Occurrence and dietary exposure to phthalates in the US population - a contextual review.

Esters of 1,2-benzene dicarboxylic acid (or phthalates) are general purpose plasticizers used in multiple polyvinyl chloride (PVC) consumer applications. Some of these plasticizers are permitted for safe use in a narrow subset of food packaging applications by global regulatory agencies, including the US FDA. Several US studies have reported the presence of trace concentrations of phthalates (parts per billion) in the diet. These findings have prompted calls for regulatory action based on the potential for adverse impacts on public health. These claims are misguided. Global food safety regulatory frameworks are designed with the expectation that low concentrations of food contact materials may be present in food. These frameworks include guardrails (in the form of content limits and/or migration limits) to minimize the potential for dietary risk. This concept of exposure and risk is often missing in many studies identifying low concentrations of phthalates in food. Dietary risk assessments, based on total diet studies, have been published by food safety agencies in the EU, Australia, New Zealand, UK, and Canada. Without exception, all risk assessments confirm that concentrations of phthalates in food are low and do not pose a public health concern. In this review, we calculate dietary risk estimates for concentrations of high molecular weight phthalates reported in some US food articles. The results confirm that dietary exposures, even in the most conservative scenarios, are below levels of concern.

The sub-chronic toxicity of a naphthenic hydrocarbon solvent in rats.

Cycloalkanes/naphthenes are constituents of complex hydrocarbon solvents, and hence an understanding of their toxicological profile is critical to establish safe limits for occupational exposures to these solvents. Although naphthenes are structurally related to and share a common metabolic fate with the straight and branched chain analogues, some toxicokinetic differences have been noted. The acute central nervous system response to volatile naphthenes in rodents has been shown to be slightly different compared to other alkane analogues. To determine whether these differences may extend to systemic effects with less volatile naphthenes, rats were exposed to 1500, 3000 or 6000 mg/m3 of a C9-C11 aliphatic solvent containing 70% naphthenes, for 90 days. Effects were limited to adaptive liver enlargement in both sexes and kidney toxicity in the male rat. For comparative purposes, the results from this study were compared to published reports of a complex hydrocarbon solvent with a higher proportion of volatile C5/C6 naphthenes and a mono-constituent naphthene (decahydronaphthalene). The results indicate that the systemic effects of naphthenes are similar to the straight and branched chain analogues and that the effects that are most relevant for human health evaluations of alkanes are acute central nervous system effects.

The reciprocal calculation procedure for setting occupational exposure limits for hydrocarbon solvents: An update.

Hydrocarbon solvents are liquid hydrocarbon fractions, often with complex compositions. Due to the potential for human exposure, primarily to the more volatile solvents, substantial effort has been directed toward the development of occupational exposure recommendations. Because of the complex and variable nature of these substances, a proposed approach is to calculate occupational exposure levels (OELs) using an adaptation of the mixture formula developed by the ACGIH® in which "group guidance values" are assigned to similar constituents. This approach is supported by the results of toxicological studies of hydrocarbon solvents and their constituents which have shown that, with a few well-characterized exceptions, these substances have similar toxicological properties and produce additive effects. The objective of the present document is to summarize recommended revisions to the earlier proposals; these recommendations take into account recent toxicological information and changes in regulatory advice. Practical demonstrations on how to use these recommendations to develop occupational exposure advice in different situations (from simple complex solvents to blends of complex solvents) are also provided. Finally, a quantitative ideal gas method is proposed as a means of calculating occupational exposure limits for solvent blends in which, because the blended components have differing vapor pressures, there may be substantial differences between the liquid and vapor phase compositions.

Characterization of the toxicological hazards of hydrocarbon solvents.

Hydrocarbon solvents are liquid hydrocarbon fractions derived from petroleum processing streams, containing only carbon and hydrogen atoms, with carbon numbers ranging from approximately C5-C20 and boiling between approximately 35-370°C. Many of the hydrocarbon solvents have complex and variable compositions with constituents of 4 types, alkanes (normal paraffins, isoparaffins, and cycloparaffins) and aromatics (primarily alkylated one- and two-ring species). Because of the compositional complexity, hydrocarbon solvents are now identified by a nomenclature ("the naming convention") that describes them in terms of physical/chemical properties and compositional elements. Despite the compositional complexity, most hydrocarbon solvent constituents have similar toxicological properties, and the overall toxicological hazards can be characterized in generic terms. To facilitate hazard characterization, the solvents were divided into 9 groups (categories) of substances with similar physical and chemical properties. Hydrocarbon solvents can cause chemical pneumonitis if aspirated into the lung, and those that are volatile can cause acute CNS effects and/or ocular and respiratory irritation at exposure levels exceeding occupational recommendations. Otherwise, there are few toxicologically important effects. The exceptions, n-hexane and naphthalene, have unique toxicological properties, and those solvents containing constituents for which classification is required under the Globally Harmonized System (GHS) are differentiated by the substance names. Toxicological information from studies of representative substances was used to fulfill REACH registration requirements and to satisfy the needs of the OECD High Production Volume (HPV) initiative. As shown in the examples provided, the hazard characterization data can be used for hazard classification and for occupational exposure limit recommendations.

The sub-chronic toxicity of regular White Spirit in rats.

Hydrocarbon solvents are mostly complex substances (UVCB) with carbon numbers in the range of approximately C5-C20. One of the most common types is a C9-C14 aliphatic solvent containing approximately 20% aromatics and commonly known as White Spirit in Europe and mineral spirits in the US. In previous repeated inhalation toxicity studies, White Spirit was reported to cause minimal systemic effects in most animal species with few effects other than male rat-specific kidney changes at levels up to approximately 2000mg/m(3). In the present study male and female rats were exposed to White Spirit vapors, 6h/day, 5days/week for 13weeks at levels of approximately 2000, 4000, or 8000mg/m(3) to assess the potential for effects at higher exposure levels. All of the rats survived the treatment period. In life observations were largely restricted to acute central nervous system (CNS) effects in the high exposure group. Terminal body weights of high exposure groups animals were significantly below control values. Statistically significant differences in the clinical and hematological observations were small and within normal physiological limits. Weights of some organs including liver, spleen and kidneys were elevated, but microscopic examination indicated that the only pathological effects were changes in the kidneys of the male rats, consistent with an α2u-globulin-mediated process, which is gender and species-specific and not relevant to humans. The overall no observed adverse effect level (NOAEC) was 4000mg/m(3).

The sub-chronic toxicity in rats of isoparaffinic solvents.

Results from a 13-week inhalation study in rats on a C10-C12 isoparaffinic solvent are compared to the results of repeated inhalation and oral toxicity studies of four other isoparaffinic hydrocarbon solvents. Statistically significant findings which were consistent across all studies included: nephropathy and small but significant changes in hematological parameters in male rats and liver enlargement in both male and female rats. The male rat kidney changes were due to an alpha 2u globulin process and not relevant for human health or risk assessment. The liver enlargement without pathologic changes or elevations in liver enzyme markers was considered to be an adaptive response. The reason for the reductions in hematological parameters that were observed in males only is not clear, but it is suggested that these were either due to normal variation or a secondary consequence of the nephropathy. The overall No Observed Adverse Effect Concentration (NOAEC) was the highest concentration tested in the study, >10,000 mg/m(3). Because of the overall pattern of response, this solvent is considered to be representative of low aromatic C9-C14 aliphatic solvents in general. The data are useful for risk assessment and other purposes including the development of occupational exposure recommendations.