[Federal Register Volume 61, Number 93 (Monday, May 13, 1996)]
[Notices]
[Pages 22066-22068]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-11908]



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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.

[[Page 22067]]

    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 Administration. 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 carcinogencity 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 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 ,-unsaturated ketone, it exhibits mutagenicity in 
short-term tests in Salmonella with metabolic activation. It is a known 
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.

    Stoddart Solvent (Casno: 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 cancer 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

[[Page 22068]]

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 deg.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 [email protected]

    Dated: May 1, 1996.
Kenneth Olden,
Director, National Toxicology Program.
[FR Doc. 96-11908 Filed 5-10-96; 8:45 am]
BILLING CODE 4140-01-M