National Toxicology Program; Announcement of Intent To Conduct Toxicological Studies of 16 Chemicals

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health Service

National Toxicology Program; Announcement of Intent To Conduct

Toxicological Studies of 16 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 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.

Chemical 1. 2-Cyclohexene-1-one (CAS No. 930-68-7) 14-day, 13-week

and 2-year toxicology and carcinogenesis inhalation studies.

2-Cyclohexene-1-one (2-CHX-1) belongs to a class of chemicals

termed alpha, beta-unsaturated ketones. This class of chemicals was

nominated by National Cancer Institute for carcinogenicity and

mechanistic toxicity studies with high priority due to demonstrated

human industrial and consumer exposure and inadequate health effects

testing. 2-CHX-1 is being studied as an example of a cyclic member of

the class of aliphatic alpha, beta-unsaturated ketones. It is used as

an industrial chemical intermediate in the chemical, pharmaceutical,

and agricultural chemical industries. It is used in the synthesis of

resorcinol, phenol, 11-deoxy-prostaglandins, immunostimulants, anti-

inflammatory agents, fungicides and herbicides. Consumer exposure

includes the use of 2-CHX-1 in low-odor permanent wave hair

preparations, antifungal agents and mold inhibitors for bread storage

containers, smoke flavor preparations, and detergents. 2-CHX-1 is

present in tobacco smoke and is present in side-stream smoke from

tobacco combustion. Natural occurrence of 2-CHX-1 includes wild rice

fermentation products, a component of beech wood and roasted coffee. 2-

CHX-1 may also be present in foods and consumer products as an impurity

in the flavor enhancer tetrahydronaphthalenone. The major effect

reported on the toxic effects of 2-CHX-1 in animals is the depletion of

glutathione in various tissues of rodents. 2-CHX-1 is a weak, direct

acting mutagen in the Salmonella assay and in a rat hepatocyte/DNA

repair test. 2-CHX-1 was able to react covalently with deoxyguanosine.

Chemical 2. Methyl Vinyl Ketone (CAS No. 78-74-4) 14-day, 13-week

and 2-year toxicology and carcinogenesis inhalation studies.

Methy Vinyl Ketone (MVK), a member of the class of chemicals termed

alpha, beta-unsaturated ketones, was nominated by the National Cancer

Institute for carcinogenicity and mechanistic toxicity studies with

high priority due to demonstrated human industrial and consumer

exposure and inadequate health effects testing. MVK was selected as the

prototype non cyclic member of the major class of straight-chain

aliphatic alpha, beta-unsaturated ketones. MVK is used commercially in

the production of pesticides, perfumes, plastics and resins. It is a

pharmaceutical intermediate in the synthesis of steroids, vitamin A,

and anticoagulants. Consumer exposure to MVK is widespread due to its

presence in cigarette smoke, its production by gamma-irradiation from

sugars in tropical fruit, and as a ubiquitous air pollutant due to its

presence in vehicular exhaust. MVK is an alkylating agent and may

interact with DNA to form covalent adducts. MVK was reported by the NTP

to be mutagenic in the Salmonella assay. [[Page 4631]]

Chemical 3. Ethyl vinyl ketone (CAS No. 1629-58-9) 14 and 90-day

inhalation toxicity studies in F344 rats and B6C3F1 mice.

Ethyl vinyl ketone (EVK) is a secondary conjugated carbonyl

compound from the subclass of aliphatic alpha, beta-unsaturated

ketones, and has a wide distribution in the environment, particularly

in foods. EVK is a component of the semi-volatile fraction of

cigarette/tobacco smoke and is a volatile organic compound linked to

odor and taste problems associated with water purification and fish

breeding. Consumption in foods and beverages also represents a broad

but very low level route of human exposure. The principal use of EVK is

as a natural and synthetic flavoring agent in orange aqueous essence

and oils for flavor and aroma enhancement, especially of frozen orange

juice concentrates. The limited available test data on this compound

include demonstrations of positive mutagenicity and the formation of

DNA-damaging adducts. These data support the possibility that EVK may

pose a mutagenic and carcinogenic risk to humans.

Chemicals 4 & 5. Trimethoprim/Sulfamethoxazole (CAS No. 8064-90-2)

13-week and 2-year dosed-feed studies in F344 rats and B6C3F1 mice.

Trimethoprim/Sulfamethoxazole (TMP/SMZ) (Bactrim) is a

chemical combination used to treat urinary tract infections and

pneumonia. TMP/SMZ was nominated by the National Cancer Institute for

carcinogenicity and neurotoxicity testing based on significant human

exposure and the potential for increased use in the treatment of

pneumonia in AIDS patients. In addition, because TMP/SMZ appears to

exhibit antifolate activity, the role of folate deficiency in possibly

enhancing the known carcinogenicity of Sulfamethoxazole may need to be

investigated. A study to screen for TMP/SMZ reproductive/developmental

toxicity effects was done as a part of the NIEHS AIDS Program.

Chemical 6. Dicyclopentadiene (CAS No. 77-73-6) 13-week and 2-year

studies in F344 rats and B6C3F1 mice.

DCPD was nominated by the National Cancer Institute for evaluation

of carcinogenicity and reproductive toxicity. DCPD is a high production

chemical, with over 130 million pounds produced annually and over 43

million pounds imported in 1988. The nomination was based on the high

and increasing production volume, the presence of DCPD in ground and

surface water near sites where it is used, limited data on the hazards

associated with subchronic exposure, and the absence of data on the

hazards associated with long term exposure. DCPD is currently being

evaluated in the NTP Continuous Breeding Protocol and Teratology

protocols (gavage studies).

Chemical 7. Ethyl cyanoacrylate (CAS No. 7085-85-0) short-term

inhalation studies.

Ethyl cyanoacrylate (ECA) was nominated by the Consumer Products

Safety Commission. ECA is the major component of instant setting

adhesives widely available in retail stores and there is widespread

potential consumer exposure. There is potential occupational exposure

to ECA vapors that exists wherever ECA glues are used for assembly, in

packaging, or other adhesive applications. Irritant dermatitis and eye

irritation in workers has been reported. There is one report of women

occupationally exposed to ECA vapors giving premature birth to babies

with malformations. There is very little toxicological data and no

carcinogenicity data available for this chemical. A related chemical,

isobutyl cyanoacrylate, is now used for medical applications because it

does not produce formaldehyde during degradation as does the ECA.

Evaluation of developmental and reproductive toxicity, neurotoxicity,

and evaluation of carcinogenicity, using the inhalation route, have

been recommended.

Chemical 8. Methylene Blue (CAS No. 7220-79-3) two-year toxicity/

carcinogenesis and toxicokinetic gavage studies in F344 rats and B6C3F1

mice.

Methylene Blue (MB) was nominated for carcinogenicity testing by

the National Cancer Institute (NCI) based on the widespread use of this

compound and the potential for high exposure in animals and humans.

Methylene blue is used therapeutically in the treatment of

methemoglobinemia and cyanide poisoning. Other reported medicinal uses

of MB have included the management of chronic urolithiasis and

treatment of cutaneous viral infections as well as the treatment of

manic-depressive psychosis. As a dye/stain, MB is used in surgical and

medical marking, as an indicator dye, a bacteriologic stain, a food

colorant and a dye for cotton and wool. Data from the National

Occupational Exposure Survey (NOES) indicate that 69,563 workers,

including 42,026 female employees, were potentially exposed to

methylene blue between 1981 and 1983. In four-week and 13-week gavage

toxicity studies conducted by NTP, the hematopoietic system was the

major target of MB toxicity. Dose-related hemolytic anemia was seen in

all of the groups treated with MB. Increased methemoglobin formation,

decreased hematocrit, increased in reticulocyte production,

splenomegaly, and increased Heinz body formation were seen in rats and

mice of both sexes exposed to MB. Histologically, there was hyperplasia

of the bone marrow in response to the anemia.

Chemical 9. Butanal Oxime (CAS No. 110-69-0) 14-day and 90-day

prechronic dosed water toxicity studies in F344 rats and B6C3F1 mice.

Butanal oxime was nominated for toxicity and carcinogenicity

evaluation by the National Cancer Institute. Along with methyl ethyl

ketoxime and cyclohexanone oxime, butanal oxime is part of an oximes

class study. Cyclohexanone oxime and methylethyl ketoxime have been

studied in NTP 90-day drinking water toxicity studies in rats and mice,

and industry sponsored inhalation carcinogenicity studies of methyl

ethyl ketoxime have been completed. Unlike the other oximes, butanal

oxime metabolism results in the release of cyanide, and is therefore

expected to have a different toxicological profile. There is limited

toxicology information available on butanal oxime.

Chemical 10. Cyclohexene Oxide (CAS No. 286-20-4) 28-day, 13-week,

and 2-year topical and/or gavage toxicity/carcinogenesis studies in

F344 rats and B6C3F1 mice.

Cyclohexene Oxide (CHO) was nominated by the National Cancer

Institute for carcinogenicity, toxicity, and mechanistic studies as a

representative cycloalkene monoepoxide which is produced in substantial

annual volumes with potential human exposures. CHO is found widely in

natural products, pharmaceuticals, and agricultural chemicals and, it

has a wide range of uses, including the production of other chemicals

and as a laboratory reagent. It is primarily used as an industrial raw

material in organic synthesis of various chemical intermediates for a

wide range of industrial products and there is the potential for worker

exposure. In addition, a survey identified CHO in the drinking water of

two of 17 municipalities suggesting the potential for more widespread

exposure to the general population. CHO has a low acute toxicity in

rats and rabbits, is a severe eye irritant, and is a moderate skin

irritant. It is also a weak to moderate mutagen. There is minimal

chronic toxicity information available.

Chemical 11. p-tert-Butylcatechol (CAS No. 98-29-3) 14-Day and 13-

week dosed-feed studies.

p-tert-Butylcatechol (TBC) was nominated for carcinogenicity

studies by the National Cancer Institute based [[Page 4632]] on high

and increasing level of production and usage, potential for human

exposure, suspicion of carcinogenicity, and interest in evaluating the

toxicity of the dihydroxybenzenes chemical class of antioxidants. In

1989, U.S. production of TBC was reported to be 1.5 million lbs. TBC is

used primarily as an antioxidant and stabilizer and there is potential

for worker exposure. Consumer exposure occurs through TBC contamination

of, and subsequent leaching from PVC products and other plastics and

rubber products and from contact with Thermofax duplicating

papers. In addition, TBC is also being considered as a replacement for

BHT and BHA, two chemicals used as food additives because of their

antioxidant properties, but which have been found to be carcinogenic in

rodents at high levels. TBC as well as BHA and BHT are non-mutagenic.

Chemical 12. Diisopropylcarbodiimide (CAS No. 693-13-0) 2-year

carcinogenesis studies in F344 rats and B6C3F1 mice.

Diisopropylcarbodiimide together with Dicyclohexylcarbodiimide were

nominated as representatives of the carbodiimide chemical class by the

National Cancer Institute because of widespread potential exposure to

personnel in biomedical laboratories and pharmaceutical and chemical

industries, the lack of adequate toxicity data, and the suspicion of

carcinogenicity because it is an alkylating agent. Both chemicals are

potent sensitizers and have produced severe contact dermatitis, severe

eye irritation, and delayed-onset temporary blindness. Fourteen-day

topical studies have been completed and 90-day topical exposure studies

are underway in F344 rats and B6C3F1 mice.

Chemical 13. Dicyclohexylcarbodiimide (CAS No. 538-75-0) 2-year

carcinogenesis studies in F344 rats and C6C3F1 mice.

Dicyclohexylcarbodiimide together with Diisopropylcarbodiimide were

nominated as representatives of the carbodiimide chemical class by the

National Cancer Institute because of widespread potential exposure to

personnel in biomedical laboratories and pharmaceutical and chemical

industries, the lack of adequate toxicity data, and the suspicion of

carcinogenicity because it is an alkylating agent. Both chemicals are

potent sensitizers and have produced severe contact dermatitis, severe

eye irritation, and delayed-onset temporary blindness. Fourteen-day

topical studies have been completed and 90-day topical exposure studies

are underway in F344 and B6C3F1 mice.

Chemical 14. Dimethyl adipate (CAS No. 627-93-0) 13-week and 2-year

toxicity/carcinogenesis studies in F344 rats and B6C3F1 mice.

Dimethyl adipate (DMA) was nominated to the NTP for study by the

Consumer Products Safety Commission (CPSC) because of widespread

consumer exposure. Its primary consumer use is as a replacement for

methylene chloride in paint strippers, along with other dibasic esters

such as dimethyl glutarate and dimethyl succinate. This use is expected

to increase because the standards for methylene chloride exposure are

under review by regulatory agencies and new more stringent ones may be

established. There is the potential for workers to be occupationally

exposed to DMA and systemic exposure is primarily by inhalation of an

aerosol or through percutaneous absorption. There is limited toxicity

information available on DMA. NTP is coordinating its plans to conduct

studies for this chemical with the Environmental Protection Agency and

the Interagency Testing Committee.

Chemical 15. 2,3-Butanedione (CAS No. 431-03-8) 13-week and 2-year

toxicity/carcinogenesis studies in F344 rats and B6C3F1 mice.

2,3,-Butanedione was nominated by the National Cancer Institute

based on widespread human exposure and suggestive evidence of

carcinogenicity from preliminary animal studies and genetic toxicity

studies. The chemical is the parent compound of the a-diketones

chemical class. The annual production of 2, 3-butanedione is less than

1 million pounds, and it is used in manufacturing processes and as a

food (flavoring) additive. It was estimated in 1983 that 3,437 workers

were potentially exposed to 2,3-butanedione in the workplace. Its

widest exposure is through its natural occurrences in a wide variety of

foods, including dairy products (5.9 ppm), meats, baked goods (44 ppm),

produce, candy (21 ppm), and beverages (in coffee at levels up to 10

ppm), and is used as a flavor additive in foods. It is also a

constituent of tobacco smoke. 2,3-Butanedione is also a bacterial

mutagen. There was no information on the effects of chronic exposure to

2,3-Butanedione in the open literature.

Chemical 16. Methyl styryl ketone (CAS No. 122-57-6) 13-week and 2-

year toxicity/carcinogenesis studies in F344 rats and B6C3F1 mice.

Methyl styryl ketone (MSK) was nominated by the National Cancer

Institute based on its potential for human exposure. MSK is an apha,

beta-saturated ketone that was produced at 55,000 lbs were imported in 1993) and is also present as a natural

product. It is used as an intermediate in organic syntheses and in

other industrial applications, and is a flavoring and fragrance

additive in many products, including cosmetic products (soaps (50-100

ppm), creams and lotions (50-100 ppm), and perfumes (50-500 ppm); food

products (baked goods (5.2 ppm) and candy (4.4 ppm)). It was recently

identified as a flavoring additive to cigarettes, but its level of use

was not reported. It occurs naturally in essential oils of flowers, as

a pyrolysis product in waste gases resulting from the removal of

coating materials in recycling processes, and as an ozonization product

of the humic substance, p-hydroxybenzaldehyde. It has been estimated

that 5,483 workers were potentially exposed to MSK in the workplace in

1983. MSK has been identified in wastewaters, and has been shown to

bioaccumulate in blue crabs in the southern Chesapeake Bay. MSK is a

bacterial mutagen. There was no information on the effects of chronic

exposure to MSK in the open literature.

Anyone having relevant information (including ongoing toxicological

studies, current or future trends in production and import, use

pattern, human exposure levels, environmental occurrence and

toxiocological 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: January 17, 1995.

Kenneth Olden,

Director, National Toxicology Program.

[FR Doc. 95-1664 Filed 1-23-95; 8:45 am]

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