Phenol, 4-nonyl-, branched

Specific investigations: other studies

Description of key information

Estrogen-like effect:

The relative estrogenic potency of Nonylphenol was reported in in vitro studies to be 10^3 – 10^6 lower than for estradiol (Soto, 1991; White, 1994; Routledger & Sumpter, 1997; Laws, 2006). Similar results were found in in vivo studies.

In vivo NP was found to be about 1000 - 2000 times less potent than estradiol in an uterotrophic assay (Lee & Lee, 1996). Treatment of female SD rats at dose levels of 100 and 300 mg/kg bw/d for 3 days resulted in 1.2 and 1.5-fold increase in uterine weights compared to the control group. The NOAEL was 30 mg/kg bw/d (CMA 1997). In a similar uterotrophic assay a LOAEL of 47.5 mg/kg bw/day and an NOAEL of 9.5 mg/kg bw/day was reported (ICI, 1996). In a 28 day study according to OECD 407 p-Nonylphenol was administered to 10 SD rats/sex/dose by gavage at dose levels of 0, 10, 50, 250 mg/kg bw/day. A NOAEL of 10 mg/kg bw/day was reported. The LOAEL was 50 mg/kg bw/day (Woo, 2007). According to Yamasaki (2003) NP did not show androgen agonistic or androgen antagonistic effects in a Herschberger assay.

Additional information

NP shows estrogen-like action in several in vitro assays:

The relative estrogenic potency varied in different test systems and is reported to be a factor of 10^-3 – 10^-6 lower than for estradiol. Routledger & Sumpter (1997) reported NP to be 30.000 times less potent in a yeast assay compared to 17ß-estradiol. Soto et al. (1991) found NP at 10 µM eliciting a proliferative response comparable to 30 mM estradiol in an in vitro assay on MCF-7 cells. On a molar basis the estrogenic potency is 3.3 x 10^5 lower than in estradiol. At concentrations of 1 and 0.1 µM the proliferative response produced by NP was similar to that observed in the negative control. In a similar assay White et al. (1994) reported NP at 10 µM eliciting a proliferative response that was concluded to be 1000 times less potent than 17ß-estradiol. No estrogenic activity was detected at NP concentration up to 100 nM. Laws (2006) characterize the estrogen receptor (ER)–binding affinity of Nonylphenol using a rat uterine cytosolic (RUC) ER-competitive binding assay. The inhibitory concentration (IC 50) of NP was 0.3 µM compared to 0.00052 µM for 17ß-estradiol.

NP shows estrogen-like action in several in vivo assays:

In an uterotrophic assay NP was administered to groups of three immature SD rats by a single intraperitoneal injection at dose levels of 0, 1, 2, or 4 mg/animal (Lee & Lee, 1996). A dose-dependent increase in uterine weight was observed at all dose levels, with associated increases in uterine protein and DNA content and uterine peroxidase activity. NP was blocked by co-administration of an estrogen antagonist, providing evidence that the effect of nonylphenol is mediated through the estrogen receptor. The potency of NP was estimated to be 1000 - 2000 times lower compared to 17ß-estradiol.

In another uterotrophic assay (CMA, 1997) 4-Nonylphenol was administered to 10 female SD rats by oral gavage at dose levels of 0, 30, 100 and 300 mg/kg bw/day for 3 days. Treatment with 100 and 300 mg NP/kg bw resulted in uterine weights that were 1.2 and 1.5-fold increased compared to the control group. The NOAEL was 30 mg/kg/d. In a similar assay daily oral administration of NP produced a significant dose related increase in uterine weight in immature female rats at dose levels of 47.5 mg/kg and above when applied by gavage to 6 immature female Alpk:APfSD (Wistar-derived) rats/dose for three consecutive days. The NOAEL was 9.5 mg/kg/d.

In a subacute toxicity 28 d study p-NP was administered to 10 SD rats/sex/dose by gavage at 0, 10, 50, 250 mg/kg bw/day. A NOAEL of 10 mg/kg bw/day was estimated. The LOAEL was 50 mg/kg bw/day based on alteration of glucose and inorganic phosphates levels in females, increase of thyroid weight in males and increase of serum LH in female. At a dose level of 250 mg/kg bw/day: Hepatic and renal toxicity was evident in both sexes with increase of relative liver and kidney weights as well as histopathological changes, such as centrilobular liver cell hypertrophy and a variety of renal tubular lesions, and alteration of serum biochemical parameters. Three females died or became moribund during the experiment at this dose level. Effects on the endocrine system were evident at the same dose level as a decrease in both absolute and relative weights of seminal vesicles and ventral prostate in males; increase in both absolute and relative adrenal weights in females; irregular estrous cyclicity and vaginal mucosal hyperplasia in females (Woo, 2007). Yamasaki (2003) reported that NP does not show androgen or androgen antagonistic effects in an Herschberger assay.

Conclusion:

NP shows estrogen-like action in several in vitro and vivo assays. However, while substances may have the potential to interact with the endocrine system, they do not necessarily adversely affect human or ecosystem health. Only in situations where the endocrine disrupting effect is critical (i.e., is the most potent) in comparison to other toxic hazards, should the endocrine disruption be considered for the hazard and risk assessment. For NP potential estrogenic effects occur only at concentrations above the LOAEL of other endpoints. Hence, this estrogenic effect poses no additional hazard.