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Both in vivo studies conducted by the NTP USA are still under discussion. Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity  of Anthraquinone in M/F F344/N rats and in M/F B6C3F1 mice (The National Toxicology Program, NIH Publication No. 05-3953, 2005).
According to the results of the NTP USA studies, the Anthraquinone should be considered as carcinogen, category 2 and assigned the symbol T and the risk phrase R45. However, the available data raise concern and further experiments are necessary (The Draft Assessment Report – Anthraquinone, Belgium, 2006).
According to the published data by Butterworth (2004), the presence of 9-nitroanthracene used in the NTP cancer bioassays was responsible for the carcinogenic effects as a result of its genotoxic activity; however, the evidence for this was only indirect (The Draft Assessment Report – Anthraquinone, Belgium, 2006).
Dr. J. A. Cook in his Letter from April 7, 2010 (attached to this CSR, Annex 2) strongly suggested that Anthraquinone, CAS #84-65-1 was a non-carcinogen, mainly due to the fact that the test article yielding positive results in the NTP Report contained 9-nitroanthracene contamination which confounded interpretation of the studies, while pure Anthraquinone was negative. Furthermore, Anthraquinone was predicted to be a non-carcinogen in most of the mechanism-mediated and structure-activity relationship evaluations, and results of in vitro and in vivo studies were inconclusive.
Hence, based on the Letter of Dr. Cook, based on the ongoing discussions, recent knowledge, uncertainties involved in the interpretation of the test results, and considering controversial data available from in vitro and in vivo carcinogenicity studies, Anthraquinone is considered as a non-carcinogenic substance.
The weight of evidence determination that Anthraquinone is not carcinogen was prepared by SIEF member Chemical Products Corporation (see attachement).

Key value for chemical safety assessment

Additional information

The registrant did not provide carcinogenicity studies.The studies from NTP Technical report on the toxicology and carcinogenesis studies of Anthraquinone (CAS No.84-65-1) in F344/N rats and B6C3F1 mice (feed studies) (The National Toxicology Program, NIH Publication No. 05-3953, 2005) were included in this report.

Groups of 50 M and 50 F F344/N rats were fed diets containing 469, 938, 1,875, or 3,750 ppm for 105 weeks (2 year). Survival of all M was similar, but survival of exposed F was greater than that of the controls. Mean body weights of exposed M during the latter part of the study and mean body weights of exposed F throughout most of the study were less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) occurred with positive trends and were increased in all exposed F. The incidences of renal tubule adenoma in all exposed M exceeded the historical control range, and the incidence was significantly increased in the 938 ppm. Increased incidences of nonneoplastic lesions of the kidney associated with Anthraquinone exposure included hyaline droplet accumulation, pigmentation, and mineralization in the renal medulla and transitional epithelial hyperplasia in M/F and renal tubule hyperplasia in F. Incidences of nephropathy were increased in F, and severities of nephropathy were increased in M. At 3 months, the concentration of α2u-globulin in the kidney of 3,750 ppm M was greater than that in the control group. The incidence of urinary bladder transitional epithelial papilloma was significantly greater in 1,875 ppm M than in the control group, and the incidences in groups M exposed to 938 ppm or greater exceeded the historical control range. There were positive trends in the incidences of transitional epithelial hyperplasia and papilloma or carcinoma (combined) of the urinary bladder in F. The incidences of hepatocellular adenoma or carcinoma (combined) were slightly increased in exposed M/F; the incidences in groups of F exposed to 938 ppm or greater exceeded the historical control range. The incidences of several nonneoplastic follicular cell hypertrophy was present in all M/F exposed to 3,750 ppm or greater. Incidences of inflammation and transitional cell hyperplasia in the urinary bladder of 30,000 ppm F were greater than those in the controls (The National Toxicology Program,NIH Publication No. 05-3953,2005).

Groups of 50 M and 50 F B6C3F1 mice were fed diets containing 0, 833, 2,500, or 7,500 ppm (equivalent to average daily doses of approximately 90, 265, or 825 mg/kg to M and 80, 235, or 745 mg/kg to F) for 105 weeks. Survival was less for 7,500 ppm M than for the control group. Mean body weights of 7,500 ppm M during the last 6 months of the study and mean body weights of 7,500 ppm F at the end of the study were less than those of the control groups. Feed consumption was similar in all groups of M/F. Incidences of hepatocellular neoplasms (including multiple neoplasms) increased with a positive trend in M/F, and the incidences were increased in all exposed groups. Incidences of hepatoblastoma were significantly increased in males exposed to 2,500 or 7,500 ppm. The incidences of several nonneoplastic lesions of the liver were increased in exposed mice. There was a marginal increase in the incidences of neoplasms of thyroid gland follicular cells in M/F. Incidences of intracytoplasmic inclusion body of the urinary bladder and hematopoietic cell proliferation of the spleen in M/F and thyroid gland follicular cell hyperplasia and kidney pigmentation in M were greater in exposed groups than in the controls (The National Toxicology Program,NIH Publication No. 05-3953,2005).

The final reports of the 2 carcinogenicity studies (above), conducted by the NTP USA, with Anthraquinone in rats and mice are still under discussion. According to the published data by Butterworth (2004), the presence of 9-nitroanthracene used in the NTP cancer bioassays was responsible for the carcinogenic effects as a result of its genotoxic activity; the evidence for this is only indirect (The Draft Assessment Report – Anthraquinone, Belgium, 2006).

Although the genotoxic activity was demonstrated, the carcinogenicity of 9-nitroanthracene was not demonstrated or published. The positive results reported with S. typhimurium does not mean that the chemical possess carcinogenic activity as only a correlation exists between the results of genotoxicity assays and rodent carcinogenicity for some chemicals, but not for all chemicals. It is also not known whether the relatively low levels of 9-nitroanthracene measured in the NTP material, if this compound is carcinogenic, would be potent enough to cause the reported tumors (The Draft Assessment Report – Anthraquinone, Belgium, 2006).

Justification for classification or non-classification

According to the EC criteria for classification and labelling requirements for dangerous substances and mixtures the test substance Anthraquinone does not have to be classified for carcinogenicity.