Chlorinated Paraffins

2023-05-29 14:01| 来源: 网络整理| 查看: 265

Cancer

The National Toxicology Program (NTP) has conducted oral carcinogenicity bioassays in both rats and mice administered C10–12, 60% chlorine, and C22–26, 43% chlorine, (NTP 1986a, 1986b). Results of these studies are summarized in Table 19–7.

Evidence of carcinogenicity was observed in F-344/N rats given C10–12, 60% chlorine, by gavage 5 d/wk for 104 wk. Dose-related and statistically significant increases in the incidences of hepatocellular carcinomas and of hepatic carcinomas plus adenomas combined were observed in both males and females. Statistically significant increases in the incidence of mononuclear-cell leukemia occurred in male rats as compared with controls. The incidence of tubular-cell adenomas and adenocarcinomas of the kidney were elevated in male rats, but not significantly. Statistically significant increases in the incidence of thyroid follicular-cell carcinomas plus adenomas combined were observed in female rats. A dose-dependent and statistically significant increase in hepatocellular adenomas and hepatocellular adenomas and carcinomas was observed in B6C3F1 mice given C10–12, 60% chlorine, by gavage for 2 yr (NTP 1986a). Dose-dependent and statistically significant increases in the incidences of alveolar and bronchiolar carcinomas, and thyroid follicular-cell adenomas and carcinomas occurred in male and female mice, respectively.

No tumor types were found to be significantly increased in male F-344/N rats given C22–26, 43% chlorine, by gavage for 5 d/wk for 103 wk. However, the incidence of pheochromocytomas of the adrenal medulla was significantly increased in female rats. A dose-related increase in the incidence of malignant lymphoma occurred in male mice given C22–26, 43% chlorine, at 2,500 or 5,000 mg/kg-d, 5 d/wk for 103 wk (NTP 1986b). The incidence of hepatocellular adenomas and carcinomas combined was elevated in female mice, but not significantly. Survival among females was low among treated and control animals due to a high incidence of utero-ovarian infection and may have decreased the potential of the study to detect treatment-related carcinogenicity (NTP 1986b).

The European Union (EU) is currently evaluating the health risks posed by chlorinated paraffins. At technical meetings on October 1–3, 1996, and February 19–21, 1997, it was agreed by specialized experts representing the Member States that C10–13 chlorinated paraffins are not genotoxic. However, no agreement could be reached regarding the significance of the tumors reported by NTP (1986a) or their relevance to man. In a June 1997 meeting of the Commission Group of Specialized Experts in the fields of Carcinogenicity, Mutagenicity, and Reprotoxicity, it was concluded that no significance could be placed on the slight excess in lung, pancreas, stomach, Hadrian gland tumors, or leukemias reported in NTP (1986a). The Specialized Experts decided that only the observed tumors of the liver, kidney, and thyroid should be considered significant. It was also agreed that the liver and thyroid tumors could be attributed to peroxisomal proliferation which could cause a hormonal imbalance and that humans would be much less sensitive to peroxisome proliferation than rats and mice. No plausible mechanism for the observed kidney tumors was agreed upon, but it was thought that either α2u-globulin accumulation or chronic nephropathy might be contributing factors. In 1998, the EU Scientific Committee for Toxicity, Ecotoxicity, and the Environment generally agreed with the conclusions of the Specialized Experts with the exception of ruling out the significance of the increased incidence of lung tumors in male mice. However, it was felt that this reconsideration does not alter the outcome of the risk characterization for man. The Committee also noted that one cannot totally discount the possibility that liver and thyroid tumors could arise in man following exposure to short-chain chlorinated paraffins, but there would be very large differences in carcinogenic sensitivity between animals and humans in the induction of these tumors. The Commission also in agreed with the use of a NOAEL of 100 mg/kg-d for kidney carcinogenicity in male mice (EUSCTEE 1998).

TABLE 19–6Teratogenicity Studies on Chlorinated Paraffins

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Species, StrainDoses (mg/kg-d)Duration, RouteEffectsReferenceShort-chain chlorinated paraffins C10–13, 58% Cl2 Rat, Charles River100, 500, 2,000d 6−19 of gestation, gavageDams: Eight of 25 pregnant dams from the high-dose group died following administration. Signs of maternal toxicity were observed in both mid- and high-dose groups.Fetuses: Increased number of post-implantation losses, increased number of early and late resorptions, and a decrease in viable fetuses per dam in the high-dose group. Adactyly and/or shortened digits were observed in the high-dose group. No effects were observed at the lowest dose level.Authors interpretations: Digital malformations observed at a dose that produced significant mortality in treated dams cannot be interpreted as a direct teratogenic effect and are more likely to be a secondary response due to maternal toxicity.IRDC 1982, as reviewed by Serrone et al. 1987 (438–016)Rabbit, Dutch Belted10, 30, 100d 6−27 of gestation, gavageEmbryotoxicity was seen in both the mid-dose and the high-dose groups. No effect was observed on the occurrence of malformations at any dose level.IRDC 1982/83, as reviewed by Serrone et al. 1987 (438–031; 037)Medium-chain chlorinated paraffins C14–17, 52% Cl2 Rat, Charles River500, 2,000, 5,000d 6−19 of gestation, gavageDams: Maternal toxicity was observed in the high-dose group.Fetuses: There were no biologically or meaningful relevant statistically significant differences in Caesarean section observations or in the incidence of fetus malformations in litters belonging to the treated groups as compared with corresponding controls.IRDC 1981/83/84, as reviewed by Serrone et al. 1987 (438–017; 034; 047)Rabbit, Dutch Belted10, 30, 100d 6−27 of gestation, gavageDams: No maternal toxicity was observed but body weight losses were observed in the high-dose group dams.Fetuses: There were no biologically meaningful differences in the numbers of litters/fetuses with malformations or in the developmental and genetic variations when the treated groups were compared with controls.IRDC 1982/83, as reviewed by Serrone et al. 1987 (438–020; 032; 036)Long-chain chlorinated paraffins C20–30, 43% Cl2 Rat, Charles River500, 2,000, 5,000d 6−19 of gestation, gavageDams: Maternal toxicity observed in the high-dose group. One female died on d 18 of gestation.Fetuses: No differences in the incidence of fetal malformations were observed when treated groups were compared to controls.IRDC 1981/83, as reviewed by Serrone et al. 1987 (438–015; 033)Rabbit, Dutch Belted500, 2,000, 5,000d 6−27 of gestation, gavageTwo of 12 dams at the high dose and one of the 13 dams at the mid-dose aborted. In the high-dose group, there was a slight increase in mean post-implantation loss and a slight decrease in the mean number of viable fetuses when compared to controls. The data did not indicate a teratogenic response.IRDC 1981, as reviewed by Serrone et al. 1987 (438–018; 030)C22–26, 70% Cl2 Rat, CD500, 2,000, 5,000d 6−19 of gestation, gavageDams: No maternal toxicity was observed in any of the pregnant rats that were given chlorinated paraffin.Fetuses: There were no biologically meaningful differences in the incidence of developmental variations and malformations in the treated groups as compared with controls.IRDC 1983, as reviewed by Serrone et al. 1987 (438–045; 046)Rabbit, Dutch Belted100, 300, 1,000d 6−27 of gestation, gavageDoes: No biologically meaningful differences were observed in maternal appearance, behavior, or body-weight gain.Fetuses: There were no adverse treatment-related differences in Caesarean section observations or in the incidence of fetus malformations in the liters of the treated groups as compared with controls. There was no difference between treated and control fetuses in the occurrence of genetic and developmental variation.IRDC 1981, as reviewed by Serrone et al. 1987 (438–018; 030)TABLE 19–7Carcinogenicity, Studies on Chlorinated Paraffins

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Species, Strain, Sex, NumberDose (mg/kg-d)Duration, RouteResultsReferenceShort-chain chlorinated paraffins C12, 60% Cl2 Rat, F344, M/F, 50/sex/dose0, 312, 625104 wk, gavageTumor incidence: Hepatocellular carcinoma Adenoma+carcinomas Test for trendMales:NTP 1986a00/500/5031210/5013/5062516/4816/48 p

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