Toxicological Evaluation and Limit Values for ... - MiljÃ¸styrelsen

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7 EvaluationA study in humans involving two volunteers provides evidence thatnonylphenol is rapidly absorbed from the gastrointestinal tract in humans.Also, the fact that only a small proportion of the dose was recoveredin faeces within 56 hours suggests that almost complete absorptionof a dose had occurred. Following oral administration, most of the nonylphenolwas present in the blood as glucuronide or sulphate conjugates, incontrast to the findings for intravenous administration where similar proportionsof unconjugated and conjugated nonylphenol were detected;these findings are indicative of extensive first pass metabolism. First passmetabolism does not occur when the route of exposure is inhalation.Therefore, an inhalatory dose of NP may be more toxic than the samedose administered orally.No data have been found which describe the health effects of NP orNPEs in humans after oral ingestion or exposure via inhalation.The systemic toxicity of NP and NPE by inhalation is unknown. Datafrom a mouse study suggest that NP can cause mild sensory irritation tothe respiratory tract at high exposure levels. At a vapour concentration of267 mg/m 3 there was no effect.The acute oral toxicity of NP and NPE is low.NP has not been tested for mutagenicity in a study of good quality. Nodata regarding the carcinogenicity of NP have been found. NPEs with 9or 30 ethylene oxide units were negative in the Ames test. Two-yearfeeding studies showed no tumourigenic effects of NPEs with 4 or 9 ethyleneoxide units, however, the studies did not include a sufficient numberof test animals and are for this reason inconclusive.NonylphenolA 28-day study NOAEL of 100 mg/kg b.w./day for NP, and a 90-daystudy NOAEL of 50 mg/kg b.w./day for NP have been determined instudies of good quality. The results of the 28-day study and the 90-daystudy are in agreement with each other. In a multigeneration study, alsoof good quality, increased incidence of renal tubular degeneration and/ordilatation were found. There was no dose level without effect. It is difficultto decide for certain whether or not the kidney effect was related totreatment because these changes were not seen in the 90-day study,which was conducted using the same strain of rats, and because a dosedependenttrend was not apparent in all generations/sexes. The lack ofconcordance between the studies cannot be explained on the basis of aslightly longer exposure period in the multigeneration study because kidneyeffects were seen in the F3 generation which were exposed for only 8weeks, nor solely on the basis of in utero and neonatal exposure becausethe effect also occurred in the F0 generation. Giving special emphasis tothe fact that the increased incidence occurred consistently across all fourgenerations in the multigeneration study, it is considered that this cannotbe dismissed as background variation. The F3 generation showed the34
highest incidence of kidney changes, indicating that the effect may becomemore pronounced after exposure during several generations. Consequently,the conclusion has been drawn from this study that there is aLOEL for repeated exposure of 15 mg/kg/day, based on histopathologicalchanges in the kidneys. Since renal tubular degeneration and/or dilatationare common findings in untreated rats, and as they were not accompaniedby other related signs or symptoms in the affected rats, they are not consideredsigns of severe toxicity by the rapporteur.Alkyl phenols, including NP, have been shown in laboratory studies tomimic the effects of oestrogen in vitro and in vivo.NP has been found positive in the uterotrophic response assay in immatureWistar-derived rats, in immature Sprague-Dawley rats, and in ovariectomisedSprague-Dawley rats. Although the uterotrophic assay is astandard assay for oestrogenic effect, the significance to human health ofoestrogenic effects in this assay has not been established.In the 28-day study, and especially the 90-day study of NP, rather extensiveexaminations of sexual organs were performed. Sexual organ morphology,oestrous cycle pattern, and sperm quality were studied and werefound to be unaffected by treatment. Absolute ovary weight was found tobe slightly decreased in the highest dose group. The relative ovary weightwas not reduced, and histopathological changes of the ovary were notfound. Other targets which may be affected by oestrogen (haemoglobin,red blood cell count, pituitary gland, mammary gland, endometrium)were not affected by NP in this study. It is therefore concluded that, althoughNP may possess oestrogenic activity, it did not affect endpointscommonly associated with oestrogenic activity at the highest dose usedin this study, which was high enough to cause general toxicity in the rats.However, the results of the three-generation study indicate that effects onmale and female reproductive parameters may occur at dose levels above15 mg/kg/day. In females, accelerated sexual maturation, increased oestrouscycle length and reduced ovarian weights were found, while malesexhibited a reduced number of spermatids. The effects were found in oneor more of the three filial generations.NOAEL for NPIn conclusion, for NP a LOAEL of 15 mg/kg/day is set, based on thereproductive/developmental effects seen in the oral three-generationstudy. This dose level is also a LOEL for the kidney effects also identifiedin this study.Nonylphenol ethoxylateFor NPEs, a number of 90-day studies in rats and dogs exist. The studiesare all rather old (reports dated 1959-1965) and probably do not fulfilpresent standards. Histopathology apparently has only been performed inthe highest dose groups, and therefore it is not possible to evaluate thetoxicological significance of increased organ weights of other dosegroups. For this reason, a change in organ weight was regarded as anadverse effect in the absence of histopathological data. NOAELs rangingbetween 40 and 160 mg/kg/day in rats for NPEs with 4-15 ethylene oxideunits have been found. In dogs, 90-day NOELs of 40 mg/kg/day werefound for NPEs with 4, 6, 9, 15, and 20 ethylene oxide units. For NPEswith ethylene oxide chains of 20 or 30, NOAELs of 1000 ->500035
Page 1 and 2: Environmental Project No. 512 2000M
Page 3 and 4: 1 General description1.1 IdentityNo
Page 5 and 6: with varying average lengths of the
Page 7 and 8: 1.4 Environmental occurrenceNP and
Page 9 and 10: 2 Toxicokinetics2.1 Absorption, dis
Page 11 and 12: 3 Human toxicity3.1 Short term toxi
Page 13 and 14: 9 concentrated vapour atambient tem
Page 15 and 16: Table 3. Dermal LD 50 -values in ra
Page 17 and 18: Table 4a Number of animals with his
Page 19 and 20: with 40 ethylene oxide units, no ef
Page 21 and 22: *) In the original report, dose was
Page 23 and 24: Table 7 Results of studies in dogs
Page 25 and 26: Dermal contactNo data have been fou
Page 27 and 28: generation reproduction toxicity st
Page 30 and 31: 5 Regulations, limit valuesAmbient
Page 32 and 33: units is low, as LD 50 values varyi
Page 36 and 37: mg/kg/day were found in rats. In do
Page 38 and 39: = 25 mg/kg soilNPEBased on the TDI
Page 40 and 41: is set at the limit value. A C-valu
Page 42 and 43: Odum J, Lefevre PA, Tittensor S, Pa

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