Application of the threshold of toxicological concern approach to ingredients in personal and household care products.

In the absence of chemical-specific data, the threshold of toxicological concern (TTC) provides a method to determine a conservative estimate of a chronic oral exposure below which there is a very low probability of risk. The TTC approach was originally developed to support exposures to indirect food additives and was based on linear low-dose risk estimates to assure protection in the event that the chemical was later determined to be a carcinogen. Subsequently, TTC values based on noncancer endpoints were proposed for chemicals without structural alerts for genotoxicity. The original database supporting the TTC values for noncancer endpoints includes >600 structurally diverse chemicals. The objectives of this work were to evaluate the applicability of the TTC database to ingredients used in consumer products based on a comparison of the diversity of chemical structures with those in the original TTC database and to confirm that the range of NOELs for these ingredients is consistent with the range of NOELs in the original database. The results show good coverage of the product ingredient structures and confirm that the NOELs for the ingredient chemicals are similar in range to the original dataset, supporting the use of the TTC for ingredients in consumer products.

An updated evaluation of the carcinogenic potential of 1,4-dioxane.

This paper presents a critical review of the information pertaining to the potential carcinogenicity of 1,4-dioxane. The primary target organs for cancer via the oral route are the liver and the nasal cavity, however, the relevance of nasal cavity tumors to human exposures has been questioned. Liver tumors were accompanied by degenerative changes and appear only to occur at high doses where clearance mechanisms are saturated and liver toxicity is significant. Genetic toxicity data suggests that 1,4-dioxane is a very weak genotoxin. An increase in hepatocyte cell proliferation was reported and 1,4-dioxane was shown to act as a tumor promoter in rat liver and mouse skin carcinogenicity assays. Two reports are available from the literature regarding physiologically based pharmacokinetic (PBPK) modeling approaches to assess the risk of liver cancer for 1,4-dioxane. A comparison of cancer risk estimates from linear and nonlinear models in the presence or absence of PBPK modeling suggests that USEPAs current cancer slope factor significantly overestimates the potential cancer risk from 1,4-dioxane. This critical review of the scientific literature indicates that a formal reevaluation of the carcinogenic potency of 1,4-dioxane is warranted.