome of genotoxicity tests in vitro and in vivo and due to the fact that NP does not induce constant cellular proliferation there is no experimental data basis indicating a possible carcinogenic activity of NP.

5 Reproductive Toxicity

There is no classification of this toxicological endpoint proposed in the EC-RAR. Nevertheless the rapporteur has added the following remark: "However, it is recognised that this is a borderline decision as there is a degree of coherence across the data which raises concerns for reproductive toxicity, possibly by a mechanism involving endocrine disruption. " Therefore the available data on reproductive toxicity of NP ist presented:

Estrogenic activity

NP showed an estrogenlike action in a several in vitro- and in vivoassays. The relative estrogenic potency varied in the different test systems and was by a factor of 10^-3 - 10^-6 lower than for estradiol.(e.g. in vitro: Routledge & Sumpter 1997; Soto et al 1991; White et al 1994 or in vivo: ICI 1996; Odum et al 1997; CMa 1997b; Lee & Lee 1996).

Fertility

There is a highquality 3-generation feeding study available on rats with application of 4-NP in the feed in concentrations of 0, 200, 650 or 2000 ppm (NTP 1997). The mean 4-NP intake was calculated as 0, 15, 50 and 160 mg/kg/d respectively during the nonreproductive phase; the 4-NP uptake for lactating animals was higher. This study shows that exposure to
> 650 ppm 4-NP during several generations can lead to subtle disturbances in the reproductive system of the progenies. At this dosage there are already histopathological effects at the kidneys of the F0 animals (tubular dilatation or degeneration and cysts) together with an elevated kidney weight.

Females: At 650 ppm the body weight gain of F1 animals (7%) and of F3 animals (10%) is lower in comparison to the controls; at 2000 ppm this occurs in animals of all generations (9 -12%). In the F1 and F2 animals of the 2000 ppm group there were small increases in estrous lengh (14 and 18 %, resp.) and in all three generations the time to the vaginal opening was shorter (by 1.5-7.3 days for 650 ppm and by 2.9-6.0 days for 2000 ppm). The earlier onset of puberty (vaginal opening) is thought to be due to the estrogenic activity of NP but it must not necessarily be interpreted as an adverse effect per se. At 2000 ppm the ovary weights were reduced in all 3 generations (by ca. 12 %); at 650 ppm this occurred in F2 animals only. The ovaries didn't show any histological alterations. Fertility and mating performance were not changed in any of the dosage groups. Males: At 650 ppm the body weight gain of F2 animals was lower (8%) as compared to the controls, at 2000 ppm this was true for all generations (7-9 %). a reduction of sperm density (8-13 %) was detected in the epididymis at 650 and at 2000 ppm. At 2000 ppm the testicular spermatid counts were also decreased (12-13%). Since these effects appeared in the F2-generation only and were not found consistently the relevance of this finding should be interpreted with caution. There were no effects on fertility and mating performance in any dosage group. There are no definite evidences showing that the reported effects on the reproductive system represent secondary effects of the nephrotoxicity of NP. Due to the estrogenic action of NP a specific action of NP on the male reproductive system seems plausible.