National Toxicology Program

[Federal Register: May 13, 1996 (Vol. 61 No. 93)]
[Notices]
[Pages 22066 - 22068]

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Toxicology Program

Announcement of Intent to Conduct Toxicological Studies of 9 Chemicals;

Request for Comments: As part of an effort to obtain public input into the selection of chemicals for evaluation, the National Toxicology Program (NTP) routinely announces in the Federal Register the lists of chemicals for which plans to develop protocols for toxicological studies are underway. This announcement will allow interested parties to comment and provide information on chemicals under consideration. Chemicals and types of studies under consideration are listed below.

Allyl Bromide (CAS No. 106-95-6) is used in both organic and biochemical synthesis, commonly as a chemical intermediate, in the synthesis of perfumes and pharmaceuticals, polymers and resins, and the production of agricultural chemicals.

The National Cancer Institute nominated allyl bromide based on widespread use, its persistence as an environmental pollutant and the lack of toxicology data. There is potential for human exposure both from production and manufacturer as well as during its end use. Possible routes of human exposure include inhalation, oral and dermal routes. Allyl bromide is one of a group of organohalogen compounds identified in waste water or drinking water. Plans are underway to develop protocols for toxicity and carcinogenicity studies.

Divinylbenzene (CAS No. 1321-74-0) (DVB) is a specialty monomer used in polymer applications that require additional heat resistance and strength. It is used in styrene-butadiene rubber to improve the swelling shrinkage, and extrusion properties of the product. In addition, DVB is used as a cross-linking monomer for copolymerization with styrene, and acrylic or methacrylic acid to produce ion exchange resins.

DVB was nominated to the NTP by the National Cancer Institute for carcinogenicity testing based upon its structural relationship to styrene and benzene, and the potential for significant human exposure. The major route of potential human exposure in the industrial setting is considered to be inhalation during manufacturing processes involving about 35,000 workers. Commercial DVB generally consists of a mixture of the meta and para isomers of DVB and ethylvinylbenzene.

Fourteen-day studies and toxicokinetic studies are planned and the decision to conduct 90-day and chronic studies will be made after review of this data.

Diazoaminobenzene (CAS No. 136-35-6) is used as an intermediate in organic synthesis, dye and agricultural chemical manufacturing. Diazoaminobenzene is a metal complexing agent and polymer additive used as a coupler to promote adhesion to natural rubber and steel and as a blowing agent in resins and urea-formaldehyde adhesives, polyurethane coatings.

Diazoaminobenzene was recommended by the National Institute of Environmental Health Sciences for toxicological testing based on the potential for worker exposure and the lack of adequate toxicological data. Several structural analogs of Diazoaminobenzene are carcinogenic, suggesting the possible carcinogenicity of Diazoaminobenzene, as well. It is used in D&C Red Dye and has been found as a contaminant in food samples collected by the Food and Drug Adminstration. It is mutagenic in Salmonella. Published carcinogenicity studies in mice are considered inadequate and none have been conducted in rats. Plans are underway to develop protocols for toxicity and carcinogenicity studies.

Ethidium Bromide (CAS No. 1239-45-8), because it interchelates in DNA, is commonly used for identification of DNA in research setting

Ethidium bromide was nominated by a University faculty member because of its increasing use as a reagent of DNA chemistry and its widespread use as a DNA probe in sequencing reactions and the increased potential for exposure to laboratory workers. Plans are underway to develop protocols for toxicity and carcinogenicity studies.

Formamide (CAS No. 75-12-7) is used as a solvent, a softener, an intermediate in organic synthesis and in water-soluble ink formulations.

The National Cancer Institute nominated a class of chemicals which included formamide, N-methylformamide (NMF), and N,N-dimethylformamide (DMF), for NTP testing. DMF studies on have been completed and published by the NTP (prechronic), and industry (chronic). NMF was nominated only for genotoxicity testing and was found to be negative in the salmonella assay. Studies conducted by others have demonstrated that NMF is metabolized in the same manner as DMF. No further testing is therefore recommended for NMF. Formamide was nominated by the NCI for carcinogenicity testing. The limited information available on formamide indicates that it is metabolized to formate. Since rodents metabolize formate much more efficiently than primates, they may be insensitive to formamide toxicity. Therefore comparative metabolism of formamide will be evaluated in rat, mouse, and human liver slices studies prior to any pre-chronic studies. In addition, metabolism/disposition studies will be conducted initially in rats and then in mice using nose-only inhalation. Based on the results of these studies and any new information that becomes available in the literature, NTP will determine the appropriate animal model for future toxicity studies.

5-Hydroxymethyl Furfural (CAS No. 67-47-0) (HMF) is formed during the thermal decomposition of sugars and carbohydrates. HMF has been identified in a wide variety of heat processed foods including milk, fruit juices, spirits, honey, etc. HMF is also found in cigarettes.

The National Institute of Environmental Health Sciences nominated HMF based on the potential for widespread exposure in the diet, evidence for carcinogenic potential of other members of this class, and the fact that little is known about HMF toxicity. NTP plans to develop protocols to investigate the metabolism, toxicity and carcinogenicity of HMF.

Isoeugenol (CAS No. 97-54-1) is found in cloves, tobacco, and other plants and flowers. Isoeugenol is used to manufacture vanillin, and is widely used in fragrances and as a flavoring additive. Many consumers are potentially exposed to isoeugenol from its use in cosmetics and food.

Isoeugenol was nominated for carcinogenicity testing by the National Cancer Institute based on its structural similarity to the carcinogens eugenol, safrole, isosafrole, and estragole, and its potential for human exposure as a food flavoring agent and a fragrance ingredient. Plans are underway to develop protocols to investigate the toxicity and carcinogenicity of Isoeugenol.

Methyl Styryl Ketone (CAS No. 1896-62-4) is a naturally occurring product and a synthetic flavor and fragrance additive. Its most important use is as a flavoring and fragrance additive in many commercial products (for example; soap, detergent, perfume, creams and lotions, baked goods, frozen dairy products, nonalcoholic beverages). MSK is also listed on the recently released list of tobacco additives used in cigarette manufacture

The rationale for the National Cancer Institute's (NCI) nomination included wide-spread low level human exposure from its use as a flavoring agent and use in perfumes, lotions, soap, and detergents. As an a,b-unsaturated ketone, it exhibits mutagenicity in short-term tests in Salmonella with metabolic activation. It is a know Michael acceptor and is expected to react with either food stuffs or proteins in the target tissues. Toxicology data is very limited.

There is a CAS number for Methyl Styryl Ketone that refers to unspecified isomers of Methyl Styryl Ketone. It should be noted that the trans isomer (CAS 1896-62-4) is being studied to avoid any future confusion. Methyl Trans Styryl Ketone (MSK) was nominated by NCI for comparative toxicity studies, metabolism, and carcinogenicity based on potential for human exposure. Metabolism studies are underway. Plans are underway to develop protocols for comparative disposition and short-term toxicity studies.

Stoddard Solvent (CAS No: 8052-41-3) is used as a multipurpose petroleum solvent; uses include paint vehicles; thinning agent for paints, coatings, and waxes; printing inks; adhesives; solvent in liquid photocopier toners; solvent in dry cleaning; degreaser for engine parts in machine and auto repair shops.

Stoddard solvent (high flash, low aromatic grade), was nominated by the United Auto Workers as one of several organic solvents that are used with substantial exposure in transportation, equipment and related metal working industries. For most of these solvents, there was evidence for human health risks particularly occupational cancers and respiratory toxicity found in epidemiology studies, from cases reports, from acute and subacute testing in animals from inadequate chronic exposure studies. Stoddard solvent is a mixture of numerous hydrocarbons derived by refining crude oil. The mixture consists of three major groups of components: linear and branched alkanes (30-50%), also known as paraffins; cycloalkanes (30-40%); and aromatic hydrocarbons (10-20%). There are various types of Stoddard solvent with different flash points and composition of linear alkanes, cycloalkanes, and aromatic hydrocarbons. ASTM specifies four types of mineral spirit (Stoddard solvent): Type I--Regular; Type II--High flash point; Type III--Odorless; and Type IV--Low Dry Point. Stoddard solvent type III selected for testing is a mixture with high aliphatic and low aromatic contents, little odor, and 100° F minimum flash point. In 1990, production volume was about 38 million pounds. NTP is developing protocols for toxicity and carcinogenicity studies.

Anyone having relevant information (including ongoing toxicological studies, current or future trends in production and import, use pattern, human exposure levels, environmental occurrence and toxicological data) to share with the NTP on any of these chemicals, should contact Dr. William Eastin within 60 days of the appearance of this announcement. The information provided will be considered by the NTP in designing these studies.

Contact may be made by mail to : Dr. William Eastin, NIEHS/NTP, P.O. Box 12233, Research Triangle Park, North Carolina 27709, by telephone at 919-541-7941, fax 919-541-4714, or email at Eastin@NIEHS.NIH.GOV.

Dated: May 1, 1996

Kenneth Olden, Ph.D.
Director
National Toxicology Program

[Billing Code 4140-01]