[Federal Register Volume 59, Number 175 (Monday, September 12, 1994)]
[Unknown Section]
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From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-22464]
[[Page Unknown]]
[Federal Register: September 12, 1994]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Toxicology Program; Announcement of Intent To Conduct
Toxicological Studies of 22 Chemicals
Request for Comments: As part of an effort to inform the public,
the National Toxicology Program (NTP) routinely announces in the
Federal Register the lists of chemicals for which it intends to conduct
toxicological studies. This announcement will allow interested parties
to comment and provide information on chemicals under consideration for
short- and long-term toxicology and carcinogenesis studies.
Chemical 1. Riddelliine (CAS No. 23246-96-0)--2-year studies via
oral gavage in B6C3F1 mice and F344 rats. Riddelliine is a
pyrrolizidine alkaloid found in plants of the genus Senecio in the
Western United States. Riddelliine and other alkaloids in these plants
if ingested in high quantities can cause the death of livestock, or may
contaminate meat as a residue. Riddelliine may also contaminate
commercial grains, milk and honey, and is found in some herbal teas. In
NTP 90-day studies Riddelliine was found to cause hepatic toxicity in
mice and rats and hepatic neoplasia in rats. Two-year carcinogenicity
studies of standard design are proposed to determine the shape of the
dose response curve for carcinogenicity in rats, and further evaluate
the toxic and carcinogenic potential in mice.
Chemical 2. Urethane/Ethanol mixture (CAS No. 51-79-6/64-17-5)--2-
year studies via dosed-water in B6C3F1 mice and F344 rats. Urethane and
ethanol are byproducts of fermentation and are commonly found in
alcoholic beverages and in many foods. Urethane has been recognized as
a rodent and Non-human primate carcinogen, while the International
Agency for Research on Cancer has determined that alcoholic beverages
are human carcinogens. Risk assessment efforts for urethane are
complicated by information in the literature suggesting that the
metabolism and perhaps the tumorigenicity of urethane might be
inhibited by the co-presence of ethanol. NTP 13-week studies were
inconclusive in demonstrating an effect of ethanol on urethane
carcinogenesis. Two-year studies are planned to examine this issue
further. The studies will include separate groups of male and female
mice exposed to urethane, ethanol, or to several levels of urethane and
ethanol in the drinking water. The studies will include an assessment
of the toxicokinetics of urethane, with and without ethanol, following
repeated dosing. Studies of urethane DNA adducts are planned to address
the issue of the dosimetry of DNA alterations.
Chemical 3. Urethane (CAS No. 51-79-6)--2 year studies via dosed-
water in B6C3F1 mice and F344 rats.
The studies planned for urethane are outlined in the plans for
urethane/ethanol mixture studies described above.
Chemical 4. Ethanol (CAS No. 64-17-5)--2-year studies via dosed-
water in B6C3F1 mice and F344 rats.
The studies planned for ethanol are outlined in the plans for
urethane/ethanol mixture studies described above.
Chemical 5. Dichlorodiphenyl sulfone (CAS No. 80-07-9)--2-year
studies via dosed-feed in B6C3F1 mice and F344 rats.
Dichlorodiphenyl sulfone is a component of high temperature
plastics. Specific production figures are unknown, but the production
of plastics made from dichlorodiphenyl sulfone and related monomers was
over 1.5 billion pounds in 1988. Very little toxicology information is
available on this chemical. One study reported liver and cardiac
lesions in animals exposed to dichlorodiphenyl sulfone. A known inducer
of cytochrome P450s, dichlorodiphenyl sulfone was shown to cause marked
hepatomegaly in NTP prechronic studies. Other studies have shown facile
oral absorption and a relatively simple metabolite pattern, as well as
self induction of metabolism with repeated administration.
Carcinogenicity studies with dichlorodiphenyl sulfone are planned
with both sexes of rats and mice using the dosed feed route of
administration.
Chemical 6. Elmiron (CAS No. 37319-17-8)--14-day studies via oral
gavage in B6C3F1 mice and F344 rats.
Elmiron is a pentosan polysulfate used as an experimental drug in
the United States for the compassionate treatment of interstitial
cystitis, and used in Europe to prevent thrombosis and hyperlipidemia.
The United States Food and Drug Administration Nominated elmiron to the
NTP as an ``orphan'' drug in need of chronic toxicity and
carcinogenicity evaluation. Currently, 14-day studies are being
undertaken with oral administration of the drug to rats and mice, to
determine if expected effects on the clotting system will be the basis
on which to select doses for further evaluations. Chronic toxicity and
carcinogenicity evaluations by standard designs are under
consideration.
Chemical 7. Benzophenone (CAS No. 119-61-9)--2-year studies via
dosed-feed in B6C3F1 mice and F344 rats.
Benzophenone is found in many consumer products, e.g., as a
fragrance and flavor enhancer, photoinitiator, ultraviolet curing
agent, a polymerization inhibitor, and in the manufacture of pesticides
and various pharmaceuticals. Benzophenone and the structurally related
compound 2-hydroxy-4-methoxy benzophenone were nominated for study from
a class of ether compounds having widespread potential for human
exposure. The carcinogenic potential of benzophenone has only been
evaluated by topical administration to female Swiss mice. No indication
of carcinogenicity was reported. In NTP 13-week studies, the oral
administration of benzophenone was found to cause hepatocellular
hypertrophy in rats and mice, and evidence of cholestatic liver injury
and renal damage in rats. Marked induction of hepatic CYP 450 IIB was
observed in rats and mice. Chronic toxicity and carcinogenicity studies
proposed for this chemical are of the standard design, but with a stop
exposure group using a dose which produced marked liver and kidney
lesions in prechronic studies. Toxicokinetic studies are also planned.
Chemical 8. 2-Hydroxy-4-methoxybenzophenone (CAS No. 131-57-7)--2-
year studies via dosed-feed in B6C3F1 mice and F344 rats. 2-Hydroxy-4-
methoxybenzophenone is a UV stabilizer used in cosmetic, pharmaceutical
and plastic products. Consumer exposure is likely greatest through its
use in skin moisturizers and sunscreens where products containing up to
6% 2-hydroxy-4-methoxybenzophenone are permitted. In NTP 13-week
studies by the oral and topical routes, similar sites of toxicity were
seen, primarily the liver and kidney, and effects on sperm density and
the length of the estrous cycle were noted. Other NTP studies indicated
that absorption was good after both oral and topical administrations,
and major metabolites after intravenous administration were identified.
Two-year studies of standard design are planned for this chemical by
the oral route of administration rather than a topical one to provide
information more comparable to that obtained with Benzophenone. In
addition, the severity of the lesions in the topical prechronic studies
was limited, indicating that a rigorous evaluation of the
carcinogenicity of the chemical would be better achieved using oral
administration.
Chemical 9. Methacrylonitrile (CAS No. 126-98-7)--2-year studies
via oral gavage in B6C3F1 mice and F344 rats. Methacrylonitrile is an
industrial chemical widely used in a variety of organic processes
related to the manufacture of polymers. It is a highly reactive
unsaturated aliphatic nitrile found in cigarette smoke, and is known to
liberate cyanide in vivo. Methacrylonitrile has been studied
extensively by the NTP including studies of 14-day and 90-day durations
in rats and mice by gavage. In addition, absorption, disposition,
toxicokinetics, cell proliferation and developmental toxicity studies
have been performed. This chemical will be the subject of modeling
efforts with physiologically-based-pharmacokinetic modeling techniques,
and is also recommended for 2-year chronic toxicity and carcinogenicity
studies of a standard design.
Chemical 10. Acrylonitrile (CAS No. 107-13-1)--2-year studies via
oral gavage in B6C3F1 mice and F344 rats. Acrylonitrile is extensively
used for the manufacture of synthetic fibers, resins, elastomers,
rubber and plastics. Estimated production is in the range of 30 million
to 1.5 billion pounds per year. There is limited evidence for the
carcinogenicity of acrylonitrile in workers and Zt has been shown to
produce chromosome damage in the blood cells of exposed workers.
Acrylonitrile has produced brain, stomach and zymbal gland tumors in 2-
year studies in rats, but has not been studied in mice. Brain tumors
are rare chemically induced lesions in rodents. There is little chance
that the outcome of a mouse cancer study would change the
classification of acrylonitrile as a rodent carcinogen, but given the
quantitiative differences in acrylonitrile metabolism in rats and mice,
it is possible that clues to possible critical metabolities will be
gained from comparative studies in mice. Therefore, as part of the
nitrile class study, acrylonitrile will be studied in mice by the
standard NTP protocol. Toxicokinetic estimates will be derived by
analysis of an acrylonitrile-glutathione conjugation product in the
urine.
Chemical 11. m-Nitrotoluene (CAS No. 99-08-1)--2-year studies via
dosed-feed in B6C3F1 mice and F344 rats.
The nitrotoluenes are high production volume chemicals used in the
synthesis of agricultural and rubber chemicals and in various dyes.
There are known differences in the patterns of metabolism of the
chemicals with the ortho-isomer undergoing a unique series of host and
gut microflora-mediated reactions leading to an intermediate with high
capacity to bind to hepatic DNA and induce unscheduled DNA synthesis.
In extensive NTP prechronic studies, the comparative toxicity of the
nitrotoluene isomers was determined. An unexpected finding was the
presence of chemically induced mesothelioma in male rats receiving o-
nitrotoluene. Studies to elucidate the possible role of gut microflora
in the mesothelioma response demonstrated that microflora metabolism
was not necessary for the mesothelioma response. To further understand
the carcinogenic potential of these chemicals and to relate this
information to the extensive existing knowledge of their metabolism,
chronic toxicity and carcinogenicity studies are planned with all three
isomers.
Chemical 12. o-Nitrotoluene (CAS No. 88-72-2)--2-year studies via
dosed-feed in B6C3F1 mice and F344 rats.
The studies planned for o-nitrotoluene are outlined in the plans
for m-nitrotoluene described above.
Chemical 13. p-Nitrotoluene (CAS No. 99-99-0)--2-year studies via
dosed-feed in B6C3F1 mice and F344 rats.
The studies planned for p-nitrotoluene are outlined in the plans
for m-nitrotoluene described above.
Chemical 14. m-Cresol (CAS No. 108-39-4)--2-year studies via dosed-
feed in B6C3F1 mice and F344 rats.
The cresols are monomethyl derivatives of phenol, and are found as
constituents of coal tar, in various industrial solvents and resins,
and in some essential oils. Cresols are on the list of Hazardous Air
Pollutants in the Clean Air Act Amendments of 1990 and on the Superfund
Priority List of Hazardous Substances. There are no adequate published
chronic toxicity and carcinogenicity studies of the cresols and this
was identified as a research need by an International Programme for
Chemical Safety working group in mid- 1994. The NTP has performed
comparative 13-week toxicity studies in rats and mice by the dosed feed
route. The isomers were found to exhibit generally similar patterns of
toxicities, with the o-isomer being somewhat less toxic than m- or p-
cresol. Comparative chronic toxicity and carcinogenicity studies in
rats and mice are planned for the cresols. The studies will follow
standard designs.
Chemical 15. o-Cresol (CAS No. 95-48-7)--2-year studies via dosed-
feed in B6C3F1 mice and F344 rats.
The studies planned for o-cresol are outlined in the plans for m-
cresol described above.
Chemical 16. p-Cresol (CAS No. 106-44-5)--2-year studies via dosed-
feed in B6C3F1 mice and F344 rats.
The studies planned for p-cresol are outlined in the plans for m-
cresol described above.
Chemical 17. 2,4-Decadienal (CAS No. 25152-84-5)--13-week and 2-
year studies via oral gavage in B6C3F1 mice and F344 rats.
2,4-Decadienal is one of the class of dienaldehydes that occur
naturally in a variety of foods. They occur as byproducts of the
peroxidation of polyunsaturated lipids. Ingested lipid oxidation
products and oxidized fats have been reported to cause damage to the
liver and kidneys, increased cellular proliferation in the
gastrointestinal tract, and other non-specific tissue injury. Certain
alpha, beta unsaturated lipids, including 2,4-decadienal and 2,4-
hexadienal are known to react with DNA, and several researchers have
suggested a possible link between lipid peroxidation products in the
diet and human cancer. 2,4-Decadienal will be studied in prechronic and
chronic toxicity and carcinogenicity studies in rats and mice.
Chemical 18. 2,4-Hexadienal (CAS No. 142-83-6) 13-week and 2-year
studies via oral gavage in B6C3F1 mice and F344 rats.
The studies planned for 2,4-hexadienal are similar to those
outlined above for 2,4-Decadienal.
Chemical 19. Dipropylene glycol (CAS No. 25265-71-8) 2-year studies
via dosed-water in B6C3F1 mice and F344 rats.
Dipropylene glycol is a component of antifreeze, air fresheners/
sanitizers and is used as a stabilizer in cosmetics, as a component in
polyester, alkyd resins, plastics, as a plasticizer and as a solvent.
It is a relatively high production volume chemical with nearly 100
million pounds used in the United States annually. It was found to be
of low to moderate toxicity in NTP 13-week studies. Mortality,
hepatocellular lesions including atypical foci and an adenoma were seen
in rats at the top dose. Findings in mice were limited to increased
liver weights. Carcinogenicity studies of a standard design are
proposed for dipropylene glycol.
Chemical 20. Arsenic trioxide (CAS No. 1327-53-3) study plans are
being formulated.
Arsenic trioxide is a byproduct of copper or lead smelting
operations and is used in pesticides, in the manufacture of glass,
pharmaceuticals and other industrial chemicals. Arsenic and arsenic
compounds have been classified as human carcinogens by the
International Agency for Research on Cancer, but the demonstration of
the carcinogenicity of arsenic trioxide and other arsenical compounds
in rodents has been difficult. Arsenic is a common water contaminant
and there is need for information on biomarkers of exposure for low
dose risk estimations. For these reasons the program has selected
arsenic trioxide for study as part of an initiative to examine human
carcinogens which have not adequately been evaluated in rodent studies.
Specific study designs are under development.
Chemical 21. Tamoxifen (CAS No. 10540-29-1)/conjugated estrogens
study plans are being formulated.
Studies on tamoxifen and conjugated estrogens will be designed to
address several issues. Conjugated estrogens are listed by the
International Agency for Research on Cancer as human carcinogens
causing endometrial cancer, however these chemicals have never been
adequately studied in animals. These chemicals find wide use in human
medicine and in skin care preparations. Estrogens are prescribed for
prevention of osteoporosis in post-menopausal women and are used as
oral contraceptives. Tamoxifen is a mixed estrogen agonist/antagonist
known to be effective in the treatment and prevention of estrogen
sensitive breast cancer. Tamoxifen also causes endometrial cancer in
humans. Studies are being designed to help characterize dose-response
relationships and cancer risks for estrogen agonist and antagonists.
Chemical 22. MX [3-Chloro-4-(dichloromethyl)-5-hydroxy-2-furanone]
(CAS No. 77439-76-0) study plans are being formulated.
MX is a mutagenic byproduct of water and wood pulp chlorination and
has been determined to account for about half of the mutagenic potency
of finished drinking water. The EPA has Nominated MX for
carcinogenicity studies with the expectation that the outcome could
influence United States drinking water contaminant standards. Study
designs are incomplete.
Anyone have 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]. GOV.
Dated: September 7, 1994.
Kenneth Olden,
Director, National Toxicology Program.
[FR Doc. 94-22464 Filed 9-9-94; 8:45 am]
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