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Carcinogenicity

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Description of key information

A carcinogenicity weight of evidence assessment of Alchisor TAL 123 is composed of an evaluation of evidence from constituents of Alchsior TAL 123. On the basis of this weight of evidence assessment Alchisor TAL 123 is determined to lack a carcinogenic potential.

Key value for chemical safety assessment

Additional information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol. As defined in the Read-across Justification Document in section 13, data provided for these constituents when considered together is representative of Alchisor TAL 123 and suitable for assessment purposes. Study data for each constituent has been evaluated. In a protective approach the most sensitive study result from across the three constituents has been identified and used to address the hazard endpoint in question.

On the basis of weight of evidence and in accordance with column 2 of REACH Annex X, further specific carcinogenicity testing of Alchisor TAL 123 constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol is not required. Constituents of Alchisor TAL 123 are not classified as mutagen category 3 and there is no evidence from repeat dose toxicity studies that they have any potential to cause hyperplasia and/or pre-neoplastic lesions.

Weight of evidence across the constituents of Alchisor TAL 123 constitutes a range of supporting reports. In the case of the C9-C14 aliphatics (2-25% aromatics), a weight or evidence is composed of specific constituent category study reports, and read across from the categories;

·        C9-C14 aliphatics (2-25% aromatics);

·        C9 aromatics;

·        C10-C12 aromatics;

·        C9-C14 aliphatics (<2% aromatics);

·        Decalin;

Dodecan-1-ol and undecanol-1-ol weight of evidence is composed of study reports from various types of repeated dose studies which do not offer any evidence of treatment-related induction of hyperplasia / pre-neoplastic lesions for 1-dodecanol or structurally related alcohols (though reporting is limited in many cases). Adequate reliable data is available from constituents of Alchisor TAL 123 in support of this weight of evidence argument. Therefore the dataset presents a reliable adequate basis for Alchisor TAL carcinogenicity assessment purposes.

C9-C14 Aliphatics (2-25% aromatics)

C9-C14 aliphatics (2-25% aromatics): In support of the carcinogenicity weight of evidence assessment for the C9-C14 aliphatics (2-25% aromatics) constituent category mutagenicity assays and sub-chronic studies have been evaluated. In bacterial reverse mutation tests, C9-C14 aliphatics (2-25% aromatics) were not mutagenic in the presence or absence of metabolic activation (OECD TG 471). Likewise, there were no mutagenic effects reported in a read-across in vitro mammalian gene mutation test (mouse lymphoma L5178Y cells, OECD TG 476). No in vitro chromosomal effects were reported in a human peripheral lymphocyte assay (OECD TG 473). The test substance, C9-C14 aliphatic, 2-25% aromatics, was also non-clastogenic when tested in an in vitro sister chromatid exchange assay in Chinese hamster ovary cells (OECD TG 479). There were no chromosomal aberrations noted in an in vivo mammalian bone marrow chromosome aberration test (mouse, OECD TG 475) or in a mammalian erythrocyte micronucleus test (mouse, OECD TG 474). These data demonstrate that these substances are not categorisable mutagens either in vitro or in vivo. Furthermore, there was no evidence of hyperplastic responses or pre-neoplastic lesions in oral and inhalation sub-chronic studies reported for in the C9-C14 aliphatic (2-25% aromatics).

 

C9 & C10-C12 aromatics: Read across data from; C9 and C10-C12 aromatics, C9-C14 aliphatics, (<2% aromatics) and decalin have been evaluated to further support the carcinogenicity weight of evidence assessment for C9-C14 aliphatics (2-25% aromatics). In bacterial reverse mutation tests, C10-C12 aromatics were not mutagenic in the presence or absence of metabolic activation. Likewise, there were no mutagenic effects reported in a read-across in vitro mammalian gene mutation test (HGPRT forward mutation assay) in the supporting substance, C9 aromatics. No in vitro chromosomal effects were reported in a Chinese hamster ovary assay that examined the C9 aromatics. The test substance, C10-C12 aromatics, was also non-mutagenic when tested in an in vivo mouse bone marrow micronucleus assay. These data demonstrate that these substances are not categorisable mutagens either in vitro or in vivo. Furthermore, there was no evidence of hyperplastic responses or pre-neoplastic lesions in sub-chronic and chronic repeat-dose studies in either the C9 aromatics or the C10-C12 aromatics.

C9-C14 aliphatics, (<2% aromatics): There was no evidence of carcinogenic activity of Stoddard solvent IIC (C9-C14 aliphatics, (<2% aromatics)) in female F344/N rats or in B6C3F1 male mice exposed to 2200 mg/m3. The NTP concluded there was equivocal evidence of carcinogenic activity of Stoddard solvent IIC in female B6C3F1 mice based on increased incidences of hepatocellular adenoma. The NOAEC for male rats was determined to be 138 mg/m3. The incidences of benign pheochromocytoma in 550 and 1100 mg/m3 male rats and benign or malignant pheochromocytoma exceeded the historical chamber control ranges, suggesting that exposure to Stoddard solvent IIC caused the increased incidences of these adrenal medulla neoplasms. The incidence of malignant pheochromocytoma was noted as 1 malignant tumor in control animals and 2 malignant tumors in 1100 mg/m3 male rats. However, the adrenal pheochromocytoma are not considered relevant to humans.The increased incidences of adrenal pheochromocytoma that occurred in male rats are rarely observed in humans and other animals (Nyska et al., 1999).

Decalin: There was no evidence of carcinogenic activity of decalin in female F344/N rats or in B6C3F1 male mice exposed to 400ppm. Male rats exposed to 50 ppm of decalin had higher rates of tumors of the kidney. These male rat kidney tumors appears to have been associated with an alpha-2u-globulin mediated metabolism. This mechanism is specific to male rats and is not relevant to humans. Female mice displayed increases in liver and uterus tumors however, because the highest neoplasm incidence increase occurred in 25 ppm females, there was not a significant response in the 100 ppm group, and there were no supporting increases in neoplasm multiplicity, it was unclear if the increased neoplasm incidences in females were related to decalin. In the absence of an exposure concentration related response in either sex, the hepatocarcinogenic effect of decalin in female mice was considered an equivocal finding.

Dodecan-1-ol

In a reliable supporting study (Ando 1969) the co-carcinogenicity potential of dodecan-1-ol (in addition to C10, C14, C16 and C18 alcohols) was assessed in mice. For 5 days, starting 24hrs after the implantation of ascites tumour cells the mice were exposed to dodecan-1-ol and the 4 additional alcohols at test concentrations of 2.5 and 10 mg/mouse in one test and 2,4 and 8 mg/mouse of C10, C12 and C14 alcohols in a second test. C16 and C18 alcohols were also tested at 2.5 and 10mg/mouse. The study concluded that treatment with dodecan-1-ol extended the survival time of mice implanted intraperitoneally with Ehrlich ascites tumour cells.

In support of the carcinogenicity weight of evidence assessment of dodecan-1-ol a dodecan-1-ol:decalin mixture was used as vehicle in co-carcinogencity study with benzo(a)pyrene. In this limited study, dodecan-1-ol was not a skin carcinogen when applied topically to the skin of mice twice weekly for 100 weeks as a 50:50 mixture with decalin (approximately 800 mg 1-dodecanol/kg bw per application). When applied at various concentrations with benzo(a)pyrene, 1-dodecanol reduced the latent period for development of benzo(a)pyrene-initiated skin tumours in a dose related manner. To further support the weight of evidence carcinogenicity assessment of dodecan-1-ol several other study reports have been evaluated.None of these studies involving dodecan-1-ol indicate any carcinogenic potential; although reporting is limited and the reliability is poor in some of them.

Undecan-1-ol

Undecan-1-ol is not supported by any substance specific carcinogenicity studies. Although Column 2 of REACH Annex X requires a carcinogenicity study (required in Section 8.9.1) if the substance has a wide dispersive use, the weight of evidence across the alcohols category suggests that undecanol is unlikely to be carcinogenic. This is based on a large set of various types of repeated dose studies across the alcohols category which do not offer any evidence of treatment-related induction of hyperplasia / pre-neoplastic lesions for structurally related alcohols (though reporting is limited in many cases). In addition, undecanol does not have any genotoxic effects.

Carcinogenicity and mutagenicity study reports presented for constituents of Alchisor TAL 123 indicate a lack of carcinogenicity potential. Consequently in a weight of evidence carcinogenicity assessment, following the protective approach as detailed above Alchisor TAL 123 is determined to exhibit no carcinogenicity potential.

Justification for classification or non-classification

Constituents of Alchisor TAL 123 have no mutagenic activity in test item specific studies. In addition read across evidence also indicates that constituents pose no likely carcinogenic potential. These findings therefore do not warrant the classification of Alchisor Tal 123 as a carcinogen under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.