[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.
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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
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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
