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Carcinogenicity

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Description of key information

The available data and available weight of evidence demonstrate that the C9-C14 aliphatic, <2% aromatics are highly unlikely to be carcinogenic and are not classifiable as carcinogens.  

Key value for chemical safety assessment

Additional information

The weight of evidence is derived from study records reported for the C9-C14 aliphatic, <2% aromatics. C9-C14 aliphatic, <2% aromatics are not genotoxic and are not classifiable as mutagens based upon the results of reliablein vitroandin vivostudies. In bacterial reverse mutation studies, the C9-C14 aliphatic, <2% aromatics were not mutagenic in the presence or absence of metabolic activation (IUCLID section 7.6.1). In mammalian cellsin vitro, and in ratsin vivothere were no mutagenic, clastenogenic or aneugenic effects reported in read-across from studies on C9-C14 aliphatic, <2% aromatics: a negative chromosome aberration (Human Periferal Lymphocyte Chromosomal Aberration Test, Chinese Hamster Ovary Sister Chromatid Exchange Assay); and anin vivoinhalation exposure bone marrow chromosomal aberration study and micronucleus test (IUCLID sections 7.6.1 and 7.6.2).

Stoddard solvent IIC – There was no evidence of carcinogenic activity of Stoddard solvent IIC 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/m3male 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 relevance of the pheochromocytoma in humans is equivocal at best. The increased incidences of adrenal pheochromocytoma that occurred in male rats are rarely observed in humans and other animals (Nyska et al., 1999; Hartwig 2009). Pheochromocytomas that occur in animals by secondary mechanisms are not considered to be releant to humans or should be used as a basis for classification (Hartwig, 2009). 

Decalin - There was no evidence of carcinogenic activity of decalin in female F344/N rats or in B6C3F1 male mice exposed to 400 ppm. 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.

Skin tumor promotion - Evidence of increased tumor promotion was observed in the skin of mice treated with PMA (positive control, 29/30) or with 100% v/v normal paraffin test material (15/30). The skin tumors were predominately of epithelial origin and were papillomas, keratoacanthomas and squamous-cell carcinomas. These tumors were generally well- differentiated with the exception of a few of the squamous-cell carcinomas which were anaplastic with some spindle-cell formations. Early studies that examine structurally analogous test materials, kerosene and jet fuels, were noted to promoter dermal tumors in mice. It was noted that tumor development was associated with moderate to severe skin irritation. Since the materials contain very low or no polycyclic aromatic components (PAC’s), it was suggested that tumor development may have resulted from chronic skin irritation. Therefore, a series of studies were conducted to examine the effect of skin irritation on the tumorigenicity of kerosene. In studies conducted by the American Petroleum Institute (API) and CONCAWE, the absence of skin irritation resulted in no statistically significant differences in tumorigenicity between control animals and animals treated with the test materials (Nessel, Craig S., James J. Freeman, Richard C. Forgash, and Richard H. McKee 1999; CONCAWE 1991)). Accordingly, it was concluded that the tumors were the consequence of repeated dermal irritation and not kerosene or jet fuel per se.

 

Similar findings were noted in the tests of normal paraffins. The tumor promotion activity was greatest in the treated groups displaying the highest degree of dermal irritation, i.e. 100% v/v normal paraffin test material. A low tumor incidence occurred in the groups receiving 50% or 28.6% /v normal paraffin test material (not statistically different from the control group), which correlated to low degrees of dermal irritation. The skin tumor promoting properties of these substances are considered related to repeated dermal irritation (Nessel, 1999).

Hartwig, Greim H, A Reuter, U Richter-Reichhelm HB ,Thielmann HW. Chemically induced pheochromocytomas in rats: mechanisms and relevance for human risk assessment. Crit Rev Toxicol 2009;39(8):695-718.

Nessel, Craig S., James J. Freeman, Richard C. Forgash, and Richard H. McKee. 1999. The Role of Dermal Irritation in the Skin Tumor Promoting Activity of Petroleum Middle Distillates. Toxicological Sciences 49, 48-55 (1999).

Nyska, A., Haseman, J.K., Hailey, J.R., Smetana, S., and Maronpot, R.R. (1999). The association between severe nephropathy and pheochromocytoma in the male F344 rat - the National Toxicology Program experience. Toxicol. Pathol. 27, 456-462.

Justification for classification or non-classification

These findings do not warrant the classification of C9-C14 aliphatic, <2% aromatic hydrocarbons as a carcinogen under the Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.