There are currently available no systematic experimental data on the skin sensitizing properties of acrylates that are of relevance in occupational settings. Limited information from previous guinea-pig tests or from the local lymph node assay (LLNA) is available; however, these data are incomplete and somewhat contradictory. For those reasons, we have examined in the LLNA 4 acrylates: butyl acrylate (BA), ethyl acrylate (EA), methyl acrylate (MA), and ethylhexyl acrylate (EHA). The LLNA data indicated that all 4 compounds have some potential to cause skin sensitization. In addition, the relative potencies of these acrylates were measured by derivation from LLNA dose-response analyses of EC3 values (the effective concentration of chemical required to induce a threefold increase in proliferation of draining lymph node cells compared with control values). On the basis of 1 scheme for the categorization of skin sensitization potency, BA, EA, and MA were each classified as weak sensitizers. Using the same scheme, EHA was considered a moderate sensitizer. However, it must be emphasized that the EC3 value for this chemical of 9.7% is on the borderline between moderate (<10%) and weak (>10%) categories. Thus, the judicious view is that all 4 chemicals possess relatively weak skin sensitizing potential.

A category approach was used in the evaluation of a group of chemicals (triethyl phosphate, tripropyl phosphate, and tributyl phosphate) in drinking water, in support of determination of safe-harbor level for use by a standard-setting organization. Both non-cancer and cancer endpoints were considered, and risk assessment methodology developed by the U.S. Environmental Protection Agency (USEPA) was used to determine a class-based evaluation level (CBEL) and a total allowable concentration (TAC) in drinking water considered adequately protective of human health. The critical study was a chronic oncogenicity study on tributyl phosphate, with a no-observed-adverse-effect-level (NOAEL) of 9 mg/kg-day. The critical effect, combined incidence of bladder papilloma/transitional cell carcinoma, was likely non-genetic in nature, as supported by the lack of genetic toxicity observed in tributyl phosphate. The effect thus demonstrated a threshold, and this study used an oral reference dose approach and a total uncertainty factor of 100. This conservative analysis demonstrated the TAC should be twenty times greater than the default value of 0.01 mg/L.

Current U.S. and Japanese regulatory guidelines mandate the use of at least six animals for dermal and ocular irritation testing, while EEC/OECD guidelines require only three animals. An analysis of data from this laboratory in general supports the use of as few as three animals for acute irritancy testing. Data from a series of 140 dermal and 118 ocular irritation tests were examined to determine injury rates associated with testing, and to generate six-, five-, four-, three-, and two-rabbit primary dermal irritation indices for dermal tests and to categorize ocular tests similarly. Results were then examined to determine whether fewer animals could have been used to obtain findings similar to those originally noted with six rabbits. These results suggest that the number of animals used in dermal and ocular irritation testing can be reduced, especially if a sequential approach involving a preliminary in vitro/SAR test is taken. In addition, low rates of severe injury were evident for dermal and ocular irritation tests, as well as low discomfort rates for ocular irritation tests using a topical anesthetic. Using a low level of dermal irritation as a screen for ocular testing could reduce injury and discomfort rates further.

The principal focus of this chapter is on the epoxy compounds frequently encountered in industrial use as uncured epoxy resins. These resins are marketed in a variety of physical forms from low‐viscosity liquids to tack‐free solids and require admixture with curing agents to form hard and nonreactive cross‐linked polymers. They are in demand because of their toughness, high adhesive properties (polarity), low shrinkage in molds, and chemical inertness. It is the uncured resins that are of main interest to toxicologists, for a well‐cured resin should have few or no unreacted epoxide groups remaining in it. The toxicology of the curing agents is not treated in this chapter. They are most frequently bi‐ or trifunctional amines, di‐ or tricarboxylic acids and their anhydrides, polyols, and compounds containing mixed functional groups, such as aminols and amino acids, as well as other resins containing such groups. Some of the other epoxide compounds described in this chapter are used as reactive diluents in epoxy resin mixtures; others are of commercial importance for their multiple uses in the synthesis of other compounds (specifically, epichlorohydrin). As reactive diluents, monomeric epoxides are added to epoxy resins to reduce viscosity and modify the handling characteristics of the uncured materials. The epoxide functionalities of these diluents react with the resin curing agents in the same manner as the resin to become part of the finished polymer. Epoxy resins have found application as protective coatings, adhesives for most substrates (metals included), caulking compounds, flooring and special road paving, potting and encapsulation resins, low‐pressure molding mixtures, and binding agents for fiberglass products. Uncured, they are used as plasticizers and stabilizers for vinyl resins. Epoxy resin coating formulations can generally be limited to one of three forms: solution coatings, high‐solid formulations, and epoxy powder coatings. Solid epoxies are used in coating applications, as solid solutions or heat‐converted coating. Solution coatings are often room‐temperature applications, and typically there is little potential for vapor exposure. The potential clearly exists for skin contact during application of coatings of this type. Heat‐converted coatings are usually applied and cured by mechanical means and exposure to vapors or contact with skin is minimal. Solid resins are used for other applications such as electrical molding powders and decorative or industrial powder coatings. For applications of this kind, exposure to vapors and dust can occur and is greatest during formulating and grinding. Considering that epoxides can react with nucleophiles, particularly basic nitrogens, one might expect the epoxides to react with cellular biomolecules such as glutathione, proteins, and nucleic acids, and indeed this has been demonstrated for some of these epoxide compounds. The nature and magnitude of these interactions with these biomolecules is most likely related to the toxicity and observed for any given molecule in this class of compounds. However, the potential for any epoxide to react with cellular nucleophilic biomolecules depends on several factors, including the reactivity of the particular epoxide, the dose and dose rate, as well as the molecular weight, and solubility, the latter two influencing access to molecular targets within the cell. In addition, the efficiency of metabolism via epoxide hydrolase or other metabolic routes of detoxication may significantly influence the toxicologic potential and potency of these materials. Epoxide hydrolase activity is widely distributed throughout the body, but it is organ, species, and even strain variant. The liver, testes, lung, and kidney have considerable epoxide hydrolase activity; the activities in the skin and gut, however, are considerably lower. In this regard it should be noted that mouse tissues have a much lower level of EH activity than does the human tissue; in fact, at least two strains of mice, C57BL/6N and DBA/2N, have no EH activity in their skins. Therefore, it may be questioned if toxicity or treatment‐related effects observed in dermal mouse studies are relevant for hazard evaluation. Epoxy compounds may also be metabolized by the cytoplasmic enzyme glutathione‐ S ‐transferase, which converts epoxides to 2‐alkylmercapturic acids. This enzyme, because it is in the aqueous phase, may play a minor role in the detoxification of large lipophilic epoxides, but is active against low molecular weight epoxides. Due to differences in physiochemical properties and the effectiveness and nature of the detoxification of these materials through metabolism, the toxicity of these compounds ranges from the highly active, electrophilic, low molecular weight mono‐ and diepoxides to the nontoxic and inert cured materials, which possess only a few epoxy groups per molecule. In general, the acute toxicity of epoxy resin compounds as observed in laboratory animals can be considered low; oral and dermal LD 50 values generally vary. Usually the irritating properties of epoxy liquids or vapors limit significant exposure to produce systemic toxicity. Effects most commonly observed in animals have been dermatitis (either primary irritation or secondary to induction of sensitization), eye irritation, pulmonary irritation, and gastric irritation, which are typically found in the tissues that are the first to come into contact with the epoxy compound. In general, it appears that epoxy compounds of higher molecular weight (e.g., epoxy novolac resins and diglycidyl ether of bisphenol A) produce less dermal irritation than those of lower molecular weight. In some instances, liquid epoxy compounds splashed directly into the eye may cause pain and, in severe cases, corneal damage. Skin irritation is usually manifested by more or less sharply localized lesions that develop rapidly on contact, more frequently on the arms and hands. Signs and symptoms usually include redness, swelling, and intense itching. In severe cases, secondary infections may occur. Workers show marked differences in sensitivity. Of the compounds in this chapter, four (resorcinol diglycidyl ether, epichlorohydrin, glycidaldehyde, and glycidol) were the subject of studies in which there was clear evidence of tumorigenic effects in rodents. Larger molecular weight glycidyloxy compounds such as castor oil glycidyl ether, the diglycidyl ether of bisphenol A, and advanced bisphenol A/epichlorohydrin epoxy resins have been negative in dermal bioassays. Epidemiology studies have not provided any evidence for an association between workplace exposure and cancer to any of the materials in this chapter.

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