Toxicological Evaluation and Limit Values for Nonylphenol, Nonylphenol Ethoxylates, Tricresyl, Phosphates and Benzoic Acid

6. Summary

Description

NP is a clear to pale yellow viscous liquid with a slight phenolic odour.
NPEs vary from liquids to paste-like liquids to waxy solids. Viscosity and water solubility increases with increasing ethylene oxide chain length.

Environment

NP and NPEs do not occur as natural substances.

NP is released to the environment from production and use as a chemical intermediate, in the polymer industry, and as nonylphenol itself. The major part is released to water, while small percentages are released to air and soil. NP is thought to be degraded in air by reaction with photochemically produced hydroxyl radicals.

Human exposure

The routes of human exposure to NP and NPEs are dermal contact and inhalation by workers involved in manufacture and use, dermal and inhalation exposure of consumers from household pesticide products, dermal contact to cleaning products and cosmetics, mucous membrane contact to spermicides; and exposure via the environment through drinking water, air, and food.

Toxicokinetics

After oral administration, absorption of NP in humans may be significant. Limited data indicate that first pass metabolism may account for inactivation by conjugation of a major part of the NP present in blood. The main part of NP and NPE metabolites are believed to be glucuronic acid conjugates, which are excreted via the kidney. No data exist regarding inhalation or dermal exposure, but it is assumed that absorption will occur.

Human toxicity

There are no data on human oral or inhalatory toxicity of NP or NPE.

single exposure

The LC₅₀ of NP and NPE by inhalation is unknown. For NP, no data have been found. NPEs with 4 or 7 ethylene oxide units caused no mortality in concentrations up to 20 mg/l, indicating a low acute toxicity of NPE by inhalation.

Oral LD₅₀ values for NP mostly in the range of 1200 - 2400 mg/kg have been reported indicating a low order of acute oral toxicity of NP. For various NPEs (number of ethylene oxide units 4-10, 12, 13, 15 or 20) oral LD₅₀ values between 1000 and more than 5000 mg/kg have been reported. Acute oral toxicity seems to be independent of NPE ethylene oxide chain length.

A dermal LD₅₀ of 2031 mg/kg NP in rabbits has been reported. The acute dermal toxicity of NPEs with 4, 5, 7, 9,10, 12, 13 and 40 ethylene oxide units is low, as LD₅₀ values varying between 2000 mg/kg and 5-10,000 mg/kg have been reported.

local effects

The sensory irritation potential of nonylphenol has been investigated in mice in a respiratory depression test. At 3636 mg/m³ a mean respiratory rate depression of about 25% was found during exposure. However, at 267 mg/m³ there were no changes in the respiratory rate. These results suggest that nonylphenol can cause mild sensory irritation to the respiratory tract at high exposure levels.

NP is corrosive on contact with skin and is a severe eye irritant. Exposure to the saturated vapour may lead to mild sensory irritation of the respiratory tract.

repeated exposure

In a 28-day study performed according to OECD guideline 407, rats received doses of 0, 25, 100 or 400 mg/kg b.w./day of NP in the diet. In a 90-day study performed according to EPA guidelines and of GLP quality, rats were administered NP in the diet at levels of 0, 15, 50 and 150 mg/kg b.w./day. In both studies reduced body weight, food consumption, and food utilisation was found; while relative kidney and liver weights were increased. In the 90-day study, females showed a slightly decreased ovary weight. In both studies, these biologically and statistically significant adverse effects were found at the highest dose level only. The NOAEL of the 28-day study is thus considered to be 100 mg/kg b.w./day by the rapporteur, while the NOAEL in the 90-day study is considered to be 50 mg/kg b.w./day by the rapporteur.
In a multigeneration study in rats increased incidence of renal tubular degeneration and/or dilatation were found in both sexes and across all generations. There was no dose level without effect. The lowest dose level, 15 mg/kg b.w./day is therefore a LOEL.

For NPEs, quality studies performed between 1959 and 1965 indicate that toxicity depends on ethylene oxide chain length. A collection of 90-day feeding studies in rats with NPEs with 4-40 ethylene oxide units, shows NOAELs ranging between 40 mg and 5 g/kg/day. The lowest toxicity was found for NPEs with ethylene oxide chain lengths of 20 or more. Toxic effects included retarded growth and increased liver weight, for some compounds necrosis of liver cells.
In dogs, similar effects have been found. Dose-response relations seem comparable. However, in this species a specific toxic effect of certain NPEs on the heart has been found, related to ethoxylene oxide chain lengths of 15, 17.5, and 20 (but not for NPEs with chains outside this range). The cardiac effect is focal myocardial necrosis, sometimes lethal. A dose of 1 g/kg/day reliably induced cardiotoxicity. A dose of 40 mg/kg/day was also able to induce the lesion (microscopically detectable lesions only, table 6: NPE with 20 EO). The NOAEL for cardiotoxicity in the dog is not known, nor is the mechanism. Guinea pigs also seem to develop this type of lesion, while cats, rats, and rabbits do not.

NPEs with 4 or 9 ethoxylene oxide units have been administered orally to rats and dogs over periods of 2 years in studies of non-guideline standard. In the dog study, the group size was only 3 of each sex. In rats, reduced weight gain was observed after administration of NPE with 4 EO. In dogs, increased relative liver weight without accompanying histopathological findings, but with elevated serum alkaline phosphatase level was observed. In both rats and dogs, the NOAEL for NPE with 4 ethoxylene oxide units was 40 mg/kg/day. NPE with 9 ethoxylene oxide units did not cause any effects in rats in highest dose administered, 270 mg/kg/day. In dogs, the only effect was an increased relative liver weight without accompanying histopathological findings at the highest dose level, 88 mg/kg/day.

Reproductive and developmental effects

NP has been shown to the effects of oestrogen via activation of the oestrogen receptor. NP has shown oestrogenic effect in fish, daphnids, and in human breast tumour cells. In uterotrophic assays NP has shown oestrogenic effect in immature Wistar rats, in immature Sprague-Dawley rats, and in ovariectomised Sprague-Dawley rats.

In 28-day and 90-day studies of NP, the latter study having special emphasis on reproductive organ function and morphology, sexual organ morphology, oestrous cycle pattern, and spermatogenesis were not found to be affected by treatment. Absolute, but not relative, ovary weight was slightly reduced in the highest dose group in the 90-day study.

A three-generation study has revealed effects on female and male reproductive parameters of NP, without effects on fertility. The NOAEL for reproductive effects in this study was 15 mg/kg/day.

Neither NP nor NPE (9 or 30 ethylene oxide units) induced malformations in rat foetuses exposed during organogenesis.

Genotoxicity

The existing mutagenicity studies of NP are not of sufficient quality to allow a proper evaluation of mutagenic potential. NPEs with 9 or 30 ethylene oxide units were negative in the Ames test.

Carcinogenicity

For NP, no data have been found.

NPEs with 4 or 9 ethylene oxide units have been administered in 2-year studies. However, because of an insufficient number of animals, the studies do not allow a proper evaluation of carcinogenic potential.