[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