National Toxicology Program; Announcement of Intent To Conduct Toxicological Studies of 22 Chemicals

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