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

More documents

Recommendations

Info

In a similar assay, groups of ten ovariectomised female Sprague-Dawleyrats were dosed once daily for three consecutive days with ethanol/oilsuspensions of nonylphenol at levels of 0 (vehicle control), 30, 100 and300 mg/kg/day (Chemical Manufacturers Association 1997b - quoted inEU-RAR 1998). Positive control groups received ethynyloestradiol inethanol at levels of 10, 30 and 80 µg/kg/day according to the same dosingregimen. The route of administration was not stated. One day after thefinal dose the females were killed and the uterus was removed from eachanimal and weighed. Uterus weights at 300 mg/kg/day were significantlyincreased (1.5-fold) in comparison with the vehicle control group. Aslightly greater response (a 2-fold increase) was seen in the 30 and 80µg/kg/day positive control groups.In another uterotrophic assay, groups of three immature (aged 20-21days) Sprague-Dawley rats each received a single intraperitoneal injectionof nonylphenol at dose levels of 0, 1, 2 or 4 mg/animal (approximately25, 50 or 100 mg/kg) (Lee and Lee 1996). Oestradiol, administeredby the same route, served as a positive control. The animals were killed24 hours later and each uterus was removed, weighed and analysed forprotein and DNA content and peroxidase (thought to be a uterotrophicmarker enzyme) activity. There was a dose-dependent and statisticallysignificantly increase in uterine weight at all levels, with associated increasesin uterine protein and DNA content and uterine peroxidase activity.In further experiments, the uterotrophic activity of nonylphenol wasfound to be blocked by the co-administration ICI 182,780, an oestrogenantagonist, providing evidence that the effect of nonylphenol is mediatedthrough the oestrogen receptor. Also, the potency was compared withoestradiol; in this assay oestradiol was found to be about 1000 - 2000times more potent than nonylphenol.Overall, these in vitro and in vivo studies show that nonylphenol hasoestrogenic activity of a potency that is between 3 to 6 orders of magnitudeless than that of oestradiol. The oestrogenic effect of NP appears tobe mediated through the oestrogen receptor since its action can beblocked by oestrogen antagonists. The structure of the aliphatic sidechain(nonyl) is believed to be highly important for oestrogenic activity.Linear NP is not oestrogenic, while one or more of the branched-chainisomers may be able to mimic oestradiol in binding to the oestrogen receptor.(Odum et al. 1997).NP oestrogenic effect in 28- and 90-day studyIn the 28-day and 90-day studies of NP described in section 4.2 sexualorgan morphology, oestrous cycle pattern, and spermatogenesis were notfound to be affected by treatment at any dose level. In the 90-day studythe absolute, but not relative, ovary weight in the highest dose group wasslightly decreased without accompanying histopathological changes.NIEHS three-generation study of NPThe effects of nonylphenol on fertility and reproductive performancehave been investigated in a comprehensive, good-quality multigenerationstudy, conducted in compliance with GLP (NIEHS 1998 - quoted in EU-RAR 1998). The overall study design was based on the OECD two-26
generation reproduction toxicity study guideline, with an extension toinclude the production of an F3 generation. This study has previouslybeen described in the present report in relation to long term toxicity.Groups of thirty male and thirty female Sprague-Dawley rats were exposedto nonylphenol via incorporation in the diet at concentrations of 0(control) 200, 650 or 2000 ppm over three generations. Calculatednonylphenol intakes were, respectively, about 0, 15, 50 and 160mg/kg/day during non-reproductive phases and rising to around 0, 30,100 and 300 mg/kg/day during lactation. Nonylphenol exposure commencedfor the F0 generation at about 7 weeks of age and continued untilstudy termination when the F3 generation were about 8 weeks old. F0animals were mated (one male with one female) within each dose groupto produce the F1 generation, selected F1 animals were similarly matedto produce the F2 generation and selected F2 animals were mated to producethe F3 generation. For the F0 generation and retained F1, F2 and F3animals, clinical signs of toxicity, bodyweights and food consumptionwere reported. Oestrous cycles were monitored prior to mating. At thenecropsy of adult animals, sperm samples were taken (but not from theF3 generation) for analysis of density, motility (using a computer assistedsperm motion analysis system, only conducted on control and high dosegroup males) and morphology, a number of organs were weighed andselected organs were sampled for histopathology. Additionally, testicularspermatid counts were made. Parameters assessed in the young offspringincluded litter size, bodyweights, survival, gross appearance, ano-genitaldistance, sexual development and, for animals killed at weaning, grossappearance of organs at necropsy and reproductive organ weights. Therewas evidence of general toxicity in adults of all generations, seen as areduction in bodyweight gain at 50 and 160 mg/kg/day and histopathologicalchanges in the kidneys at all dose levels. Considering the reproduction-relatedparameters, there were no adverse effects on fertility ormating performance. However, several other parameters were affected.Oestrous cycle length was increased by about 15% in the F1 and F2 femalesat 160 mg/kg/day, in comparison with controls. The timing ofvaginal opening was accelerated by 1.5-7 days at 50 mg/kg/day and by 3-6 days at 160 mg/kg/day in females of the F1, F2 and F3 generations.Also, absolute ovarian weights were decreased at 50 mg/kg/day in the F2generation and at 160 mg/kg/day in the F1, F2 and F3 generations; however,no effect on ovarian weight was apparent in the F1 and F3 generationswhen analysed as an organ-to-bodyweight ratio. In males, changesin sperm endpoints were seen only in the F2 generation; epididymalsperm density was decreased by about 10% at 50 and 160 mg/kg/day andspermatid count was decreased by a similar amount at 160 mg/kg/day.However, there may have been methodological problems with the epididymalsperm density measurements, because the density in all F2 generationgroups, including controls, was considerably greater (by about25-40%) than reported for the F0 and F1 generation males; the age ofeach generation was similar at necropsy, so major differences in thesperm density would not be expected.NP effects on the foetusIn a study performed according to OECD guideline 414, of GLP quality,female rats were administered corn oil solutions of NP (presumably bygavage) at dose levels of 0, 75, 150, and 300 mg/kg/day from gestationalday 6 to 15. Females were killed on day 20 of gestation, and foetuses27
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: Dermal contactNo data have been fou
Page 30 and 31: 5 Regulations, limit valuesAmbient
Page 32 and 33: units is low, as LD 50 values varyi
Page 34 and 35: 7 EvaluationA study in humans invol
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

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?