[Federal Register Volume 59, Number 175 (Monday, September 12, 1994)]
[Unknown Section]
[Page 0]
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]
BILLING CODE 4140-01-M