[Federal Register Volume 60, Number 15 (Tuesday, January 24, 1995)]
[Notices]
[Pages 4630-4632]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-1664]



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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 <1,000,000 lbs in 1989 
(>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]
BILLING CODE 4140-01-M