FIRST DRAFT
United Siaiei rr&ft TTW n?«
Environmental ProtectlDn ivnu-tin-u i ci
Ag«ncy November, 1990
>EPA Research 3nd
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR METHYL METHACRYLATE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: 00 NOT CITE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It 1s being circulated for comments
on its technical accuracy and policy implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document scries
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for
emergency and remedial actions under the Comprehensive Environmental
Response, Compensation and Liability Act (CERCIA). Both published
literature and information obtained for Agency Program Office files are
evaluated as they pertain to potential human health, aquatic life and
environmental effects of hazardous waste constituents. The literature
searched for In this document and the dates searched are Included In
"Appendix: Literature Searched." Literature search material Is current up
to 8 months previous to the final draft date listed on the front cover.
Final draft document dates (front cover) reflect the date the document 1s
sent to the Program Officer (OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include*. Reference doses
(RfDs) for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 1s an estimate of an
exposure level which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval i.e., for an Interval which
does not constitute a significant portion of the lifespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, a carcinogenic potency factor, or
q^* {U.S. EPA, 1980), Is provided. These potency estimates are derived
for both oral and Inhalation exposures where possible. In addition, unit
risk estimates for air and drinking water are presented based on Inhalation
and oral data, respectively. An RfD may also be derived for the noncarclno-
genlc health effects of compounds that are also carcinogenic.
Reportable quantities {RQs} based on both chronic toxicity and
carcinogenicity are derived. The RQ H used to determine the quantity of a
hazardous substance for which notification Is required In the event of a
release as specified under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxicity
and carcinogenicity} represent two of six scores developed (the remaining
four reflect ignltablllty, reactivity, aquatic toxicity, and acute mammalian
toxicity). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxicity and cancer based RQs are
defined In U.S. EPA, 1984 and 1986c, respectively.
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EXECUTIVE SUMMARY
Hethyl methacrylate (CAS No. 80-62-6), an eslcr of methacryl1c acid. Is
a colorless liquid with a boiling point of 100°C at 760 mm Hg and a vapor
pressure of 35 inn Hg at 20°C. Hethyl methacrylate is moderately soluble In
water and Is soluble In acetone, ether and ethanol (Hacklson el ah, 1981;
Weast and Astle, 1985-1986). This chemical Is readily polymerized by light
and heat, necessitating the addition of an Inhibitor, usually 10-15 ppm of
monomethyl ester of hydroqulnone (Nemec and Kirch, 1981).
The production of methyl methacrylate has been limited to one process,
the acetone cyanohydrIn process (ACN), but more economical alternative
methods have been proposed, the most promising of which Is derived from
C^-oxIdatlon technology (Nemec and Kirch, 1981).
Recent production figures for methyl methacrylate indicate that the
three U.S. producers of the chemical have a total production capacity of
1155 million pounds {SRJ, 1989). Actual production volumes could be lower,
but these data were not available for 1989. Approximately 800 million
pounds of the chemical was produced 1n the United States and an additional
28.9 million pounds was Imported to the United States In 1985 (USI1C, 1905;
Bureau of Census, 1905). Data from 1981 show that 7054 of the methyl
methacrylate produced was used as a captive Intermediate (SRI, 1983).
Approximately 100% of the methyl methacrylate produced is used for Hie
production of acrylic polymers, which are used In the production of acrylic
sheet, molding and extrusion powders, surface coating resins and emulsion
polymers. These have adhesive, leather, paper, polish, sealant and textile
applications (SRI, 1983). In medicine, the polymers are used In ortho-
pedics, neurosurgery and ophthalmology (Doyerle et al., 1979).
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Mo thy1 methacrylate released to the atmosphere would be expected to
undergo photochemical degradation, with a half-life of 2:7 hours under urban
conditions and of >3.0 hours for rural conditions (Joshl et al., 1982).
Soluble In water, methyl methacrylate could also be removed from the
atmosphere 1n rain (U.S. EPA, 1985).
Methyl methacrylate In water 1s lost primarily through volatilization.
The half-life of the chemical In a typical river, 1 m deep with a 1 m/sec
current and 3 m/sec wind has been estimated to be 6.3 hours (Howard, 1909;
Lyman et al., 1982). Direct photolysis of methyl methacrylate 1s not a
significant route of degradation In the aquatic environment; however, In the
presence of free radicals that are formed In natural waters by the action of
light, methyl methacrylate could undergo polymerization to some extent and
become Inactive (Otsu et al., 1979). Hydrolysis of methyl methacrylate does
occur, but only under extremely alkaline conditions {Ellington et al.,
1987). For example, at pK 11.12, the estimated hydrolysis half-Hfe of
methyl methacrylate Is 2.5 hours while, at pH 7, the half-life Is 3.9 years
(Ellington et al., 1987).
Methyl methacrylate can undergo rapid blodegradatlon, but this may occur
only in the presence of acclimated organisms (Thorn and Agg, 1975). In one
study, methyl methacrylate was completely degraded by activated sludge In
-20 hours (Slave et al., 1974).
In soil, volatilization would be the main elimination process for methyl
methacrylate; however, because of 11s low potential for adsorption IK0C*87
(Lyman et al., 1982)3 and Us solubility In water [1.59 g/100 g solution
(Howard, 1989)J, some of the chemical would be expected to leach Into
groundwater (Howard, 1989).
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The primary sources of human exposure to methyl methacrylate are occupa-
tional, occurring mainly as a result of Industrial operations and medical
procedures. The potential routes of exposure Include inhalation. Ingestion
and skin and eye contact (Hacklson et al., 1981J, In addition, Internal
exposure may result from the use of methyl methacrylate In orthopedic
Implants and dental appliances.
Industrial exposure has been associated with the use of the chemical In
various acrylic products (Hacklson et al., 1981}. Monitoring data show
several Instances In which the atmospheric levels of methyl methacrylate
exceeded the current TLV-TWA of 410 mg/m* (100 ppm). For example, In a
survey of five plants manufacturing po1y(methy1 methacrylate), mean 8-hour
time-weighted averages for exposure by Job category ranged from 11-145 ppm
(v/v} for mixers and from 25-174 ppm for distillers In one plant. In other
job categories, however, levels were lower, ranging from 4 ppm (v/v) for
maintenance workers to B8 ppm (v/v) for distillers. High levels of methyl
methacrylate were also detected In the air of a factory producing polymetiiyl
methacrylate sheets [20-736 mg/nt3 (5-177 ppm)] (Delia Torre et al., 1982}
and 1n the breathing zones of workers near reactors for polymer production
(Samlml and Falbo, 19B2), On the other hand, concentrations of less than
100 ppm of methyl methacrylate have been detected In the air samples from
various facilities. The use of closed systems, exhaust ventilating systems
and care In handling apparently can minimize exposure to methyl methacrylate
(Samlml and Falbo, 1982).
Operating room personnel and orthopedic patients are at risk for
exposure to methyl methacrylate monomer released to the atmosphere during
the mixing and curing of the polymer. Patients may also be exposed to the
monomer In tissues surrounding Implants. Peak atmospheric concentrations
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have been reported during mixing and In the first 15 minutes after mixing
IMattla, 1983; Pickering et al., 1986; Carre et al., 1987; Schoenfeld et
al., 1979). levels of methacrylate monomer as high as 705 ppm have been
detected near the edge of the howl during mixing and setting of orthopedic
cement. The use of a fume cabinet, an exaust hood or other ventilation
during mixing can reduce atmospheric concentrations of the monomer consider-
ably (Brune and Beltesbrekkc, 1901; Hattla, 1983; Pickering et al., 1986}.
Although atmospheric concentrations would not be expected to exceed the OSMA
limits for methyl methacrylate {100 ppm), even low levels can result 1n
allergic sensitization (Pickering et al., 1986).
Hethyl methacrylate monomer has been detected 1rt the blood of patients
following orthopedic Implants (Eggert et al., 1974) and in the saliva
shortly after the insertion of dental plates (Baker et al., 1988). Simula-
tion experiments have demonstrated thai methyl methacrylate monomer can be
released from bone cement during In vivo polymerization (Schoenfeld et al.,
1979; Wiliert et al., 1973). Small amounts of methyl methacrylate may also
be available for leaching at the surface of contact lenses (GalIn et al.,
1977; Holyk and E1fr1g, 1979; Schoenfeld et al., 1979; ludwlg et al., 1987).
According to one source, methyl methacrylate was present In the efflu-
ents from several Industries at concentrations ranging from 1.2 pg/l for
pesticides manufacturing to 69.6 vq/i for electronics (U.S. EPA, 1987).
Methyl methacrylate has been detected in drinking water taken from sampling
taps at treatment works (Fielding et al., 1981) and from a commercial
delonlzlng-charcoal filtering unit {Dowty et al., 1975). In both cases, the
chemical was not present In untreated water samples. Hethyl methacrylate
(~1Q ppb) was also detected at the Chicago Central Hater Works in final tap
water (after chlorinatlon) during a study in which 204 water samples were
collected from 14 heavily Industrialized river basins (Ewlng et al., 1977).
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Methyl methacrylate has not been detected In food, but the results of
laboratory experiments suggest that the chemical could migrate from food
wrap into food.
In 1976, an estimated 1.0% of the total production of methyl methacry-
late was emitted to the atmosphere. The main sources of atmospheric methyl
methacrylate are methyl methacrylate production facilities, end-product
manufacturing facilities and bulk storage facilities (Patterson el al.,
1976). Methyl methacrylate monomer may also be released to the atmosphere
from the pyrolysls of the methyl methacrylate polymer.
The 24-hour LC^ of 1760 mg/i for Daphnla magna and 96-hour LC
values for fish that range from 151.5 mg/l {flowthrough) for the fathead
minnow {Relnert, 1987) to 360.1 mg/st (static) for the guppy {Pickering and
Henderson, 1986), Indicate that the chemical Is of low acute toxicity to
aquatic animals.
Methyl methacrylate was also of low acute toxicity to three different
protozoa, the blue-green alga and Pseudomonas putlda In the cell multiplica-
tion Inhibition assay (Bringmann and KOhn, 197B, 1980, 1981), but was very
toxic to the green alga (Brlngrnann and KOhn, 1978). Using a system based on
biological oxidation, Stack (1357) demonstrated that the methyl methacrylate
concentration of 300 mg/i was not toxic to unacclImated microorganisms
from domestic sludge.
No data were found for the chronic toxicity of methyl methacrylate to
aquatic organisms. Based on the log BCf of 0.55 (Lyman et al., 198?} and
log P (octanol/water partition coefficient) values of 0.7-1.38 (FuJIsawa and
Hasuhara, 1981; Hansch and Loo, 1962; Relnert, 1987), no bloconcentratlon or
bloaccumulatlon of methyl methacrylate would be expected. No data uere
found for the toxicity of methyl methacrylate to terrestrial fauna or flora.
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Data from animal studies Indicate that methyl methacrylate Is readily
absorbed following inhalation or oral exposure, and that H rapidly
partitions out of the blood {Bratt and Hathaway, 1977}. Animal studies also
Indicate that the compound has a large volume of distribution as determined
by Its detection 1n the brain, lungs, liver, kidneys, Intestine, adipose
tissue, skin, bone and salivary glands (Wenzel et al., 1973; Bratt and
Hathaway, 1977; Raje et al., 1985). Ijn vivo and in vitro metabolism of
methyl methacrylate Indicates that the compound may be hydrolyzed to
methacryllc acid and methanol. Hethacryllc acid, methyl malonlc add, ethyl
malonic acid, B-hydroxy1sobutyrlc acid, and mercapturlc add have been
Identified as urinary metabolites In the rat (Bratt and Hathaway, 1977;
Delbresslne et al., 1981; Crout et al., 19B2), and methyl malonlc add
Identified as a urlnar metabolite In one human subject (Crout et al.,
1982). Several studies provided data affirming the rapid excretion of
methyl melhacrylate-derIved C02> Over 80% of 14C-melhyl methacrylate
parenterally administered to rats was excreted as 14,C02 (Heme! et al.,
1973; Bratt and Hathaway, 1977; Crout el al., 19B2). Oral administration of
94 mg of sodium methacrylate to a human subject resulted In 1.OX of the dose
being eliminated as a urinary metabolite 24 hours later (Crout el al., 1982).
Epidemiologic studies provide little evidence of serious toxicity
resulting from long-term inhalation exposure to methyl methacrylate.
Various symptoms Including headache, fatigue, memory loss, and Irritability
were reported for Individuals occupaUonally exposed to methyl methacrylate
vapor for periods approximating 10 years (Blagodatln et al., 1971; Kuzelova
et al., 1985}. Monroe et al. (1981) noted that the chronic bronchitis of a
study group could not be attributed to the occupational exposure to methyl
methacrylate If smoking habits of the workers were considered. Delia Torre
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et al. (1982) reported mucosal irritation and minor nervous system disorders
in workers exposed to methyl methacrylale for ~12 years. Chronic exposure
to methyl methacrylate did not result In Increased mortality according to a
report by Collins et al. (1989}. Nondescript sexual disorders (decreased
sexuality) were reported for men (Hakarov, 1984) and women (Hakarov el al.,
19B4) chronically exposed to methyl methacrylate. Frlgo et al. (1901)
Indicated an Increase In serum serotonin and increased myometrium contrac-
tile activity In a woman exposed to methyl methacrylate.
Chronic animal studies using various species (rats, mice, hamsters}
provide evidence of toxicity Prom Inhalation exposure to methyl meth-
acrylate. Hild rhinitis was observed 1n rats but could not be definitively
attributed to the chronic exposure to methyl methacrylate (Hazellon
Laboratories, 1979b}. However, this same study noted a reduction In weight
gain for female but not mala rats dlscontlnuously exposed to methyl
methacrylale at 400 ppm for 52 weeks of a 104-week exposure duration.
Equivocal results were obtained for hamsters In that a 2-fold Increase in
mortality was observed for male but not female golden hamsters exposed to
methyl methacrylate for 78 weeks (Hazelton Laboratories, 1979a). A 2-year
NIP (1986} study Indicated that Inhalation exposure to methyl methacrylate
at all exposure levels produced an Increase 1n nasal cavity 1nflammatlon and
degeneration of olfactory epithelium, but had no effect on survival of Iho
rats or mice used 1n the study. Minor reductions (5-11%) 1n body weight
gain were noted for male rats (1000 ppm) and female rats (500 ppm), and
slightly greater reductions (10-18%) were detected for male and female mice
1n all exposure groups.
No studies were located addressing human chronic or subchronlc oral
exposure to methyl methacrylate.
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Chronic oral exposure studies conducted by Borzelleca et al. (1964}
demonstrated that methyl methacrylate administered In the drinking water
(6.85 or 68.46 ppm) to male and female Wlstar rats for 104 weeks failed to
produce any significant toxic effects.
Although no subchronlc human Inhalation exposure data are available,
subchronlc Inhalation exposure studies have been conducted using rats and
mice. As with the chronic studies, reduced body weight gain was reported by
several Investigators for rats exposed to methyl methacrylate for periods
ranging from 3-6 months (Tansy et al, 1976, 1900b; NTP, 1906}. Exposure to
high levels of methyl methacrylate (2000-5000 ppm) resulted In reduced
weight gain and deaths of animals before termination of the experiment 1n
the BNW Laboratories (NTP, 1906}. However, studies conducted by Industrial
Blotest Laboratories (IBT) for NTP (19B6) failed to demonstrate any signs of
toxicity In rats exposed to methyl methacrylate at concentrations up to 1000
ppm for 14 weeks. All male and female mice exposed to methyl methacrylate
at concentrations ranging from 500-5000 ppm (BNW) exhibited metaplasia of
the nasal epithelium, and deaths occurred In the 2000, 3000 and 5000 ppm
exposure groups (NTP, 1906).
Other exposure-related effects have also been reported Including liver
and kidney lesions (Motoc et al., 1971; Lomonova et al., 1980), hlstopatho-
logical changes 1n various levels of the respiratory tract (Hotoc et al.,
1971; Tansy et al., 1976, 19B0b; NTP, 1986}, cardiovascular effects
(Lomonova et al., 1980; Blanchct et al., 1982), and reduced motility of the
small Intestine (Tansy et al., 1976).
Subchronlc, oral exposure animal studies using rats, mice, or dogs have
been conducted by various Investigators. Hale and female beagle dogs given
dietary methyl methacrylate (10, 100 or 1473 ppm) for 1 year exhibited no
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significant signs of toxicity based on gross pathology and histopathologic
findings (Borzelleca et al., 1964). Methyl methacrylate administered orally
to rats over periods ranging from 3-B months resulted In exposure-related
Increases In hlstopathologlcal alterations of the liver, Increased serum
enzyme activity levels, and a duration-related Increase In the severity of
ulcerations of the glandular epithelium of the stomach (Hotoc et al., 1971).
Husaln et al. (1985} reported altered behavior and biogenic amine levels in
rats given methyl methacrylate In olive oil over a 21-day period.
The results of acute exposure to methyl methacrylate by various routes
have been reported by a number of authors. These reports Include both human
case reports and results of animal studies. Occupational asthma from methyl
methacrylate exposure was reported by Slozewlc et al. (1985) for a dental
assistant and by Pickering et al. (1986) for an orthopedic nurse. A
systemic reaction to Inhaled methyl methacrylate vapor by an operating room
nurse was characterized by headache, dyspnea, hypertension, tachycardia and
extreme lethargy (Scolnlck and Collins, 1986). Seppalalnen and Rajnleml
(1984) evaluated the neurotoxic effects of dental technicians routinely
exposed to methyl methacrylate. Compared with nonexposed controls, a
significant reduction In distal sensory conduction velocity was observed for
Individuals exposed to methyl methacrylate. Additionally, a number of
contact dermatitis reports Involving methyl methacrylate exposure ore
available (Pcgum and Hedhurst, 1971; Kassls et al., 1984; Conde-Salazaar et
al., 1988; Van Joost and Van Loon, 1988; Kanzakl et al., 1989).
There Is no convincing evidence that methyl methacrylate 1s a potential
carcinogen for humans. One epidemiology study showed excess deaths from
colorectal cancer In workers who were exposed to ethyl acrylate In addition
to methyl methacrylate at a Rohm Haas plant In Pennsylvania
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(Monroe, 1984). These results were not confirmed by a study of workers at a
Rohm Haas plant In Houston, Texas (Honroe, 1984) or by a study of workers at
two American Cyanamld plants where methyl methacrylate was manufactured or
used (Collins et al., 1989).
Studies using laboratory animals exposed by Inhalation to methyl meth-
acrylate showed that the compound was not carcinogenic In hamsters exposed
to concentrations up to 400 ppm (6 hours/day, 5 days/week) for 78 weeks
(Hazelton Laboratories, 1979a) or In rats exposed under the same conditions
for 102-106 weeks (Hazelton Laboratories, 1979b). A study by NTP (1986)
showed that methyl methacrylate was not carcinogenic in male and female mice
and rats administered the compound by Inhalation at concentrations up to
1000 ppm (up to 500 ppm for female rats) for 102 weeks. An Increase In the
Incidence of mononuclear leukemia was noted In female rats, but this
Increase was Judged to be statistically nonsignificant according to the Life
Table Test. Statistically significant unexplained decreases 1n the
Incidences of tumor at other sites were noted: namely, pituitary gland (male
rats, female mice) and preputial gland (male rats) adenomas or carcinomas,
hepatocellular adenomas or carcinomas (male and female mice),
alveolar/bronchlolar adenomas or carcinomas (male mice), and uterine
adenocarcinomas (female mice). One study on oral exposure of male and
female rats to methyl methacrylate 1n drinking water showed no induction of
neoplasms at concentrations up to 2000 ppm (Borzelleca et al., 1964).
Topical application of methyl methacrylate for 4 months did not Induce skin
or systemic tumors (Oppenhelmer et al., 1955). A study using humans showed
that a chondrosarcoma developed 1n the supraclavicular area 18 years after
extrapleural plombagc of polymethyl methacrylate spheres (Thompson and
Entln, 1969). Another study showed that fibrosarcomas can be Induced at
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the site where polymethyl methacrylate films arc subcutaneously embedded In
laboratory animals (Laskln et al., 1954; Oppenhelmer et al., 1955).
Genotoxlclty tests showed that methyl methacrylate docs not Induce
hlstldlne reversion In Salmonella typMmurlum using the plate Incorporation
or liquid preincubation test In the presence or absence of rat or hamster
liver S9, but Poss et al. (1979) reported that 8-azaguan1ne resistance can
be Induced In Salmonella strain TM677 (not confirmed). Hethyl methacrylate
induced chromosome aberrations In mouse lymphoma cells (Moore et al., I960).
l£ vivo genotoxlclty tests showed that methyl methacrylate administered p.o.
did not Induce mlcronuclel 1n bone marrow cells 1n mice (Anderson et al.,
1979; Smith, 1900). Hethyl methacrylate administered by Inhalation was
negative In the dominant lethal test In rats and positive for Inducing
chromosome aberrations In bone marrow cells 1n rats (Smith, 1980).
Hethyl methacrylate was not considered to be embryotoxlc to humans
(Splelmann, 1906), but animal studies have provided evidence for teratogenic
potential of the compound. Singh et al. (1972) noted a significant Increase
In fetal gross hemangiomas following Intraperitoneal administration of
methyl methacrylate (0.2656 or 0.4427 ml/kg} to pregnant rats on gestation
days 5, 10 or 15. No other evidence of developmental toxicity was observed.
McLaughlin et al. (1978) reported a significant Increase In fetal weight In
the offspring of mice exposed to methyl methacrylate vapor on days 6-15 of
gestation. Developmental effects characterized by delayed ossification of
sternebrae were detected following Inhalation exposure of pregnant rats to
109 mg/l for 17.2 m1nutes/day on days 6-15 of gestation. A longer
exposure period (54.2 m1nutes/day) produced maternal toxicity. Luo et al.
(1986) showed that Inhalation exposure of pregnant rats to 4.48 mg/t [2
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hours/day every 3 days) resulted In a significant Increase In resorptions,
and delayed ossification 1n the fetuses. Hethyl methacrylate Injected Into
3-day-old chick embryos at doses of 2.3-36 jimol/egg resulted 1n an
Increase In early deaths and malformations. These effects were not
dose-related nor were they observed for the lowest dose.
OSHA (1989a) has established a final rule B-hour TWA of 100 ppm {410
mg/ma). The American Conference of Governmental Industrial Hyg1en1sts
(ACGIH) recommended a TLV of 100 ppm (410 mg/m*}, and considered this
sufficiently low to protect against discomfort from Irritation. It was also
determined by ACGIH that this level was well below that giving rise to any
systemic effects. A STEL of 125 ppm (510 mg/m*) Is also Indicated (ACGIH,
1980).
Guidelines and standards regarding the protection of aquatic organisms
were not located In the available literature.
The studies by NTP (1986) satisfy the requirements of EPA's Guidelines
for Carcinogen Risk Assessment (U.S. EPA, 1986a}, which require two
well-designed and well-conducted studies using two animal species for
demonstrating noncarclnogenldty. Based on these studies and the limited
human data showing no association of occupational exposure with deaths from
cancer, methyl methacrylate Is classified as welght-of-evidence Group E
(evidence of noncarclnogenldty for humans) regarding Inhalation exposure.
Because of this classification, 1t does not receive a quantitative
evaluation. Data were not available for quantitative evaluation of the
potential carcinogenicity of methyl methacrylate by oral exposure.
A number of retrospective epidemiologic studies regarding Inhaltlon
exposure to methyl methacrylate were reviewed but not considered useful for
quantitative risk assessment. A chronic rat study by NTP (1986), demon-
strating inflammation of the nasal cavity and degeneration of the olfactory
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epithelium following a 2-year exposure, was chosen for deriving an RfC of
0.41 mg/m* (8.15 mg/day). No human studies were available For the
quantitative risk assessment of subchronlc, Inhalation exposure to methyl
methacrylate. Based on evaluation of animal studies, an RfC$ of 1.66
mg/ms (33.2 nig/day) was derived from a rat study by NTP (1986, BNW)
wherein rats exposed to methyl methacrylate exhibited inflammation and
necrosis of the nasal cavity.
Only a few animal studies and no human studies examining the effects of
oral exposure to methyl methacrylate were available. The RfD of 0.016
mg/kg/day was based on relatively negative findings (slightly altered
k1dney-to-body weight ratio of uncertain biological significance) from a
chronic drinking water exposure protocol using rats (Borzelleca et al.,
1964). An RfDs of 0.037 mg/kg/day was based on a reduction 1n spleen-to-
body weight ratio (of uncertain biological significance) In dogs subchronlc-
ally exposed to dietary methyl methacrylate (Borzelleca et al., 1964).
An RQ of 1000 was derived for methyl methacrylate based on Inflammation
and necrosis of the nasal cavity for rats exposed to 250 ppm methyl
methacrylate for 714 days (NTP, 1986).
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS NUMBER 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-2
1.4. USE DATA 1-4
1.5. SUMMARY 1-4
2. ENVIRONMENTAL FATE AND TRANSPORT 2-1
2.1. AIR 2-1
2.1.1. Chemical Degradation 2-1
2.1.2. Transport 2-2
2.2. WATER 2-2
2.2.1. Chemical Degradation 2-2
2.2.2. B1odegradat1on 2-3
2.2.3. Transport 2-3
2.3. SOIL 2-4
2.3.1. Blodegradatlon 2-4
2.3.2. Transport 2-4
2.4. SUHHARY 2-4
3. EXPOSURE 3-1
3.1. OCCUPATIONAL EXPOSURE 3-1
3.1.1. Industrial Operations 3-1
3.1.2. Medical Procedures 3-4
3.1.3. Detection Methods 3-10
3.2. SURFACE WATER CONTAMINATION 3-11
3.3. FOOD CONTAMINATION 3-12
3.4. DRINKING HATER CONTAMINATION 3-12
3.5. ATMOSPHERIC CONTAMINATION 3-12
3.6. SUMMARY 3-13
4. ENVIRONMENTAL TOXICOLOGY 4-1
4.1. AQUATIC TOXICOLOGY 4-1
4.1.1. Acute Toxic Effects on Fauna 4-1
4.1.2. Chronic Effects on Fauna 4-4
4.1.3. Effects on Flora 4-4
4.1.4. Effects on Bacteria 4-4
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TABLE OF CONTENTS (cont.)
Page
4.2. TERRESTRIAL TOXICOLOGY 4-5
4.2.1. Effects on Fauna 4-5
4.2.2. Effects on Flora 4-5
4.3. FIELD STUDIES 4-5
4.4. AQUATIC RISK ASSESSMENT 4-5
4.5. SUMMARY 4-6
5. PHARMACOKINETICS 5-1
5.1. ABSORPTION 5-1
5.2. DISTRIBUTION 5-2
5.3. METABOLISM 5-4
5.4. EXCRETION 5-6
5.5. SUMMARY 5-7
6. EFFECTS 6-1
6.1. SYSTEMIC TOXICITY 6-1
6.1.1. Subchronlc Exposure 6-1
6.1.2. Chronic Exposure 6-0
6.1.3. Other Relevant Information 6-15
6.2. CARCINOGENICITY 6-25
6.2.1. Inhalation Exposure 6-25
6.2.2. Oral Exposure 6-28
6.2.3. Other Relevant Information 6-29
6.3. GENOTOXICITY 6-30
6.4. DEVELOPMENTAL TOXICITY 6-31
6.4.1. Humans 6-31
6.4.2. Animals 6-32
6.5. OTHER REPRODUCTIVE EFFECTS 6-33
6.5.1. Humans 6-33
6.5.2. Animals 6-34
6.6. SUHHARY 6-34
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUHAN 7-1
7.2. AQUATIC 7-1
XV111
-------
TABLE OF CONTENTS (cont.)
Page
B. RISK ASSESSMENT . . . 8-1
0.1. CARCINOGENICITY B-l
8.1.1. Inhalation B-l
8.1.2. Oral B-3
B.1.3. Other Routes B-4
0.1.4. Height of Evidence B-4
0.1.5. Quantitative Risk Estimates 0-6
6.2. SYSTEMIC TOXICITY 8-7
8.2.1. inhalation Exposure 0-7
8.2.2. Oral Exposure 0-10
9. REPORTABLE QUANTITIES 9-1
9.1. BASED ON SYSTEMIC TOXICITY 9-1
9.2. BASED ON CARCINOGENICITY 9-12
10. REFERENCES 10-1
APPENDIX A: LITERATURE SEARCHED A-l
APPENDIX B: SUMMARY TABLE FOR METHYL HETHACRYLATE B-l
APPENDIX C: DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO
METHYL METHACRYLATE C-l
x1x
-------
LIST OF TABLES
No. T1Lie Page
3-1 Atmospheric Methyl Methacrylate Concentrations During
Medical Procedures 3-S
4-1 Median Response Concentrations For Aquatic Animals Exposed
to Hethyl Hetharcylate 4-?
6-1 Acute Toxicity Values For Hethyl Methacrylate 6-21
8-1 Summary of Dose and Effect Level Data from Pertinent Studies
of Short-Term Inhalation Exposure to Hethyl Hethacylate . . . 8-B
8-2 Summary of Dose and Effect Level Data from Pertinent Studies
of Chronic Inhalation Exposure to Hethyl Hethacrylate .... 8-16
8-3 Summary of Dose and Effect Level Data from Pertinent
studies of Chronic Oral Exposure to Methyl Hethacrylate . . . 8-19
9-1 Inhalation Toxicity Summary for Methyl Methacrylate 9-2
9-2 Composite Scores for Inhalation Exposure to Hethyl
Hethacrylate 9-7
9-3 Oral Toxicity Summary for Hethyl Hethacrylate 9-10
9-4 Composite Scores for Orally Administered Hethyl Hethacrylate. 9-11
xx
-------
LIST OF ABBREVIATIONS
atm Atmopshcre
BCF Bloconcentratlon factor
BNW Batelle Pacific Northwest Laboratories
BUN Blood urea nitrogen
bw Body weight
CAS Chemical Abstract Service
CI Curie
DNA Deoxyribonucleic acid
dSCV Distal sensory conduction velocity
ECG Electrocardiogram
ED50 Dose effective on 50% of recipients
FEL Frank-effect level
FEV-| 1-Second forced expiratory volume
FVC Forced vital capacity
GC Gas chromatography
GLC Gas-I1qu1d chromatography
5-HT 5-Hydroxytryptamlne
ICD international Classification of Deaths
1.m. Intramuscular
l.p. Intraperitoneal
K0c Organic carbon partition coefficient
LC50 Concentration lethal to 50% of recipients
LD50 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effeet level
LT50 Exposure duration lethal to 50% of subjects
HAK Maximum permissible concentration (Ger.)
xx1
-------
LIST OF ABBREVIATIONS (cont.)
HCV
Maximum conduction velocity
ramol
H11 Hmole
MTD
Maximum loxlc dose
MUA
Hult1-unlt acvtWUy
HW
Molecular weight
nm
Nanometer
NOAEL
No-observed-adverse-effect level
NOEL
No-adverse-effect level
Pyp
Vapor pressure In atmospheres at 25°C
pco2
Partial pressure of carbon dioxide
PEP
Peak expiratory flow
P02
Partial pressure of oxygen
ppm
Parts per million
RfC
Reference concentration (Inhalation)
RfD
Reference dose (oral)
RQ
Reportable quantity
RVd
Dose-rating value
RVe
Effect-rating value
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Methyl methacrylate Is also known as 2-propenolc acid, 2-mcthyl-, methyl
ester (9CI), methacryllc acid methyl ester {8CI}, methyl methacrylate
monomer, and HHE (CHEML1NE, 1909). The chemical Is further characterized by
the following:
Structure:
Cll? - C(CH3)C00CH3
CAS number: 80-62-6
Empirical formula: C^llgO^
Molecular weight: 100.11
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Selected physical and chemical properties of methyl methacrylate are as
follows:
Physical state:
Odor:
Melting point (°C):
Boiling point
(°C at 760 mm Hg):
colorless liquid
acrid, Fruity
-48
100
Hacklson et al., 1981
Hacklson et al., 1981
Howard. 1989
Weast and Astle,
1985-1986
Solubilities In
(a) Water (g/100 g solution)
(b) Nonaqueous solvent:
Dissociation constant (pKa):
Partition coefficient (log P):
(octanol/water)
1.5 at 20°C
>10% solubility In
acetone, ether and
ethanol
not available
0.7 (experimental);
1.36 (measured);
1.03
Hacklson et al., 1981
Weast and Astle, 1985
Bloconcentratlon factor (log): 0.55
FuJlsawa and
Hasuhara, 1981;
Hansch and Leo, 19B2;
Reinert, 1987
Lyman et al., 1982
0485d
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^oc*
Density (specific gravity):
Vapor density (alr=l):
Evaporation rate
(butyl acetate=l):
Refractive Index, np:
07 {calculated}
0.95
3.6
3.1
1.414220
Vapor pressure (ram Hg at 20'C): 35
Henry's Law Constant
latm-mVmol):
Flash point (closed cup) (°C):
Conversion factors:
3.24x10"*
(calculated from
water solubility
and vapor pressure)
10
1 mg/m»=0.24 ppm,
1 ppm»4.16 mg/m3
Lyman et al.. 1982
Mack 1 son et al., 1981
HSDB, 1989
Hacklson et al.. 1981
Weast and Astle,
1985-1986
HSDB, 1989
Howard, 1989
Hacklson el al., 1981
HSDB, 1989
Methyl methacrylate Is readily polymerized by light and heat; therefore,
an Inhibitor, usually 10-15 ppm of rnonomethyl ester of hydroqulnone, Is
added to the chemical. The reactive sites Include the terminal vlnyllc
carbon, the double bond, the allyllc methyl group, the ester moiety, and the
functional groups in the nonmethacrylate moiety {Nemec and Kirch, 1981).
1.3. PRODUCTION DATA
As of January 1, 1989, all domestically-produced methyl methacrylate was
manufactured by the acetone cyanohydrln (ACN) process (SRI, 1989). In Ihls
process, hydrogen cyanide Is reacted with acetone to produce acetone
cyanohydrln, which is treated with excess concentrated sulfuric acid to form
methacrylamlde sulfate. The methacrylamlde sulfate is reacted directly with
methyl alcohol to form crude methyl methacrylate and ammonium blsulfate, and
the crude methyl methacrylate Is purified by distillation (Nemec and Kirch,
19B1; SRI, 1983).
0485d
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Several alternative processes have been proposed for the production of
methyl methacrylate, some of which may be loss expensive than the ACN
process. C^-Oxldatlon technology Is expected to be the source of future
methyl methacrylate expansions (Nemec and Kirch, 1981). Isobutylene, a
major component In streams from ethylene plants, Is a major component
of the process, for the production of methyl methacrylate, Isobutylene 1s
oxidized to methacroleln and further oxidized to methacryllc acid. The
methacryllc acid (overall yield, 55-65%) 1s separated from by-products and
Is ester If led with methanol to methyl methacrylate (Nemec and Kirch, 19B1).
Asahl Chemical Industries, Du Pont, Mitsubishi Rayon, Nippon Shokubal KK,
Nippon Kagaku and Sohlo Cheme 1a1 Company are reportedly producing methyl
methacrylate from processes In other countries. Some of these
companies are already 1n commercial production or have plants under
construction (SRI, 1983); however, no U.S. companies were using alternative
processes as of January 1, 1909 (SRI, 1989).
Currently, there are three U.S. producers of methyl methacrylate with a
total production capacity of 1155 million pounds (SRI, 1989). These
companies (listed with their January 1, 1989, production capacities In
millions of pounds) are as follows: CYRQ Industries, Inc., New Orleans, LA
(215); E.I. du Pont de Nemours & Co., Inc., Hemphls, IN (280); and Rohm and
Haas Co., Deer Park, TX (660} (SRI, 19B9). A fourth producer, Alarlc Inc.
(reported capacity of 1.5 million pounds) was scheduled to begin production
In 1983 (SRI, 1983), but this company was not listed among 1989 producers.
Methyl methacrylate produced In the United States totaled more than 800
million pounds In 1903 (Kent, 1983) and 859 million pounds In 1985 (USITC,
1905). In 1985, an additional 28.9 million pounds of methyl methacrylate
was Imported (Bureau of Census, 1985).
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1.4. USE DATA
The consumption of methyl methacrylate Increased from 400 million pounds
1n 1968 to 751 million pounds In 1979, then gradually decreased to 676
million pounds In 1982. In 1901, 70% of the 603 million pounds of methyl
methacrylate produced was consumed as a captive Intermediate (SRI, 1983).
Essentially all of the methyl methacrylate produced 1s used for the
synthesis of acrylic polymers, which are used In the production of acrylic
sheet, molding and extrusion powders, surface coating resins and emulsion
polymers. These have applications In adhesive, leather, paper, polish,
sealant and textile production (SRI, 1983). In medicine, the polymers are
used 1n orthopedics, neurosurgery and ophthalmology (Deyerle et a!., 1979).
1.5. SUMMARY
Hethyl methacrylate (CAS No. 80-62-6), an ester of methacryllc acid, is
a colorless liquid with a boiling point of 100"C at 760 mm Hg and a vapor
pressure of 35 mm Hg at 20°C. Hethyl methacrylate Is moderately soluble In
water and Is soluble 1n acetone, ether and ethanol (Macklson et a 1., 1981;
Heast and Astle, 1985-1986). This chemical 1s readily polymerized by light
and heat, necessitating the addition of an Inhibitor, usually 10-15 ppm of
monomethyl ester of hydroquinone (Nemec and Kirch, 1981).
The production of methyl methacrylate has been limited to one process,
the acetone cyanohydrin process (ACN), but more economical alternative
methods have been proposed, the most promising of which 1s derived from
C^-oxidatlon technology (Nemec and Kirch, 1981).
Recent production figures for methyl methacrylate Indicate thai the
three U.S. producers of the chemical have a total production capacity of
1155 million pounds (SRI, 1989). Actual production volumes could be lower,
but these data were not available for 1989. Approximately 800 million
04B5d
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pounds of the chemical was produced In the United States and an additional
28.9 million pounds was Imported to the United States In 1985 {USITC, 1905;
Bureau of Census, 1905). Data from 1981 show that 70% of the methyl
methacrylate produced was as a captive Intermediate (SRI, 1983).
Essentially all of the methyl methacrylate produced Is used for the
synthesis of acrylic polymers, which are used 1n the production of acrylic
sheet, molding and extrusion powders, surface coating resins and emulsion
polymers. These have applications In adhesive, leather, paper, polish,
sealant and textile production (SRI, 1983}. In medicine, the polymers are
used In orthopedics, neurosurgery and ophthalmology (Deyerle et al., 1979).
0485d
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2. ENVIRONMENTAL FATE AND TRANSPORT
Methyl methacrylate may be released lo the atmosphere, wastewater or
land during Us production, Us use In the manufacture of resins and
plastics, and Us storage (IARC, 1979).
2.1. AIR
2.1.1. Chemical Degradation. Experimental data suggest that methyl meth-
acrylate released to the atmosphere could undergo photochemical degradation.
Singh et al. (1904} conducted a study In which volatile chemicals were rated
according to smog-forming ability, based on the properties of reactivity and
volatility. Hethyl methacrylate ranked In Class III for both properties,
indicating that the chemical would participate 1n smog Formation.
3osh1 et al. (19B2) measured the photochemical reactivity of methyl
methacrylate 1n a smog chamber, using ozone formation as the endpolnt of
reactivity. Two ratios of methyl methacrylate:nltrogen oxides (with -1054 as
NO^) were employed. A 2:1 ratio simulated urban conditions, and a ?0:1
ratio was analogous to a rural environment. At the 2:1 ratio, the time to
maximum ozone production (0.73 ppm) was 4.4 hours; while at 20:1, the maxi-
mum ozone concentration, 0.2 ppm, occurred at 1.4 hours. The Investigators
attributed the decreased reactivity al the higher ratio to the fact that, in
addition to Us participation In the formation of ozone, methyl methacrylate
also reacts with ozone. At the 2:1 ratio, 90% of the methyl methacrylate
had reacted with nitrogen oxides by the time the ozone concentration had
peaked. At the 20:1 ratio, only 1B?4 of the methacrylate had reacted when
the ozone concentration peaked, thus more methacrylate was available to
react with the ozone. The half-life of methyl methacrylate was 2.7 hours
under urban conditions and >3.0 hours for rural conditions.
04B6d
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The atmospheric reaction of methyl methacrylate with singlet molecular
oxygen (second-order rate constant, 1.18xl0~4 4,/mol/sec {Datta and Rao,
1979); estimated half-Hfe, >60 years] Is not significant In determining the
fate of the methacrylate 1n the atmosphere (U.S. EPA, 1985).
2.1.2. Transport. Because methyl methacrylate Is soluble In water [1.59
g/100 g solution at 20°C (Nemec and Kirch, 1981)], Us removal from the
atmosphere In rain would be expected (U.S, EPA, 1905).
2.2. HATER
2.2.1. Chemical Degradation. The UV absorption maximum for methyl
methacrylate Is 231 nm (Grasselll and RHchoy, 1975), Indicating that direct
photolysis, which occurs at >290 nm (Howard, 19B9), 1s not a significant
route of degradation for methyl methacrylate. However, It has been
suggested that free radicals formed 1n natural waters by the action of light
might react with methyl methacrylate (Howard, 19B9). This could possibly
enhance polymerization, thus Inactivating the monomer. Otsu et al. (1979)
reported that methyl methacrylate in dloxln, irradiated with light above 300
nm, polymerized in 1.2 hours with a polymer yield of 0.43X. The yield of
the polymer was significantly Increased when the exposure took place in the
presence of ketone polymers, possibly because of the radical dissociation
that occurs In the ketone polymers (Otsu et al., 1979).
Information on the hydrolysis of methyl methacrylate Is limited.
Organic esters in general undergo alkaline and acid hydrolysis to the
respective acids (Morrison and Boyd, 1973). Acid hydrolysis data for methyl
methacrylate were not found; however, a second order alkaline hydrolysis
rate constant of 200*40 H"1 hr"1 at 25*C has been reported for the
chemical (Ellington et al., 1987). The estimated hydrolysis half-Hfe of
methyl methacrylate Is 2.5 hours at pH 11.13 and 3.9 years at pH 7
(Ellington et al., 1987).
048bd
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2.2.2. Blodegradatlon. Hethyl methacrylate should be degradable by
biological sewage treatment If appropriate acclimatization of the biota can
be achieved to minimize toxicity to the organisms (Thorn and Agg, 1975).
Thorn and Agg (1975) maintain that to achieve blodegradatlon, the Initial
concentration of the chemical should be very low, Increasing gradually to
allow acclimatization to take place; there must be a continual discharge of
the compound, otherwise acclimatization may be lost; and the concentration
of the chemical should remain fairly constant.
Methyl methacrylatc was reportedly completely degraded by activated
sludge In -20 hours (Slave el al., 1974). The chemical was also signifi-
cantly degraded In the blodegradablllty test of the Japanese Ministry of
International Trade and Industry (H1TI), In the presence of a mixed Inoculum
of soil, surface water and sewage (Sasaki, 1978).
Pahren and Bloodgood (1961) evaluated the biological oxidation of methyl
methacrylate under aerobic conditions, using acclimated domestic sewage
seed. At the concentration of 10 mg/i, 47X of theoretical oxidation
(based on C0^ production) was achieved 1n 10 days of Incubation al 26°C.
By 22 days, 66% of theoretical oxidation had been achelved.
2.2.3. Transport. Methyl methacrylate In water will be lost primarily
through volatilization (Howard, 1989). A half-life of 6.3 hours has been
calculated for the evaporation of methyl methacrylate from a typical river,
1 m deep with a 1 m/sec current and 3 m/sec wind (Howard, 1909; Lyman et
al., 1982). Adsorption to sediment or particulate matter should not be
significant (Howard, 1989).
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2.3. SOIL
2.3.1. Blodegradatlon. No data were found for the blodegradatlon of
methyl methacrylate In soil; however, some blodegradatlon Is expected based
on the evidence In Section 2.2.2., that methyl methacrylate Is blodcgraded
In activated sludge.
2.3.2. Transport. Methyl methacrylate In the soil would be moderately to
highly volatile based on the vapor pressure of 38.4 mm Hg at 25°C, the
Henry's law constant of 3.24xlCT* atrn-rnVmol and relative wet and dry
-1/? -1/4
soil volatilities of 3.6 3.0 hours for rural conditions {Joshl et al., 1982).
Methyl methacrylate could also be removed from the atmosphere In rain
because of its solubility In water (U.S. EPA, 1985).
Methyl methacrylate In water Is lost primarily through volatilization.
The half-life of the chemical In a typical river, 1 m deep with a 1 m/sec
current and 3 m/sec wind has been estimated to be 6.3 hours (Howard, 1989;
Lyman et al., 1982). Direct photolysis of methyl methacrylate is not a
significant route of degradation 1n the aquatic environment; however, 1n the
presence of free radicals that are formed In natural waters by the action of
light, methyl methacrylate could undergo polymerization to some extent and
become Inactive (Otsu et al., 1979). Hydrolysis of methyl methacrylate does
0486d
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occur, bul only under extremely alkaline conditions (Ellington el al,,
1987}. For example, at pH 11,12, the estimated hydrolysis half-life of
methyl methacrylate 1s 2.5 hours while, at pH 7, the half-life Is 3.9 years
(Ellington et al., 1987).
Methyl methacrylate can undergo rapid blodcgradatlon, but this may occur
only In the presence of acclimated organisms (Thorn and Agg, 1975). In one
study, methyl methacrylate was completely degraded by activated sludge in
-20 hours (Slave et al., 1974).
In soil, volatilization would be the main elimination process for methyl
methacrylate; however, because of Its low potential for adsorption [K^O?
(Lyman et al., 1982)] and Its solubility In water [1.59 g/100 g solution
(Howard, 1909)], some of the chemical would be expected to leach into
groundwater (Howard, 1989).
0486d
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3. EXPOSURE
Exposure to methyl methacrylate can occur as a result of release of the
chemical Into the workplace or Into the aquatic, terrestrial or atmospheric
enviroments. Methyl methacrylate can affect the body If It Is Inhaled,
Ingested or comes in contact with the eyes or skin {Macklson et al., 1981),
but It also has excellent warning properties, based on odor detection. The
alr-d1lution odor threshold of 0.003 ppm (v/v) and a water odor threshold of
0.025 ppm (v/v) have been estimated for methyl methacrylate {Amoore and
Hautala, 1983). According to the classification devised by Amoore and
Hautala (1983), methyl methacrylate is 1n odor safety class A. Class A
chemicals at TLV concentrations In the air can be perceived by 9055 of
distracted persons (that Is, those whose attention Is not focused solely on
detecting an odor).
3.1. OCCUPATIONAL EXPOSURE
The primary sources of human exposure to methyl methacrylate are
occupational (HSDB, 1989). Exposure has been associated with Industrial
operations and medical procedures. Although current exposure figures were
not available, NI0SH estimated that In 1974. 30,000 workers 1n the United
States had been exposed to methyl methacrylate (IARC, 1979).
3.1.1. Industrial Operations. Industrial exposure to methyl methacrylate
may occur during the following Industrial uses; the casting of acrylic
sheets; the molding of acrylic sheets or polymethacrylate powders; the spray
application of unsaturated polyester resins; the brush or roller applica-
tions of unsaturated polyester resins; the manufacture of methyl methacry-
late resins for surface coatings; polymerization to produce molding and
extruding powders; the production of synthetic fibers and polyester resins;
0487d
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dye molding of articles from polyester resins; the production of emulsion
polymers for use in adheslves, sealants, fabrics, sizes, leather finishes,
paper coatings, polishes; and the machining of articles from resins
(Hacktson et al., 1961).
Cromer and Kronoveter (1976) conducted extensive air sampling 1n five
plants manufacturing poly(methyl methacrylate). During a screening study
for health effects resulting from exposure to methyl methacrylate monomer
vapors, mean 8-hour TWAs for exposure by Job category ranged from 4 ppm
(v/v) for maintenance workers to 88 ppm (v/v) for distillers. In only two
cases, both In the same plant, did the exposure ranges exceed 100 ppm (the
current OSHA standard): mixers were exposed to 11-145 ppm (v/v) and
distillers were exposed to 25-174 ppm {v/v}.
Samlml and Falbo (19B2) monitored workers' breathing zones and the
atmospheres of various work stations In a polystyrene production plant for
the following chemicals that are used In the production of styrene-based
polymers: ethyl acrylate, methyl methacrylate, n-butyl acrylate, styrene,
tt-methylstyrene, 2-ethylhexyl acrylate, acrylic acid, and methacryltc
acid. The chemicals were measured In the same sample, by gas chromato-
graphy, using analytical procedures recommended by N10SH. The procedure Is
outlined In Section 3.1.3.
Methyl methacrylate mean TWA concentrations of 46, 96 and 103 ppb
(ranges: not detected [nd]-37B, nd-796 and nd-373 ppm) were detected in the
breathing zones of workers at reactors A, B and C, respectively, where
emulsion and solution polymers were produced. The hatches of A and B were
open for the addition of material during the preparatory stages of the
process; however, reactor C was closed at all stages of the process. The
mean TWA concentrations of methyl methacrylate In the atmospheres of the
0487d
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workstations were 601, 226 and 565 ppb (ranges; nd-3.3 ppm, 22-662 ppb and
nd-3.1 ppm) for reactors A, B and C, respectively. Methyl methacrylate was
not detected in the breathing zone of workers or In the atmosphere of
reactor D, which was used mainly for the production of polymer flake. This
was also a completely closed system. The monomers used In the production of
the polymers were unloaded at a receiving dock from rail cars and truck
tankers outdoors, and because the attendant did not normally remain In the
area during the unloading operations, the potential for exposure was
minimal. Breathing zone concentrations averaged 18 ppb {nd-94 ppb) and
atmospheric concentrations averaged 66 ppb (nd-1.2 ppm). The Investigators
concluded that use of the two separate local exhaust ventilating systems In
the processes and care In handling of the monomers contributed significantly
to the relatively safe working environment of this facility.
Atmospheric concentrations of methyl methacrylate In a Polish chemical
factory ("a methyl methacrylate and styrene plant"), measured by a
colorImetr1c procedure, averaged 11.06 mg/m* (2.65 ppm), with a median of
17.6 mg/m3 (4.22 ppm) and a range of Q.20-302.3 mg/m* (0.05-91.75 ppm)
(Jodrychowskl, 1982). Methyl methacrylate has also been detected In the air
of a factory producing polymethyl methacrylate sheets (20-736 mg/ma)
(5-177 ppm) (Delia Torre et al., 19B2) and In a methyl methacrylate produc-
tion and processing facility (maximum concentrations were 150-300 mg/m* at
the prepolymerlzatlon stage) (Popler et al.. 19B5). Hethyl methacrylate was
also detected In the emissions from industrial boilers that burned hazardous
waste materials In conjunction with a primary fossil fuel (Olexsey, 1984).
Methyl methacrylate concentrations were below the limits of detection
(0.01 mg/sample) 1n the plalcmaklng department of a Denver newspaper,
although 2 of the 15 workers Interviewed had dermatitis and hives, which are
symptoms consistent with methyl methacrylate exposure (Gunter, 1982).
04B7d
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3,1.2. Medical Procedures. For surgical procedures, polymethyl meth-
acrylate powder (containing benzoyl peroxide, a polymerization activator,
and dlmethylparatoluldlne) Is used 1n combination with liquid methyl
methacrylate monomer (containing hydroqulnone, a polymerization Inhibitor)
to form self-curing acrylic cement. When these ingredients are mixed, a
white dough Is formed that sets hard In 5-10 minutes, with the production of
heat (Deyerle et al., 1979). Self-curing acrylic cement has been used 1n
orthopedic surgery 1n the bonding of prostheses Into bone for Joint replace-
ments and the stabilization of pathological fractures, and In neurosurgery
in the repair of cranial defects. A crude form of polymethyl methacrylate
(PHHA) 1s used In the manufacturing of hard contact lenses and Intraocular
lenses.
In orthopedic surgery, the cement must be allowed to harden inside the
body and In neurosurgery, the polymer Is prepared and molded by the surgeon,
but hardening takes place outside the body. Contact lenses are prefabri-
cated (Oeyerle el al., 1979). During the mixing and curing of the polymer,
methyl methacrylate monomer can be released to the atmosphere or to
surrounding tissues. Peak atmospheric concentrations have been reported
during mixing and In the first 15 minutes after mixing (Maltla, 1903;
Pickering et al.. 1986; Oarre et al., 1937; Schoenfeld et al.. 1979).
Physicians, operating room personnel, dental laboratory workers, ocular lens
laboratory workers and patients wearing prostheses or Implants containing
methyl methacrylate are at risk for exposure to the monomer.
Examples of methyl methacrylate concentrations that have been measured
In the atmospheres of operating rooms, workrooms or simulated situations
where the compound Is used are presented in Table 3-1. A few examples of
tissue levels of methyl methacrylate are also presented.
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TABLE 3-1
Atno&pherlc Methyl Hethaerylate Concentrations During Medical Procedures
--j
Source
Assay Medlun
Concentration
Analytical Method
Consent
Reference
Orthopedic ceraent
air
0.4, 1.0 and
S.O ppa
NO
Sanples collected during surgery near
mixing table on two different days
Scolnlck and
Collins, 1986
Orthopedic ceoent
air
161-374 ppn
Infrared gas
analyzer
Simulated procedure for surgery;
during nixing In open rooa
Pickering ct al.,
1SB6
Orthopedic ceoent
air
0 ppa
Infrared gas
analyzer
Sane procedure as above; during
nixing In fuae cabinet
Pickering et al.,
1986
Orthopedic ceoent
air
1.77*0.04 grti'-
2.94*0.34 qfsO
(424-705 ppn}
GC
Sanples froa 7 coraaerclal ceocnls,
collected during nixing and setting
near edge of bowl; nixing lines
<1 alnule
Parre et al.,
1997
Surgical mixture
air
0.53 ppn
NO
3-hour TWA during nixing using
exhaust stand
Hattla, 1993
Surgical Mixture
air
0.9 and 4.4 ppa
NO
Konentary peaks during nixing using
exhaust stand
Mattla, 1983
Dentil base resin
air
ft and 20 ppn
GC
Work position during finishing and
polishing of resin, 30 cn froa work-
place; no ventilation
ftrune and
Beltcsbrekke,
1981
Dental base resin
air
<5 ppn
GC
Sane procedure as above; with venti-
lation
Brune and
Seltesbrekke,
1981
Orthopedic cencnt
blood
raean, 1 t>g/m
(¦ai.. 16 »g/Rt)
GC
35 patlrnts following 69 Inplants;
nonoaer detected In blood from vena
cave only during first 3 minutes
after loplantatlon
tggert et al.
1974
«
Recently nade
palatal appliances
whole saliva,
hunan subjects
aax., 45 v9/nl
GIC
(detection Unit,
-1 yg/M)
Hononer detected for 1 week after
Insertion of cold polynerlied plate
Baker et al.,
1986
Recently nade
palatal appliances
salivary flla
on ruling
surface of
plate. Tiunan
subjects
rui. , 1B0 vg/ol
GIC
(detection Unit.
-1
Saoe procedure as above
Baker et al..
19B8
-------
TABLE 3-1 (cont.)
Source
Assay Hedlua
Concentration
Analytical Method
Consent
Reference
Recently nude
palatal appliance
Recently nade
palatal appliance
whole saliva,
hunan subjects
whole saliva,
hunan subjects
6.3 pg/ot
GLC Baseplate cured at 70*C for 3 hours Baker et al., 1908
(detection llnlt,
-1 k7/
-------
3.1.2.1. ATMOSPHERIC EXPOSURE — Under experimental conditions
simulating operating room procedures, levels of methacrylate monomer
detected In the air ranged from 0.4 ppm "near" the mixing table to 705 ppm
"near" the edge of the bowl during mixing and setting of the cement. The
use of a fume cabinet, an exaust hood or other ventilation during mixing can
reduce atmospheric concentrations of the monomer considerably (Brune and
BeUesbrekke, 1981; Hattla, 1983; Pickering et al., 1986) {see Table 3-1).
The use of short mixing times for the cements can also help to minimize air
concentrations of monomer (Oarre et al., 1987). Generally, atmospheric
concentrations would not be expected to exceed the OSHA limits for methyl
methacrylate (100 ppm), but even low levels can result 1n allergic sensiti-
zation (Pickering et al., 1986}.
Waegemaekcrs et al. (1983a) demonstrated in diffusion experiments,
using gas chromotography, that methyl methacrylate at 21DC and 35°C could
pass through seven different surgeon's glove materials and emphasized the
need for a better protective material. Appropriate preventive measures
should almost eliminate the risk of skin effects from bone cement 1n
surgical personnel (Fregert, 1983).
In several Health Hazard Evaluation surveys conducted by NIOSH for
potential worker exposure to methyl methacrylate, levels of the chemical
detected In the workplace did not exceed the current TLV-7WA of 100 ppm (410
mg/m3). For example, air samples collected In a dental office contained
methyl methacrylate concentrations of ?.4 mg/ma (29 mln personal sample)
and 0.4 mg/m* (1.5 hour area sample) (Zey, 1988); methyl methacrylate
exposures ranged from <0.4-3.3 ppm for scrub nurses, assistant surgeons and
anesthesiologists In the operating room during h 1 p surgery procedures where
methyl methacrylate was used (Apo1 and Helgerson, 1984). In a survey of a
0487d
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11/06/90
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foot clinic In which methyl methacrylate was used 1n the preparation of shoe
Inserts, methyl methacrylate concentrations of 17-417 mg/m3 were detected
for a 45-m1nute sampling. The average time spent preparing the Inserts Is
-45 minutes to 3 hours/day, which would not constitute overexposure. If the
job took 0 hours, however, overexposure could occur (Gunter and Schulenberg,
1982).
3.1.2.2. EXPOSURE FROM SURGICAL OR DENTAL APPLIANCES — Several cases
of sensitization to methyl methacrylate have been reported for individuals
using acrylic resin appliances. Polymerization and curing of the methyl
methacrylate resin may take place by heating or by cold curing at room
temperature. In the process of cold curing, polymerization is induced with
an accelerator, usually benzoyl peroxide. Polymerization of a cold-cured
resin is never as complete as that of the heat-cured type. While 3-5% of
the cold-cured resin 1s free monomer, only 0.5% of heat-cured resin Is
residual monomer (Phillips, 1973). Heat-cured products rarely produce
sensitization (Fisher, 1954).
Gulll and Odom {197B> reported a case of recurrent eczematous dermatitis
of the ear, which was due to sensitivity to the cold-cured methyl methacry-
late monomer used in the manufacture of the patient's hearing aid. Contact
dermatitis also resulted from the wearing of two different prostheses made
of fiber glass and resins that contained 95 and >99% methyl methacrylate,
respectively (Foussereau et al., 1989). Exposure to methyl methacrylate
resulting in allergy has also been associated with the wearing of plastic
fingernails (Calnan, 1980; Fregert, 1983).
Methyl methacrylate monomer has been detected in the blood of patients
receiving orthopedic Implants (Eggert et al., 1974) and in saliva shortly
after the insertion of dental plates (Baker et al., 1988} (see Table 3-1).
0487d
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Schoenfeld et al. (1979) studied the release of methyl methacrylate
monomer from bone cement during simulated In vivo polymerization of the
material. Honomer release from disc-shaped specimens of reacting cement
Into an aqueous medium (to simulate Us release Into Interstitial fluid) was
assayed by gas chromatography. The discs contained 5 g of powder and 2.5
mi of monomer. The amount of monomer released was evaluated as a function
of (1) lapsed time after Insertion, (2) the time Interval from the initia-
tion of mixing of the monomer and powder to Insertion, (3) the proportion of
monomer liquid and polymer powder, and (4) the thickness of the reaction
cement mass. Host of the monomer was released during the first 15 minutes
of Immersion (corresponding to the period 1 n which the monomer-powder mix-
ture Is curing). During this time, -49 mg (-2.IX by weight) of the monomer
appeared In the aqueous medium, and stayed constant for up to 25 hours,
Indicating that there was no further release of monomer. The residual
monomer remaining after curing is trapped In the bulk of the cement. The
Investigators concluded from this that the concern for patient safety with
regard to monomer release should probably be directed to the time period
from Insertion of the cement to completion of the curing reaction. Times
from mixing to Insertion of the cement were varied (5, 7.5, 10 and 15
minutes) to determine If timing could make a difference In the amount
actually released Into the body; however, no more than a 0.7% difference was
noticed between 5 and 10 minutes. The cement must be In place before It
sets, thus, 15 minutes Is too long to wait because It has set by that time
to the extent that It could not be properly Inserted. The minimum release
occurred when the ratio of monomer/powder was ~0.4 mi/g. In terms of unit
area covered, thin specimens released less monomer than thick ones.
0487d
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Methyl methacrylate migration from five different acrylic bone cements
was measured outside the body 1r three fractions of bone marrow (Wlllert et
al., 1973). Placed 1n the tissue medium after 90 seconds of polymerization,
the various polymers released 0.7-5.1% of the monomer by weight Into the fat
fraction, 0.2-2.OX Into the fibers and cells fraction, and 0.003-0.16% Into
the red blood cell fraction.
laker et al. (1989) detected methyl methacrylate monomer 1 n the saliva,
but not 1n the urine or blood, of Individuals wearing recently made cold
polymerized dental plates (see Table 3-1). The investigators concluded that
although the concentrations of the monomer In the saliva were small, the
levels could be sufficient for sensitization. Ingestion of large amounts
would not be expected. They also found that Immersion of the cold-
polymerized material In water for 24 hours reduced monomer release to below
detectable levels, and recommended that this be done before Insertion.
The processing of methyl methacrylate In manufacturing Intraocular
lenses depolymerlzes the methyl methacrylate to the extent that the lenses
can contain up to $% of the monomer; however, only a small fraction of
monomer at the surface Is available for leaching (Gal In et al., 1977; Molyk
and El frig, 1979; Schoenfeld et al., 1979). ludwlg et al. (1987) estimated
mathematically that for a lens mass of -15 mg, the concentration of methyl
methacrylate monomer In the aqueous humor Is -10"* of the concentratIon In
the lens, perhaps persisting for several weeks.
3.1.3, Detection Methods. Samlml and Falbo (1962), using analytical
procedures recommended by N10SH for the detection of methyl methacrylate In
air, found the following conditions to be optimal In this study:
Column; 3m x 3.175 mm (10x1/8") stainless
steel, packed with 10% fFAP on
80/100 mesh Chromosorb WAW-DMCS
0487d
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Hydrogen Gas:
Carrier Gas (Nitrogen):
2.59 atm (38 pslg); 32 mi/mln
1.2? atm (38 pslg); 22-25 mi/mln
Air (Purified):
2.59 atm (36 pslg); 270 mi/mln
Injection Port Temperature: 225°C
Detector Temperature:
255°C
Column Temperature 16 m1n, 30 sec at 70°C, 40 sec to raise
(Programmed): the temperature to 110°C at a rate of 60°C/m1n, and
18 mln at 110°C
Darre et al. (1988) developed a simple method for Instant determination
of the air concentration of methyl methacrylate. The method utilizes a
DrSger gas detector bellows pump M 21/21 In conjunction with a methyl
methacrylate DrSger tube. With 10 strokes of the bellows pump, air Is
sucked Into the tube. In the presence of methyl methacrylate monomer, the
Indication layer In the tube turns from yellow to blue, based on the
reaction of methyl methacrylate with a molybdate-palladlum salt reagent.
The total length of the blue discoloration 1s a measure of the concentration
of monomer. The range of detection with ten strokes of the bellows is
50-500 ppm. The concentrations of methyl methacrylate in the air of an
operating room during hip replacement operations were consistent with values
reported in gas chromatographic studies.
3.2. SURFACE WATER CONTAMINATION
The U.S. EPA (19B7) reported that methyl methacrylate was detected In
effluents from the following industries at the concentrations (vg/i)
Indicated: leather tanning (5.2), paint and Ink (25.8), plastics and
synthetics (1.6>, pesticides manufacturing (1.2), adheslves and sealants
(1.4), electronics (69.6), public owned treatment works (11.4) and one
unidentified source (2.3).
04Q7d
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3.3. FOOD CONTAMINATION
No data were found to document the detection of methyl methacrylate in
food; however, the results of a laboratory study suggest that methyl
methacrylate could migrate from food wrap into food. Inoue et al. {1981)
examined the migration of residual methyl methacrylate monomer from
poly(methyl methacrylate) food containers to food-simulated solvents, using
gas chromatography (detection limit, 0.05 ppm). The solvents used were
water, 4% acetic acid and 2OX ethanol. Residual methyl methacrylate levels
of 0.03-1.00% were measured 1n the cormierdal food containers and concentra-
tions of 0.?-?.16 ppm were detected 1n the alcohol, but no monomer was
detected In water or 4% acetic add.
3.4. DRINKING HATER CONTAMINATION
Methyl methacrylate has been detected by gas chromatography/mass
spectrometry In drinking water taken from sampling taps at treatment works
(Fielding et al., 1981), from a commercial delonlzlng-charcoal filtering
unit (Oowty et al., 1975}, and from the Chicago Central Water Works (Ewlng
et al., 1977). In all three cases, the chemical was not present in
untreated water samples. Dowty et al. {1975) suggest that the methyl
methacrylate In the sample from the charcoal filtering unit could have
originated from plastics used In the purification processes. Hethyl
methacrylate (—10 ppb) was also detected at the Chicago Central Water Works
In final tap water (after chlor1 nation} during a study In which 204 water
samples were collected from 14 heavily Industrialized river basins (Ewlng et
al., 1977).
3.5. ATMOSPHERIC CONTAMINATION
Patterson et al. {1976} estimated that total emissions of methyl
methacrylate were 7.9 million pounds (3.5 million kg) {-1.0% of the total
04fi7d
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production of methyl methacrylate). In 1974, 3.8 million pounds (1.7
million kg) was released from methyl methacrylate production facilities, 3.8
million pounds (1.7 million kg) was released from end-product manufacturing
facilities and 0.3 million pounds (0.14 million kg) was released from bulk
storage facilities (Patterson et al.t 1976). Using the 1983 production
figures for methyl methacrylate of >800 million pounds (362 million kg)
(Kent, 1983), emissions of 6 million pounds (3.6 million kg) can be
estimated for that year, assuming that no Improvements had been made 1n
emission control.
In a European study, methyl methacrylate levels of 5-20 ppm (20-01
mg/ma) were detected 1n the air exaust stack of an Industry where paints
based on acrylic resins were dried (Schulz and Gunther, 1972).
An additional process that may result 1n the atmospheric release of
methyl methacrylate Is the pyrolysls of methyl methacrylate that might occur
during the Industrial processing of the polymer. Johnston et al. (1908)
reviewed the combustion characteristics of the polymer and concluded that at
temperatures <500 or 600°C, simple methacrylate polymers such as poly(methyl
methacrylate) are degraded almost entirely to the monomer. Above those
temperatures, the gaseous components become prevalent.
3.6. SUMMARY
The primary sources of human exposure to methyl methacrylate are occupa-
tional, occurring mainly as a result of Industrial operations and medical
procedures. The potential routes of exposure Include Inhalation, Ingestion
and skin and eye contact (Macklson et al., 1901). In addition. Internal
exposure may result from the use of methyl methacrylate 1n orthopedic
Implants and dental appliances.
0487d
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Industrial exposure has been associated wUh the use of the chemical in
various acrylic products (Hacklson et a!., 1981). Monitoring data show
several Instances In which the atmospheric levels of methyl methacrylate
exceeded the current TLV-TWA of 410 mg/m3 (100 ppm). For example, in a
survey of five plants manufacturing poly(methyl methacrylate) mean 8-hour
THAs for exposure by Job category ranged from 11-145 ppm (v/v) for mixers
and from 25-174 for distillers 1n one plant. In other Job categories,
however, levels were lower, ranging from 4 ppm (v/v) for maintenance workers
to B8 ppm (v/v) for distillers. High levels of methyl methacrylate were
also detected in the air of a factory producing polymethyl methacrylate
sheets [20-736 mg/m* {5-177 ppm)] (Delia Torre et al., 1982) and in the
breathing zones of workers near reactors for polymer production (Sanilml and
Falbo, 1982). On the other hand, concentrations of <100 ppm of melhyl
methacrylate have been detected In the air samples from various facilities.
The use of closed systems, exhaust ventilating systems and care 1n handling
apparently can minimize exposure to methyl methacrylate (Samlml and Falbo,
1982).
Operating room personnel and orthopedic patients are at risk for
exposure to methyl methacrylate monomer released to the atmosphere during
the mixing and curing of the polymer. Patients may also be exposed to the
monomer In tissues surrounding Implants. Peak atmospheric concentrations
have been reported during mixing and 1n the first 15 minutes after mixing
(Mattla, 1983; Pickering et al., 1986; Darre et al., 1987; Schoenfeltl et
al., 1979). Levels of methacrylate monomer as high as 705 ppm have hern
detected near the edge of the bowl during mixing and setting of orthopedic
cement. The use of a fume cabinet, an exaust hood or other ventilation
during mixing can reduce atmospheric concentrations of the monomer consider-
ably (Brune and Beltesbrekke, 1981; KatUa, 19B3; Pickering el al., 1986).
0487d
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Although atmospheric concentrations would not be expected to exceed the OSHA
limits for methyl methacryiate (100 ppm), even low levels can result 1n
allergic sensitization (Pickering et al., 1986).
Hothyl methacryiate monomer has been detected In the blood of patients
following orthopedic Implants (Eggcrt et al., 1974) and In the saliva
shortly after the Insertion of dental plates (Baker et al., 1988). Simula-
tion experiments have demonstrated that methyl methacryiate monomer can be
released from bone cement during JJi vivo polymerization (Schoenfeld et al.,
1979; Wlllert et al., 1973). Small amounts of methyl methacryiate may also
be available for leaching at the surface of contact lenses (Galln et al.,
1977 ; Holyk and Elfrlg, 1979; Schoenfeld et al.. 1979; Ludwlg el al., 1987).
According to one source, methyl methacryiate was present In the efflu-
ents from several industries at concentrations ranging from 1.2 yg/i for
pesticides manufacturing to 69.6 ;ig/i. for electronics (U.S. EPA, 1987).
Methyl methacryiate has been detected In drinking water taken from sampling
taps at treatment works (Fielding et al., 1981}, and from a commercial
delonlzlng-charcoal filtering unit (Dowty et al., 1975). In both cases, the
chemical' was not present 1n untreated water samples. Methyl methacryiate
(-10 ppb) was also detected at the Chicago Central Water Works In final tap
water (after chlorInatlon) during a study 1n which 204 water samples were
collected from 14 heavily Industrialized river basins (Ewlng et al., 1977).
Hethyl methacryiate has not been detected In food, but the results of
laboratory experiments suggest that the chemical could migrate from food
wrap Into food.
In 1976, an estimated 1.0% of the total production of methyl meth-
acryiate was emitted to the atmosphere, primarily from methyl methacryiate
04B7d
3-15
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production facilities, end-product manufacturing facilities and bulk storage
facilities (Patterson et al. 1976). Hethyl methacrylate monomer may also be
released to the atmosphere from the pyrolysls of the methyl methacrylate
polymer.
0487d
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Ob/2 0/90
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Lethality data for methyl meth-
acrylate are presented In Table 4-1. The 24-hour LC^ of 1760 mg/i for
Paphnla magna and 96-hour IC5£) values for fish, which range from 151.5
mg/l {flowthrough) for the blueglll to 368.1 mg/i (static) for the
guppy, Indicate that the chemical Is of low acute toxicity to aquatic
animals.
Other observations that can be made from the acute toxicity studies
Include the following:
1. for both the goldfish and guppy, tested under the same static test
conditions, there were no differences between LCgg values at 24 and 96
hours (Pickering and Henderson, 1986). This was also true for the
blueglll when tested In a static assay; however, when the blueglll was
tested In a flowthrough assay, toxicity Increased with time, as
evidenced by lower LCcg values at 96 hours than at 24 hours (Bailey et
al., 1985).
2. For the fathead minnow 1n both hard and soft water and for the blueglll
In soft water (not tested In hard water) In a static assay, LC50
values were lower at 96 hours than at 24 hours {statlctlcally signifi-
cant with 95X confidence) (Pickering and Henderson, 1986).
3. N1nety-s1x-hour LCgp values for methyl methacrylate show that the
blueglll and guppy were the most sensitive species and that the blueglll
was more sensitive to the toxicity of methyl methacrylate In soft
{compared with hard} water (Pickering and Henderson, 1986).
4. Methyl methacrylate was more toxic In the flowthrough than 1n the static
assay (Bailey et al., 1905).
5. Fry, 1, 2 and 4 days old, appeared to be more tolerant to methyl meth-
acrylate than adults (Pickering and Henderson, 1986).
Juhnke and Ludemann (1970) conducted acute toxicity tests on the golden
orfe (Leuclscus Idus). LCQ, LC5Q and LC^^ values were 320, 350 and
3B0 mg/t, respectively. Experimental details, however, were not reported.
D488d
4-1
11/06/90
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TABLE 4-1
Kedtan flesponsc Concentration* for Aquatic Anloals (iposed to Kelhyl Methacrylate
Hedlan Response Concentration3
Speeds Test Kethed Contents'1 Seferenee
24-Hour 46-llour 9 b-Hour
Baphnla naqna
MO
1760 flj/t
NO
ND
Decfilorlnated tap H?0;
20-22'C; 02. saturated;
pH, 7.6-7.7; anlnals
24 days old
Goldfish
Carrasslui auratus
static
423.3 ng/l
(335.2-534.7)
423.3 ng/l
(335.2-534.7)
277.1 ag/t
(237.9-313.5)
25*C; 00, 7.8; pH, 7.5;
A.IB; K. 20
Goldfish
Cjrrass1 us aurataus
MO
NO
NO
ND
72-hour lC§g, 550 rag/t
fathead n Innew
Pleeohales pranelas
static
421.? mg/l
13S7.4-SI1.41
330.2 tnq/l
(291.7-39fl.JI
159.1 rag/I
(125.5-190.7)
25#C; DO, 7.8; pH, 7.S;
A,18; H. 20
Fathead nlnnov
PlmeDhalcs pronelas
static
455.1 pg/l
(374.7-664.9)
455.1 ng/t
(374.7-664.9}
160.2 rag/l
(136.3-183.4)
2S*C; DO, 7.B; pH. 7.5;
A. 16; H. 20
fathead Minnow
Plmeohal^s pronelas
static
498.6 mg/l
(194.7-617.8)
338.2 ftg/t
(291.6-398.7)
311 rag/l
(248.3-41B.7)
25-C; DO. 7.8; pH 8.2;
A, 300; H. 360
fathead minnow
Plnephales oronelas
static
331.9 rag/t
1340.9-471.41
368.1 mg/t
(326.4-426.8)
320 ng/t
(268.7-381.1)
25-C; 00. 7.8; pll, 6.2;
A, 300; II, 360
fathead minnow
Plnephales procwlas
NO
MO
NO
151.5 ng/t
ND
Cuppy
PcecIHa reticulata
static
368.1 mg/t
{326.4-426.9)
368.1 ssg/i
(326.4-426.9)
368.1 eg/I
(326.4-426.9)
25-C; 00, 7.8; pH, 7.5;
A. 18; K.20
Bluegtll
teponls nachrochlrut
static
368,1 ag/t
(326.4-426.9)
357.5 rog/t
|3U.4-417.1)
232.2 ng/|
(113.9-341.8)
25-C; DO, 7.B; pH, 7.5;
A, 18; H, 20
Blueglll
teponls raachrochlrus
static
283.0 pg/t
(267.0-300.0)
283.0 rag/t
(267.0-300.0)
203.0 rsg/t
(267.0-300.0)
22*C; dechlorlnated lap
H20; 00. -3; pH. 6-9
Bluegl11
leponls machrochirus
flowthrough
264.0 mg/t
(240.0 290.0)
264.0 rsg/t
(240.0-290.0)
191.0 ng/1
(1/0.0-206.0)
??*C, dcchlortn.itcd tap
ll20; DO, /.5; pH. 6 0
dVdlues In (i.ireritheses r<.'(iii-scnt 95% confident' Interval
''A - alkjllritty In ng/i; HO - dissolved uxyiji-n In rrij/i; H -
har itiii.-ss {I U) A>
In inj/t
Brlngiaann and
Kiitin, It??
Pickering and
Henderson, 19B6
Rclnert. 190?
Pickering and
Henderson, 19fi6
Pickering and
Henderson, 198b
Pickering and
Henderson. 1986
Pickering and
Henderson, 19B6
Reinert. 1987
Pickering and
Henderson, ltfil
Pickering and
Henderson, 198b
Bailey et al.,
1965
Bailey et at.,
I9H5
ND
Ku data
-------
In addition lo the standard static and flowthrough assays, Bailey et al.
(1985) conducted a plug-flow toxicity test In which the chemical Is released
In a single rapid discharge to simulate the chemical concentration profile
that would theoretically occur at the site of an accidental spill. The
chemical would be expected to reach a peak concentration quickly, then
decrease to background. During the exposure period, 99% of the water would
be renewed. LC,n values 1n the plug-flow procedure, determined at 1, 2. 4
PU
and 8 hours, were 1.5, 2.1, 1.3 and 1.0 times, respectively, those
determined in the flowthrough procedure.
Brlngmann and KOhn (1977, 1982) conducted studies with Daphnla magna 1n
which the toxicity of methyl methacrylate was measured 1n standard lethality
and immobilization assays. In addition to the LC5Q value shown In Table
4-1, LCq and LC100 values were B75 and 2500 mg/8., respectively
(Brlngmann and KOhn, 1977}. In the Immobilization assay, the EC5Q for
methyl methacrylate was 720 mg/i (95% confidence limit, 677-766), the
ECq was 502 mg/i and the EC-^g, 1042 mg/i (Brlngmann and KOhn,
19B2). These values further support the low toxicity of methyl methacrylate
to Daphnla.
Brlngmann and KOhn (1980) determined the toxicity threshold of methyl
methacrylate for the holozolc bacterlovlrus flagellate protozoan, Entoslphon
sulcatum, using the cell multiplication Inhibition test. Various dilutions
of the test chemical and the organisms were Incubated at 25QC for 72 hours,
and the number of protozoa were determined by means of a cell counter. The
toxicity threshold was 450 mg/i, Indicating low toxicity for methyl
methacrylate to this organism. In an analogous lest, toxicity thresholds
for the holozolc baclerlovlrus dilate protozoan, Uronema parduczl, and the
0408d
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06/26/90
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sapr0201c flagellate protozoan, Chllomonas paramaeclum were 556 and 178
mg/l, respectively, also Indicative of low toxicity (Brlngmann and KOhn,
19B1).
4.1.2. Chronic Effects on Fauna. No data were found regarding the
chronic effects of methyl metahcrylate on aquatic fauna. Based on the log
BCF of 0.55 (Lyman et al., 1982) and log P (octanol/water partition coeffi-
cient) values of 0.7-1.38 (Fujlsawa and Hasuhara, 1981; Hansch and Leo,
19B2; Relnert, 1987), no bloconcentratlon or bloaccumulatlon of methyl
methacrylate would be expected.
4.1.3. Effects on Flora. Brlngmann and KOhn (1978) determined the
toxicity threshold of methyl methacrylate for the green alga Scenedesmus
quadrlcauda and the blue-grcen alga Microcystis aeruginosa, using the cell
multiplication Inhibition test. Various dilutions of the test chemical and
organisms were Incubated at 27°C, relative humidity 5054, for 8 days and the
concentrations of the algal suspensions measured turbldlmetrlcally. The
toxicity thresholds, the concentrations at which Inhibition began, were 37
mg/l for Scenedesmus guadrlcauda (Indicating pronounced toxicity for
methyl methacrylate to this organism) and 120 mg/l for Microcystis
aeruginosa (Indicating low toxicity).
4.1.4. Effects on Bacteria. Brlngmann and KOhn (1980) determined the
toxicity threshold of methyl methacrylate for the bacteria, Pseudomonas
putlda. using the cell multiplication inhibition lest. Various dilutions of
the test chemical and the organisms were incubated at 25°C for 16 hours, and
the concentration of the bacterial suspension was measured turbldlmetrlc-
ally. The toxicity threshold, the concentration at which inhibition began,
was 100 mg/l. Indicating low toxicity for methyl methacrylate to this
organism.
0488d
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Stack (1957) tested the toxicity of methyl methacrylate 1n a system
using a laboratory culture developed with mlcoorganlsms from domestic
sewage. The toxicity threshold was defined as the concentration of the
toxic material that produces the same dissolved oxygen residual as a
biological oxidation reference containing several organic compounds. The
organisms were Incubated with either the test solutions or the reference for
3 days, and the residual oxygen was measured. In this particular system,
the toxicity threshold for methyl methacrylate to the unaccllmated micro-
organisms was >300 ppm (>300 mg/i).
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. No data were found.
4.2.2. Effects on Flora. No data were found.
4.3. FIELD STUDIES
No field studies were found for methyl methacrylate.
4.4. AQUATIC RISK ASSESSMENT
The data assessing the toxicity of methyl methacrylate to aquatic organ-
Isms are not sufficient for the development of water quality criteria by the
method of U.S. EPA/OWRS (19B5). Data were found for the acute toxicity of
methyl methacrylate to the freshwater families Oaphnldae, CyprInldae,
PoeclllIdae and Centrarchidae. Ninety-six-hour LC5Q values for fish that
range from 151.5 mg/l for the blueglll to 368.1 mg/l for the guppy,
Indicate that the chemical Is of low acute toxicity to aquatic animals.
Furthermore, If release should occur, the chemical has little potential to
persist or bloaccumulate and therefore Is unlikely to constitute a chronic
toxicity hazard.
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4.5. SUMMARY
The 24-hour LC,-p of 7760 rng/i for Oaphnla magna and 96-hour LC,.^
values for fish that range from 151.5 mg/2. (flowthrough) for the fathead
minnow {Relnert, 1987} to 368.1 mg/l {static) for the guppy (Pickering and
Henderson, 1986), Indicate that the chemical Is of low acute toxicity to
aquatic animals.
Hethyl methacrylate was also of low acute toxicity to three different
protozoa, the blue-green alga and Pseudomonas putlda in the cell multiplica-
tion Inhibition assay (Brlngmann and KOhn, 1978, 1980, 1981), but was very
toxic to the green alga (Brlngmann and KOhn, 1978). Using a system based on
biological oxidation, Stack (1957) demonstrated that the methyl methacrylate
concentration of 300 mg/i was not toxic to uriacclImated microorganisms
from domestic sludge.
No data were found for the chronic toxicity of methyl methacrylate to
aquatic organisms. Based on the log BCF of 0.55 (Lyman et al.. 198?) and
log P (octanol/water partition coefficient) values of 0.7-1.38 (Fujlsawa and
Hasuhara, 1981; Hansch and Leo, 1982; Relnert, 1987), no bloconcentratIon or
bloaccumulatlon of methyl methacrylate would be expected.
No data were found for the toxicity of methyl methacrylate to terres-
trial fauna or flora.
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5. PHARMACOKINETICS
5.1. ABSORPTION
Delchmann (1941) 1n a study on the toxicity and lethality, administered
methyl methacrylate (without polymerization Inhibitor) by stomach tube to
rats and rabbits. The rapid (2-5 minutes) onset of toxic effects {hyperpnea
followed by motor weakness, dyspnea, and death) Indicated that the test
compound and/or Us metabolites were being absorbed from the
gastrointestinal tract and distributed to target tissues. Inhalation
exposure of rats, rabbits and guinea pigs to methyl methacrylate (7.1-19.0
mg/fc) resulted In similar effects Indicating absorption of the compound.
The fate of methyl methacrylate In adult male rats was studied by Bratt
and Hathway (1977). 14C-labeled methyl 1,3-propylene-2-carboxylate {sp.
activity 0.398 mCl/mmol, >98% purity) was administered IntragastrIcally or
Intravenously as a single dose of 5.7 mg/kg (4 yCl). 14C-labelcd methyl
2-propylene-2-carboxy1ate (sp. activity 0.355 mCl/mmol, >98% purity) was
similarly administered but at doses of 6.8 mg/kg (4 mCI), 1.v. or 120
mg/kg (B4 yCl) IntragastrIcally. Excretion-retention patterns of the
14C label were then monitored over a 10-day period. For both labeled
compounds and both routes of administration, up to 65% of the radlolabel was
excreted as ,4C within 2 hours Indicating rapid absorption from the
gastrointestinal tract and rapid partitioning of the labeled portion of the
molecule out of the blood compartment. The excretory patterns and the
radlolabel Inventory were similar following the two routes of administration
suggesting rapid and extensive absorption of the Intragastrlcally
administered doses.
Raje et al. (19B5) provided Information on the absorption and tissue
distribution of methyl methacrylate monomer {99.9%) In male rats following
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Inhalation exposure to TOO ppm for 1, 2, 3 or 4 hours. The methyl meth-
acrylate monomer rapidly partitioned into the blood (11.14+1.01 mg%), brain
(25,24+2.04 vg/g) and lungs (20.60+1.01 yg/g). Methyl methacrylate
concentrations In each tissue did not vary significantly with exposure
duration suggesting a rapid and saturable absorption following Inhalation
exposure.
5.2. DISTRIBUTION
The only studies that provide definitive Information regarding the
distribution of methyl methacrylate 1n a mammalian system are those of
McLaughlin et al. (1973), Heme! el al. (1973), Bratt and Hathway ( 1977 ).
and Raje et al. (1985).
The Jtn vivo blood clearance of 14C-labeled methyl methacrylate monomer
(sp. activity 9.85 Cl/g) after Intraosseus Implantation (simulated hip
arthroplasty) and after Intravenous injection (In the external Jugular vein)
was studied by McLaughlin et al. (1973} using 12 kg beagle dogs. Blood
concentrations of methyl methacrylate reached a maximum of 3.5 mg% 3 minutes
after the inlraosseus implantation, and then decreased gradually to 0.7 m
-------
Wenzel et al. (1973) administered radiolabeled methyl methacrylate
Intravenously to Hlstar rats. Autoradiographic analyses showed that high
activities occurred 1n the blood and kidneys; low activities were detected
In the liver and bone marrow at 5 minutes after Injection. No activity was
detected 1n the brain or spinal cord at this time point. At 2 hours
postinfection, the total activity had decreased, and detected activity had
shifted to compact bone. From 4-8 hours after administration, the activity
was found only In bones, liver, Intestine, and salivary glands.
In the Bratt and Hathway (1977) study (described In Section 5.1.), a
radlolabel Inventory assessed 10 days following Intragastric or Intravenous
administration of 14C-labeled methyl methacrylate to rats Indicated that
4.1-6.6% of the radioactivity was associated with the skin and carcass of
the animals. Specifically, the authors stated that 14C 1s retained only
1n the liver and adipose tissue at this time point. The low tissue burden
1s consistent with the reported rapid distribution and excretion of methyl
methacrylate.
Raje et al. (1985) reported that methyl methacrylate concentrates In the
blood (11.14 mg%), brain (25.24 yg/g), and lungs (20.60 ng/g) of rats
following 1, 2, 3 or 4 hours Inhalation exposure to 100 ppm (409 mg/ma)
methyl methacrylate. It was noted that the concentration In any of these
tissues did not vary significantly with the exposure duration, thereby
Indicating saturable uptake.
An Wi vitro study by Cork 111 et al. (1976) using human blood. Indicated
that disappearance of 14C-labeled methyl methacrylate followed first-order
kinetics suggesting an enzymatic Involvement. A half-Hfe for methyl
methacrylate In blood was estimated at 20-40 minutes.
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5.3. METABOLISM
Several studies provide data on the in vitro and in, vivo metabolism of
methyl methacrylate. These studies Involve several species, Including humans.
In vitro metabolism was studied by Pantucek (1969) using liver slices
from male rats. The major thrust of these experiments was to ascertain if
methyl methacrylate combined with coenzyme A, undergoes D-ox1dat1on, and
enters the tricarboxylic acid cycle (TCA) 1n the form of succlnyl coenzyme
A, or alternately Is first oxidized to pyruvate. The slices and substrate
(7 mH methyl methacrylate) were Incubated at 37'C in buffered Kreb's-Ringer
solution for 30 or 60 minutes. The disappearance rate of methyl meth-
acrylate was similar to that of fumarate, a natural constituent of the 1CA;
from this observation 1t was inferred that methyl methacrylate was rapidly
metabolized and that this rapid metabolism could. In part, explain the
compound's low toxicity. Failure of the specific Inhibitor malonate to
block the metabolism of methyl methacrylate Indicated that succlnylcoenzyme
A was not an Intermediate 1n the oxidation of methyl methacrylate. The
specific inhibitor arsenlte, however, was very effective 1n blocking the
biotransformation of methyl methacrylate, thereby Indicating that pyruvate
is the Intermediate In methyl methacrylate decarboxylation. The authors
concluded that the formation of pyruvate, a natural constituent of the body,
may also explain the low toxicity of methyl methacrylate.
By using *4C-labeled methyl methacrylate labeled at different carbon
atoms, Henzel et al. (1973) reported that the parent molecule Is first split
by an unspecified esterase resulting In the formation of methanol that is
subsequently oxidized to C02 and methacryllc acid, which In turn Is
decarboxylated yielding C0?.
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In vitro metabolism experiments where methyl methacrylate was Incubated
with human serum confirmed the hydrolysis of methyl methacrylate to
methacryllc acid and methanol. In the previously described study by Bratt
and Hathway (1977), adult male rats were given methyl methacrylate as
14C-labeled methyl 2-propylene-2-carboxylate 1ntragastr1cally (120 mg/kg;
84 pCI) and urinary metabolites characterized- The following urinary
metabolites were Identified (relative proportion given as percent of
administered dose): methacryllc acid (0.0%), D-hydroxylsobutyr1c acid
(0.2%), methylmalonic add (1.4%), succinic add (0.2%), and an unidentified
add (0.4%).
Delbresslne et al. (1901) reported on the urinary metabolite profile of
rats following Intraperitoneal administration of the methyl ester of meth-
acryllc acid (0.70 mmol/kg/day) 5 days/week for 3 weeks. The mercapturlc
acid, N-acetyl-S-(2-carboxypropyl)cyste1ne was Identified as a urinary
metabolite. To a minor extent, monocarboxyl 1c adds were also detected.
Urinary thloether production was not detected following a single dose of the
methyl methacrylate (0.14 mmol/kg, 1.p.), but Increased to 11.0*3.3% of the
dose following prior administration of the carboxylesterase Inhibitor,
tr1-o~tolylphosphate (TOTP). These data confirm the production of mercap-
turlc add metabolites from methyl methacrylate, and that carboxylesterase
activity Is Involved In the detoxification of acrylic esters.
Crout et al. {1982) conducted studies of methyl methacrylate metabolism
supplementing those of Bratt and Hathway (1977). 14C-labeled methyl
methacrylate was administered 1nlraper1toneally (7 or 9 mg representing 1.39
or 1.75 wCl) to two 200 g female Histar rats. Within 10 hours, ~80% of
the dose was expired as "COg. Urinary radlolabel represented 14.5 and
7.1% of the administered dose 1n the two rats. Urinary othylmalonlc add
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represented 0.22% of the administered radlolabol. To verify that methyl
ma Ton 1c acid production resulted from the biotransformation of methyl
methacrylate, the radlolabef distribution 1n the adipose tissue of the rats
was analyzed. It was found that 97% of the radlolabel was associated with
the fatty acid fraction rather than the glycerol components, thus Indicating
that the label was derived from metabolism of methyl methacrylate through
the TCA cycle. Furthermore, specific labeling of the methyl group of methyl
methacrylate with deuterium demonstrated that the compound was metabolized
through the pathway of valine catabollsm. Crout et al. (1982) also
Investigated the fate of methyl methacrylate 1n a human subject.
aH-labeled methyl malonlc add, representing 1.0% of the administered
dose, was detected In the urine following oral administration of 94 nig of
sodium sH-labeled methyl methacrylate.
5.4. EXCRETION
The previously described metabolism studies Indicate pulmonary and
urinary excretion to be routes of removal of methyl methacrylate and Its
metabolites from mammal Ian systems.
The study by Wenzcl et al. {1973) reported that 5% of the
,4C-rad1olabeled methyl methacrylate administered 1.v. to WUtar rats was
eliminated In the urine and feces, and 90% by respiration.
In the report by Bratt and Hathway (1977) 1t was stated that up to 65%
of a single dose {5.7 mg/kg) of methyl methacrylate was exhaled as 3"CO,,
within 2 hours; 84-88% was exhaled within 10 days regardless of the route of
administration. Pulmonary excretion of the parent compound was <1.0%.
Following oral administration of a 94 mg dose of sodium methacrylate, a
human subject excreted 1.0% of the dose as a urinary metabolite 24 hours
later {Crout et al., 1982).
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5.5. SUMMARY
Animal studies using radiolabeled methyl methacrylate Indicate that the
compound Is rapidly absorbed following inhalation or oral exposure, and
rapidly partitions out of the blood compartment. Based on tissue analysis,
the compound has a large volume of distribution, having been detected in
brain, lung, liver, Intestine, adipose tissue, skin, salivary glands and
bone. The results of one study (Rajc et al., 1985} suggested that the
uptake of methyl methacrylate by the blood, brain and lungs Is a saturable
process. Metabolism of methyl methacrylate has been studied both Vn vitro
and In vivo In rodents and also In one human subject. Several studies
confirmed the initial hydrolysis of methyl methacrylate to methacryllc acid
and methanol. Hethacryllc acid, methyl malonlc acid, ethyl malonlc acid,
G-hydroxy1sobutyr1c acid and mercapturlc acid have been Identified as
urinary metabolites of the rat. Methyl malonlc acid was also Identified as
a urinary metabolite In a human subject. Up to 80X of the 14C from
radiolabeled methyl methacrylate was detected as 14C02 following 1.p.
administration of the parent compound to rats. The available data Indicate
methyl methacrylate to be metabolized by the tricarboxylic acid cycle. As
mentioned earlier, methyl methacrylate rapidly partitions out of the blood
with a clearance half-time of 40 minutes or less. Based on animal studies,
excretion of methyl methacrylate In parent form Is minimal, but extensive
excretion of methyl methacrylate-der1ved C0^ occurs at the lungs, and the
excretion of various fecal and urinary metabolites has been demonstrated.
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6. EFFECTS
6.1. SYSTEHIC TOXICITY
6.1.1. Subchronlc Exposure.
6.1.1.1. INHALATION — Studies addressing the toxic effects of methyl
methacrylate following subchronlc Inhalation exposure are described below.
6.1.1.1.1. Humans — No subchronlc, Inhalation exposure studies were
Identified In the searched literature.
6.1.1.1.2. Animals — Hotoc et al. {1971) exposed groups of 50 rats
to methyl methacrylate at concentrations of 1 mi/04 t of air (-12 ppm;
49 rng/m») for 3 months {20 exposures), 5 months (41 exposures), or 0
months (63 exposures). Dally exposure parameters were not reported. Histo-
logic examination revealed pulmonary Interstitial Infiltrates, thickening of
septa and marked alveolar desquamation. Liver and kidney lesions were also
Identified.
Tansy et al. (1976) exposed 25 male Sprague-Dawley rats (90-110 g) to
methyl methacrylate at a concentration of 116 ppm (475 mg/m3) for 0
hours/day, 5 days/week for 3 or 6 months. Compared with sham-exposed rats,
significant reductions
-------
of cilia and reduction of cellular covering over the microvilli) to the
tracheal mucosa (reported In Tansy et al., 1980b below). Rats In the
6-month exposure group exhibited a significant decrease In small Intestine
transit performance.
In a similar study (Tansy et a!., 1900a) using the same exposure,
protocol assessed the effects of methyl methacrylate on terminal body
weight, tissue weights (adrenals, epldldymal and popliteal fat pads), blood
chemistry and metabolic parameters. forty-six male Sprague-Dawley rats
(174-216 g) were exposed to 116+6 ppm methyl methacrylate for 7 hours/day, 5
days/week until 542 hours of exposure had accumulated. Control groups were
exposed to atmospheres with 0 ppm methyl methacrylate, and neither the
experimental nor control groups had access to food during the exposure
periods. Hethyl methacrylate exposure did not significantly affect the body
weight or the weights of the adrenals, or popliteal and epldldymal fats
pads. A statistically significant (p<0.05> Increase 1n total cholesterol
and a decrease In total bilirubin were noted for exposed rats. No signifi-
cant evidence of altered metabolic function or histological changes were
observed. The previously reported decrease in body weight (Tansy et al.,
1976) following methyl methacrylate exposure was not observed In this study:
this was due possibly to the greater availability of food, younger age of
the animals, and smaller numbers of animals In the 1976 study.
A companion study by Tansy et al. (1980b) reported on the histopatho-
logic and blood chemistry effects of methyl methacrylate Inhalation exposure
on male Sprague-Dawley rats. Intermittent exposure (total of 56 hours over
a 7-day period) of 10 rats to 1000 ppm methyl methacrylate produced a
significant (p<0.05) decrease 1n serum albumin, blood glucose, BUN, SGPT,
SG0T and albumin/glucose ratio. The biological significance of these f 1 nd-
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Ings, however. Is Inconclusive since none of these exposed rats exhibited
remarkable histopathologic changes, and no overt signs of toxicity were
observed. In another experiment, 60 male Swiss-Webster mice (20-25 g)
received Intermittent dally exposures of 100 or 400 ppm methyl mettiacrylale
vapor for total exposure times of 160 hours per group. Twenty-four hours
after the last exposure, the mice were given an Intraperitoneal Injection of
sodium pentobarbital (50 mg/kg} for assessment of enzyme Induction and
sleeping times. The mean Induction time was significantly (p<0.Q5)
decreased In the 100 ppm group and the mean sleeping time was significantly
(p<0.G5) decreased 1n the 400 ppm group. The data are suggestive of but not
definitive for altered enzyme status In the liver.
The effect of exposure regimen was examined by Lomonova el al. <1980).
In this study, groups of albino rats {90 rats total, number per group for
methyl methacrylate exposure not specified} were exposed to methyl meth -
acrylate at a concentration of 115*2.1 mg/m* for 3 hours/day, 6 days/week,
or 6 hours/day, 3 days/week for 4 months. Controls were exposed to
compound-free atmospheres. The rats In the 3-hour exposure regimen
exhibited cardiovascular effects characterized by a decreased amplitude of
the R and S waves of fCGs, and the presence of extrasystoles. Rats of this
group also exhibited enlargement of the liver and kidneys, histological
alterations of the myocardium and the kidneys (erythrodlapedesIs), and
enlarged sinuses In the liver. Rats of the 6-hour exposure group exhibited
behavioral changes characterized by increased restlessness, and increases in
aggressive or passive behavior. The authors concluded that a greater
exposure-free period following longer exposure Is favorable to shorter
exposure with limited exposure-free Intervals.
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Blanchet et al. (1982} exposed groups of four female Sprague-Dawley rats
to methyl methacrylate vapor at a concentration of 7.6 vol.% (76,000 ppm or
311,149 mg/m3) for 20 minutes/day for 21 or 42 days. A control group was
exposed to methyl methacrylate-free air. Following the 21-day exposure,
alterations In respiration and ECG were observed. Continuation of the
exposure resulted 1n an Initial decrease followed by an Increase In systolic
blood pressure, and an Increase In heart and respiratory rate. At the end
of the 42-day exposure period, all animals exhibited abnormal respiratory
patterns, ECG changes Indicating heart block, and an Increase In systolic
blood pressure.
A report by Chebotarev (1985) Indicated that continuous exposure of male
rats (120-140 g) to methyl methacrylate levels of 30, 100, 200, 500 or 1000
mg/m3 for 1200 hours {50 days) (equivalent to 13.3, 44.2, 8B.4, 221.2 and
442.3 mg/kg/day) caused alterations of various biochemical parameters
(primarily serum enzyme activity levels), and differential white blood cell
counts. Exposure to methyl methacrylate at 500 or 1000 mg/m3 also
resulted In excitation, Irritation of mucosal membranes of the eyes and
upper respiratory tract, and subsequent conjunctivitis, emphysema,
pneumonia, and In some cases death. Based on the toxlcometrlc data of the
report, the author recommended that time-weighted permissible concentrations
of methyl methacrylate be set al 0.1 mg/ma for single exposure, and 0.01
mg/ma for mean-yearly exposure. The data, however, were lacking 1n
sufficient quantitative detail, and no statistical analysis was provided.
NTP (1986) reported the results of subchronlc, inhalation studies
conducted by Industrial Blotest Laboratories (IBT) and Batelle Pacific
Northwest Laboratories (BNW).
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In the IBT study, groups of 10 male and 10 female F344/N rats (mean body
weight at midpoint of study: males, 20? g; females, 142 g) and B6C3F1 mice
{body weights at study midpoint: males, 26.7 g; females, 22.0 g) were
exposed to 0, 63, 125, 250, 500 or 1000 ppm methyl methacrylate, 6 hours/
day, 5 days/week for 14 weeks. The equivalent doses were 0, 33.5, 60.9,
121.8, 243.7 or 487.4 mg/kg/day for male mice; 0, 30.7, 66.5, 132.9, 265.9
or 531.7 mg/kg/day for female mice; 0, 17.5, 34.7, 71.4, 138.6 or ?77.2
mg/kg/day for male rats; 0, 19.8, 39.3, 78.5, 157.0 or 314.1 mg/kg/day for
female rats. Ho exposure-related signs of toxicity were observed, and no
gross or microscopic pathologic effects were Identified In either of the
species for any exposure levels.
In the BNW studies, the groups of 10 male and 10 female F344/N rats
(body weights at midpoint of study: males, 259 g; females, 159 g) and 86C3F1
mice (body weights at midpoint of study: males, 28.5 g; females, 24.0 g)
were exposed to 0, 500, 1000, 2000, 3000 or 5000 ppm methyl methacrylate for
6 hours/day, 5 days/week over a 14-week period. The equivalent doses were
0, 239.5, 479.0. 958.0, 1437.0 or 2437.0 mg/kg/day for male mice; 0, 258.9,
517.9, 1035,7 or 2860.8 mg/kg/day for female mice; 0, 258.3, 516.6, 516.6,
774.8 or 1291.4 mg/kg/day for male rats; 0, 303.5, 606.9, 606.9, 910.4 or
1517.4 mg/kg/day for female rats. (The 1000 and 2000 ppm exposures result
1n identical doses because of the application of a 100 and 50% absorption
factor, respectively.} All rats In the 5000 ppm exposure group, 1/10 males
and 9/10 females In the 3000 ppm group, and 1/10 males and 3/10 females \n
the 2000 ppm group died before termination of the study. Body weights of
male and female rats In the 3000 ppm group were 20 and 25% lower,
respectively, than their controls. Body weights for males and females of
the 2000 ppm groups were 7 and 11% less than the controls. Inflammation of
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the nasal turbinates occurred In all rats of the 5000 ppm group, all female
rats and 7/10 males In the 3000 ppm group, and 8/10 females and 1/10 males
In the 2000 ppm group. Nasal turbinate Inflammation Incidence was 10% or
less for rats In the 1000 ppm and control groups. Additional compound-
related effects were reported Including follicular atrophy of the spleen In
4/10 males and bone marrow atrophy In 8/10 males 1n the 5000 ppm group.
Extensive cerebellar congestion and hemorrhage were noted In the early death
of females In the 3000 and 5000 ppm groups. Halacla and gliosis were
observed In 5/9 females and 1/8 females In the 2000 and 1000 ppm groups,
respectively.
Both male and female mice of all exposure groups In the BNW studies
exhibited metaplasia of the nasal epithelium. Body weights of male mice
from all exposure groups were 13-27% less than controls, and body weights of
female mice from all exposure groups were 6-18% less than respective
controls. Eight of 10 male and B/1Q female mice of the 5000 ppm exposure
groups died before the end of the exposure period. In the 3000 ppm group,
4/10 males and 1/10 females died, and In the 2000 ppm group 2/10 males and
1/10 females died before the end of the exposure period.
6.1.1.2. ORAL -- Studies examining subchronlc toxicity of methyl
methacrylate following oral exposure are described In the subsequent two
sections.
6.1.1.2.1. Humans — No studies were located addressing the
subchronlc oral exposure of humans to methyl methacrylate.
6.1.1.2.2. Animals — Borzelleca et al. (1964) studied the effects of
oral administration of methyl methacrylate to dogs. In these studies, four
groups of two male and two female beagle dogs (average body weight at 52
weeks: 9.47 kg) received either 0, 10, 100 or 1000 ppm (equivalent to 0,
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0.25, 2.5 or 36.8 mg/kg/day, respectively) methyl methacrylate dissolved in
corn oil and administered once dally In the feed for 1 year; the dally dose
(ppm) for a 1-week period was determined by the previous week's food
consumption. The exposure concentration of the 1000 ppm group was Increased
to 1200 ppm at 5 weeks, to 1400 ppm at 7 weeks, and to 1500 ppm at 9 weeks
and for the remainder of the study, (the TWA exposure concentration for this
high-dose treatment protocol was 1473 ppm [36.8 mg/kg/day]}. Urinary and
hematologic values were normal and no gross toxic effects or histopathologic
findings were attributed to the methyl methacrylate treatment.
Spleen-to-body weight ratio was significantly reduced for dogs receiving 100
ppm methyl methacrylate, but the biologic significance of this finding was
not apparent.
Motoc et al. (1971) orally administered methyl methacrylate to albino
rats at 25 mg/kg for 3 (20 exposures), 5 (41 exposures), or 8 (63 exposures)
months. Total doses were 2750, 5500 and B125 mg/kg, respectively, for these
exposure periods. The authors reported an exposure-related Increase In
histopathologic alterations of the liver, and biochemical alterations
{elevated serum enzyme activity levels) that were greater for oral exposure
than for Inhalation exposure {see Section 6.1.1.1.2.). A duration-related
Increase In severity of ulcerations of the glandular epithelium of the
stomach was also reported.
In a 21-day study, 30 male U1 star rats (150 g) were administered methyl
methacrylate 1n an olive oil vehicle at 500 mg/kg/day (Husaln et al., 1985).
A control group received equal volumes of the olive oil vehicle. Following
the exposure, behavioral tests Including spontaneous locomotor activity,
conditioned avoidance response, and aggressive behavior assessment were
conducted. An estimation of biogenic amines (noradrenalln, dopamine, and
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5-hydroxytryptamlne [5-HT]J was also performed using six rats from each
group. The methyl methacrylate exposure adversely affected all three
behavior performances tested (p<0.001 to 0.05). Slgnlfleant (p<0.007 to
0.05) Increases In noradrenalln, dopamine, and 5-HT were detected 1n the
pons-medulla and hippocampus regions of the brains 1n treated rats 24 hours
after the last methyl methacrylate dose. Noradrenalln content was signifi-
cantly Increased in the cerebral cortex and corpus striatum (p<0.001 and
p<0.05» respectively), and dopamine levels were reduced (p<0.02) In the
corpus striatum. Levels of 5-HT were elevated 1n the hypothalamus and
midbrain (p<0.001 and p<0.05, respectively). The authors concluded that the
altered behavioral changes may have resulted from methyl methacrylate-
Induced changes In biogenic amine levels.
6.1.2. Chronic Exposure.
6.1,2.1. INHALATION ~ Studies examining chronic Inhalation exposure
to methyl methacrylate are described 1n the following sections.
6.1.2.1.1. Humans — An epidemiologic study (Blagodatln et al., 1971)
Involving 152 workers exposed to methyl methacrylate (2-200 mg/m') over a
period of 10 years reported the association of several symptoms with the
exposure. The nature and prevalence of these symptoms were as follows:
headaches {119), pain In the extremities (45), excessive fatigue (32), sleep
disturbances (32), loss of memory (30), and Irritability (25).
The effects of occupational exposure to methyl methacrylate at five
manufacturing plants were examined by Cromer and Kronoveter (1976).
Ninety-one exposed workers and 43 nonexposcd workers were evaluated relative
to general symptomatology, blood pressure, pulmonary function tests, white
blood cell counts and hemoglobin content, pulse rate, urinalysis, and blood
chemistry. The mean 8-hour TWA concentration at these plants ranged from
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4-0G ppm and the presence of other chemicals, Including ethyl acrylate, were
determined to be negligible In the assessment of health effects. Four
exposure groups were Identified based on existing exposure situations.
These were categorized as follows: current exposure of <5 ppm or <2 months
exposure (13 subjects), current exposure of 5-25 ppm (20 subjects), current
exposure of 25-50 ppm (33 subjects), and not currently exposed but exposed
1n the past for over 1 year (25 subjects). A group of 43 nonexposed workers
served as controls. No significant acute effects were detected. Evaluation
of chronic effects Indicated no significant changes In symptomatology
(coughing, expectoration, skin and allergic problems} although subjects In
the higher exposure groups did have a higher Incidence of dermal
Irritations. No significant differences were detected for urinary symptoms,
white blood cell counts, and pulmonary function tests, but a notable
although Insignificant Increase In the Incidence of dizziness, shaklncss,
and drowsiness was recorded for the 5-25 and 25-50 ppm groups. Slight
Increases of equivocal biologic significance were recorded for serum
glucose, blood urea nitrogen, cholesterol, albumin and total bilirubin
values In the higher exposure groups. In general, the authors Indicate that
exposure to methyl methacrylate at the studied levels (below the OSHA 8-hour
TWA of 100 ppm) resulted In unremarkable effects.
Hakarov et al. (1981) studied the adlpogenlc effect of methyl meth-
acrylate on 592 women and 84 men employed 1n the chemical Industry for an
average of 9 years. The average age of the workers was 37 years. A group
of 222 women and 290 men who worked 1n a machine-construction Industry
served as a control group. Exposure to methyl methacrylate was found to
produce an adlpogenlc effect on women but not men. This exposure also
resulted In Increased Insulin levels relative to the control group. No data
regarding methyl methacrylate exposure levels was provided.
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The respiratory health of workers exposed to methyl methacrylate
(exposure concentration not provided but the authors Indicated that at the
time of the survey concentrations were within ACGIH and NIOSH limits) was
examined by Nonroe et al. (19B1). The mean age of the 780 workers (men and
women) was 43.5 years, and the average length of service was 17.3 years.
Chronic bronchitis was noted for 14X of the men and 2% of the women, with
the highest prevalence (24%) 1n males who currently were smoking cigarettes.
The mean FEVj and mean FVC were reduced (p<0.05) In males who smoked and
were exposed to methyl methacrylate. However, nensmokers exposed to methyl
methacrylate also had low F£(p<0.005), but this may have been attribut-
able to a small (n»17) sample size. Generally, the length of service and
exposure to methyl methacrylate could not be associated with observed
respiratory abnormalities when smoking habits were considered.
The effects of occupational exposure to methyl methacrylate were
reported by Delia Torre et al. (1902). Subjects from the same factory were
divided Into two exposure groups representing less than or greater than a
TLV of 410 mg/m'. Exposure concentration for the low exposure group
ranged from 20-342 mg/m' and that for the high exposure group from 472-736
mg/m'. Hean exposure duration was 12 years. No alterations of liver,
cardiovascular, or peripheral nervous system function were detected 1n
subjects of either group. A moderate prevalence of Irritation of mucosal
surfaces and nervous system disorders were noted for both exposure groups.
Occupational exposure to methyl methacrylate and styrene was examined by
Jedrychowskl (1982). A group of 454 male workers exposed to methyl
methacrylate at a mean concentration of 11.06 mg/ma (range; 0.20-3B2.2
mg/m3) and styrene at a mean concentration of 2.66 mg/ma {range
0.06-31.01 mg/m3) were compared with a control group of 603 nonexposed
0490d
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workers. The frequency of obstructive lung disorders, as determined by
FEV.J values, was more than twice as great {45.4% vs. 18.OX, p<0.0!>) for
exposed workers. However, no difference was noted for prevalence of chronic
chest symptoms. The average duration of employment for the exposed workers
was 12.9 years, but U 1s not clear 1f this represents chronlclty of expo-
sure. Furthermore, the presence of styrene Imparts a confounding variable
for accurately assessing the effects of methyl methacrylate exposure.
Kakarov and Hakarenko (19B3) examined 100 subjects occupationally
exposed to methyl methacrylate 1n a plastic glass factory. F1 fty-onc? of
these Individuals were reportedly chronically exposed to the compound. A
control group consisted of 24 nonexposed individuals. The Investigators
Indicated that long-term exposure (duration and exposure levels not pro-
vided) to methyl methacrylate resulted 1n decreased levels of somatotropic
hormone and that this effect was possibly related to a narcotic action on
the ventromedlan nucleus of the hypothalamus.
A retrospective analysis of the general health of 63 workers (35 men and
28 women) exposed to methyl methacrylate (30-300 mg/m3) was performed by
Kuzelova et al. (1985). The mean duration of exposure was 10.1 years.
Although a contact allergic eczema was reported for three workers, no clini-
cal signs of toxicity could be attributed to methyl methacrylate exposure.
Subjective neurotic symptoms were reported by 41.2% of the subjects, and
nervousness, headache and weakness were reported by SOX of the subjects.
The authors suggested adoption of an occupational MAC of 0.05 mg/m3 for
methyl methacrylate.
Mortality patterns among men chronically exposed to methyl methacrylate
were studied by Collins et al. (1989). The exposure group consisted of 1361
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men occupational!? exposed to various levels of methyl methacrylate at one
of two or both of the American Cyanamld plants studied. Although the study
cohort consisted of men who had worked at the plants during a 22-year
period, specific exposure duration for Individuals or groups was not
available. It was noted, however, that no Individuals received exposure
exceeding 20 years. Eight-hour TWA exposures to methyl methacrylate varied
from 0.13-0,69 ppm {mean + S.E. = 0.40*0.09) at one plant, and from
0.72-1.00 ppm (mean + S.E. - 0.06+0.04) at the other plant. The analyses of
trends for increasing risk of mortality relative to cumulative exposure and
duration of exposure took Into account smoking status, age, specific employ-
ment period, race and latency. The researchers found no Increasing trend In
risk that was related to exposure duration or magnitude of exposure.
Additionally, no significant excesses were observed for Incidence of any
cancer group.
6.1.2.1.2. Animals — Hethyl methacrylate toxicity was studied In
male and female Lakevlcw golden hamsters (53-59 animals per sex) exposed to
the compound at concentrations of 0, 25, 100 or 400 ppm (0, 102, 409 or 1638
mg/m»} for 6 hours/day, 5 days/week for 78 weeks (Hazclton Laboratories,
1979a). The mean body weights at 40 weeks were 122.2+16.1, 118.7+18.6,
117.1+20.6 and 117.9+17.2 g for males, and 115.1+24.0, 116.8+25.0,
122.2.+26.4 and 115.1+26.2 g for females In the control, low-, mid- and
high-exposure groups, respectively. The equivalent doses were 0, 8.4, 34.1
and 136.2 mg/kg/day for male mice, and 0, 8.5, 33.9 and 136.0 mg/kg/day for
female mice. The animals were observed for clinical signs of toxicity, and
blood chemistry analyses and hlstopathologlcal examinations performed. A
compound-related, 2-fold Increase 1n mortality was noted for males of the
high-dose group at 78 weeks of exposure. Hethyl methacrylate exposure had
0490d
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no significant effect on mortality of the female hamsters. Blood chemistry
studies, gross pathologic and histopathologic examinations Indicated no
compound-related effects on any of the animals In the three exposure groups.
Hazelton laboratories (1979b) also conducted a long-term Inhalation
exposure study using groups of 70 male and 70 female Fisher rats and methyl
methacrylate concentrations of 0, 25, 100 or 400 ppm {0, 102, 409 or 1638
mg/m3). The rats were exposed for 6 hours/day, 5 days/week for 104 weeks.
Mean body weights at 52 weeks were 393.3+26.7, 399.5+25.3, 396.0+30.4 and
390.9+23.7 g for males, and 224.5+18.2, 220.2+15.0, 217.0+17.6 and
214.0+14.1 g for females of the control, low-, mid- and high-exposure
groups, respectively. The equivalent doses were 0, 11.1, 44.6 and 178.5
mg/kg/day for males, and 0, 13.6, 54.5 and 219.8 mg/kg/day for females.
After 52 weeks of exposure to 400 ppm, the body weights of female rats were
significantly lower than respective controls. With the exception of a
slightly increased incidence of mild rhinitis (serous exudate with
occasional presence of polymorphonuclear leukocytes, and distention of
mucous glands), no other significant treatment-related effects were noted as
determined by clinical toxicity, gross and microscopic pathology parameters.
It could not be determined If the rhinitis was a direct effect of methyl
methacrylatc exposure. The results of these studies are also presented In
abstract form (Smith et al., 1979).
NTP (1986) conducted 2-year inhalation exposure studies using 50 male
and female F344/N rats, and 50 male and 50 female B6C3F1 mice. The mice and
male rats were exposed to methyl methacrylate at concentrations of 0, 500 or
1000 ppm, 6 hours/day, 5 days/week for 102 weeks. The female rats were
exposed to 0, 250 or 500 ppm using the same protocol. The resulting doses
were 0, 232.6 and 432.0 mg/kg/day for male mice, 0, 235.8 and 471.7
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mg/kg/day for Female mice, 0, 214.6 and 216.0 mg/kg/day for male rats, and
0, 127.3 and 256.2 mg/kg/day for female rats. Mean body weights for rats at
at 52 weeks were 454, 448 and 440 g for males In the 0, 500 and 1000 ppm
exposure groups, and 271 , 267 and 264 g for females In the 0, 250 and 500
ppm groups. Mean body weights at 52 weeks were 39.2, 32.9 and 33.4 g for
male mice, and 34.0, 31.4 and 30.9 g for female mice of the 0, 500 and 1000
ppm groups, respectively. After 81 weeks of treatment, the mean body weight
of the male rats of the 1000 ppm group was 5-10% less than the controls, and
after week 73 the mean body weight of female rats In the 500 ppm group was
6-1IX less than that of the controls. Rats exposed to methyl methacrylate
(all exposure concentrations) exhibited greater incidences of Inflammation
of the nasal cavity and degeneration of the olfactory sensory epithelium.
These lesions were observed In nearly all of the high exposure rats. There
was no difference In survival between treated and control rats.
Mean body weights of treated male and female mice were 5-854 lower than
respective controls at the end of the 2-year study, but throughout most of
the second year of exposure the mean body weights were 10-18# lower than
controls. No difference In survival was noted for treated and control
mice. Hale and female mice from all exposure groups exhibited a significant
Increase In the Incidence of Inflammation and epithelial hyperplasia of the
nasal cavity, cytoplasmic Inclusions In the respiratory epithelium, and
degeneration of the olfactory sensory epithelium. The nonneoplastic effects
noted 1n this study are also presented 1n Chan et al. (1988).
6.1.2.2. ORAL — Studies examining the effects of chronic oral
exposure to methyl methacrylate are discussed 1n the following two sections.
6.1.2.2.1. Humans — No chronic, oral administration studies on
humans were located In the available literature.
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6.1.2.2.2. Animals ~~ Borzelleca et al. (1964) reported on the
effects of methyl methacrylate administered orally to Wlstar rats for 104
weeks. Seven groups (25 males and 25 females/group) of young Wlstar rats
{starting weights: males, 63 g; females, 60 g; median body weight for 104
week period: males, 295 g; females, 214 g) wore administered methyl meth-
acrylate In the drinking water at concentrations of 0, 6, 60 or 2000 ppm.
The low and medium exposures were Increased to 7 and 70 ppm, respectively,
at the start of the fifth month resulting In TWA exposure concentrations of
6.65 {low) and 68.46 ppm (medium). With the exception of a significantly
Increased kidney-to-body weight ratio In female rats of the 2000 ppm
exposure group, there were no treatment-related effects observed.
6.1.3. Other Relevant Information. The studies described In this section
provide Information that may be useful for the thorough understanding of the
potential toxicity of methyl methacrylate, but do not provide data
appropriate for quantitative risk assessment because there were deficiencies
In the data regarding exposure concentration, duration of exposure, the
confounding effect of exposures to other chemicals, and the anecdotal nature
of some of the data.
6.1.3.1. HUMANS — Seppalalnen and Rajnleml (1984) reported on methyl
methacrylate-lnduced local neurotoxicity among dental technicians. A group
of 20 dental assistants (6 men and 14 women) who routinely handled
nonpolymerlzed methyl methacrylate were compared with a reference group
consisting of 5 women and 13 men who had no occupational chemical exposure.
The mean ages of the study and reference groups were 42.1 and 41.7 years,
respectively. The exposure group was exposed to methyl methacrylate during
manipulation of acrylic dough and pouring of the dough Into molds.
0490d
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Additionally, some technicians applied the acrylic monomer directly with
their fingers. Maximal motor conduction velocity (HCV), motor distal
latency, orthodromic sensory conduction velocity (SCV) and distal sensory
conduction velocity (dSCV) were monitored. The HCVs and SCVs of the study
group were not significantly different from those of the reference group.
Exposed subjects exhibited significantly {p<0.05) slower dSCVs than did
reference group subjects. The reduced dSCVs were associated with the median
nerve In the branches from those fingers with the greatest exposure to the
methyl methacrylate monomer. Because of the small sample size, the authors
emphasized the preliminary nature of their findings.
Rajanleml et al. (1989) measured urinary methacryllc add levels In 11
dental technicians over a 21-hour period. The levels showed a large degree
of variation that was believed to reflect exposure rather than differences
In metabolism. The urinary analysis did, however, demonstrate percutaneous
absorption of methyl methacrylate. The ambient vapor concentrations were
considered to be too low to be a significant source of urinary methacryllc
acid.
A case of occupational asthma from methyl methacrylate exposure was
reported by Slozewlc et al. (1905). After a period of several years of
routinely mixing polymethyl methacrylate powder with monomethyl methacrylate
liquid, a 40-year-old dental assistant began to experience chest tightness,
dyspnea, and cough lasting for several hours following exposure to even
small amounts of these compounds. Clinical testing of this methyl
methacrylate-lnduced asthmatic reaction indicated a 24% decrease in PEF
{peak expiratory flow). The authors noted that no control test was
conducted nor was the subject's response to Inhaled histamine tested;
therefore, the possibility of a nonspecific provocative stimulus reaction
could not be ruled out.
0490d
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Pickering el al. (1986} also reported occupational asthma In a
56-year-old female orthopedic nurse/technician that had worked with methyl
methacrylate bone cement on the average of 12 times/week for 7 years. The
woman exhibited respiratory symptoms including persistent cough with wheez-
ing and breathlessness. Although the subject smoked 10-12 cigarettes/day,
pulmonary tests were normal when she was not exposed to methyl methacrylate.
Analysis of the case revealed that the asthmatic attacks were work-related.
Hethyl methacrylate concentrations were reported to have never exceeded 100
ppm.
A systemic reaction following acute exposure to methyl methacrylate was
reported by Scolnlck and Collins (19B6). The subject In question, a
31-year-old operating room nurse, had on two previous occasions experienced
headaches, nausea and anorexia following exposure to methyl methacrylate
vapor resulting form mixing of bone cement. Two weeks after these initial
exposures, a third exposure resulted In blfrontal headache, a heavy
sensation In the chest accompanied by difficulty In breathing. Increased
blood pressure and pulse rate, and extreme lethargy after being exposed to
methyl methacrylate vapor. Initial treatment with epinephrine corrected the
dyspnea and elevated blood pressure. All other signs and symptoms were
resolved within 3 days after the incident. Subsequent measurement of methyl
methacrylate concentrations at her work station revealed levels of 0.4, 1.0
and 1.5 ppm monitored over a !5-m1nute period.
A number of case reports regarding contact dermatitis to methyl
methacrylate are also available. Two cases of contact dermatitis to methyl
methacrylate were reported for nurses mixing bone cement (Kassls et al.,
1984}. In both of these cases, the subjects had been wearing surgical
gloves, Indicating that methyl methacrylate will diffuse through rubber
gloves (a fact also reported by Pegum and Hedhurst, 1971). Van Joost el
0490d 6-17 11/06/90
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al. (I960) reported a case of burning mouth syndrome that was due to methyl
methacrylate used 1n dental materials. Sensitization to methyl methacrylate
was verified. Allergic contact dermatitis following use of acrylic-
containing aneroblc sealants was documented by Conde-Salazaar el al. (1980)
for six workers. Subsequent patch testing revealed methyl methacrylate to
be an allergen In three of the workers. A case of contact stomatitis from
exposure to methyl methacrylate 1n dentures was reported by Kanzakl et al.
(1989). Rajanleml {1906} evaluated the occupational toxicity of methyl
methacrylate In 87 subjects who had handled the compound with bare hands.
Neurological symptoms (coldness, discomfort, or numbness of the fingers)
were reported by 22% of the subjects. A reduction In sensory conduction
velocity was noted for some of these subjects, and the neurological effects
were more common 1n those Individuals with longer exposure histories
(duration of occupational exposure ranged from 3-29 years). Of the 87
subjects surveyed, 34% reported having dermatitis on the fingers that were
exposed to the methyl methacrylate.
6.1.3.2. ANIHALS — Bright et al. (1972) studied the effects .of
methyl methacrylate Infusion on sheep, dogs, and a chimpanzee. Methyl
methacrylate was Infused at doses of 1-200 mg/100 ml of blood. Three
types of responses were observed depending on the Infusions level. At
levels up to 5 mg/100 ml, no changes were recorded for the monitored
parameters. From 10-50 mg/100 ml, Immediate hypotension with depressed
cardiac contractility and increased venous pressure was noted. These
changes were accompanied by focal pulmonary and eplcardlal hemorrhages. At
dose levels exceeding 100 mg/100 ml, rapid cardiovascular collapse with
terminal ECG changes and pulmonary hemorrhage were observed.
The hepatotoxlc effects of intragastrlcally administered methyl
methacrylate in olive oil were reported by Mallory et al. (1973). Groups of
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20 Swiss mice were given single doses (0.1 cc total volume) of methyl
methacrylate 1n corn oil at methyl methacrylate concentrations of 1, 2, 3,
4, 5, 6, 8, 10, 11, 15 or 20%. Histological evaluation of the livers were
performed 72 hours after the dosing. No changes In liver histology were
noted for mice receiving <6% methyl methacrylate. Swollen liver cells with
morphologically altered nuclei, and congested sinusoids were observed 1n 15%
of the mice exposed to the 6% methyl methacrylate. Exposure to the 11%
concentration resulted in a SOX Incidence of central and mldzonal fatty
changes In the liver accompanied by central lobular alteration. At concen-
trations of 15-20%, massive fatty Infiltration and disruption of liver
nuclei were noted for 70% of the dosed mice. It was noted that the methyl
methacrylate doses employed 1n this study were much greater than those that
would be encountered In clinical or environmental situations.
McLaughlin et al. (1973) Investigated pulmonary toxicity In dogs after
simulated arthroplasty using methyl methacrylate, and after intravenous
Injection of methyl methacrylate. No toxic effects were reported for dogs
undergoing arthroplasty. In the five dogs receiving methyl methacrylate at
a dose of 10 mg/kg, 1.v., no changes In hematocrit, PO^, PC0,, or pH were
detected. Of seven dogs administered the compound at 25, 50 or 75 mg/kg,
1.v. (throe successive doses, 1 hour apart), those of the highest dose group
exhibited a significant (p^O.Ol) decrease In pH and arterial PO^, and an
Increase In arterial PC0.,, base deficit and hematocrit. After the last
administration, signs of pulmonary edema were observed 1n dogs receiving the
25, 50 or 75 mg/kg doses. At autopsy, all dogs exhibited areas of pulmonary
hemorrhage. Dose-related accumulations of crystalline material were
observed In the terminal bronchlolar areas or scattered throughout the
Interalveolar septa of dogs receiving the successive doses of methyl
methacrylate.
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A 10-day mouse study was conducted by McLaughlin et al. (1979) In which
eight female ICR mice (45.1 g) were exposed to methyl methacrylate vapor at
a concentration of 1500 ppm for 2 hours/day, 5 days/week. No overt signs of
toxicity were observed, and histologic examinations were negative.
Lawrence et al. (1974) conducted toxicity tests of varying protocols for
a wide range of dental materials Including methyl methacrylate and
determined the LD^, LC5Q and LT&0 values for multiple routes of
administration. Cumulative toxicity tests In mice Indicated that the LD^q
for methyl methacrylate administered 1.p. decreased from 0.6743 ml/kg
after the first week to 0.2622 mi/kg after week 15, with a plateau being
reached on or about week 14. It was concluded that toxicity of the monomer
increased as a function of time.
Table 6-1 summarizes acute toxicity data for methyl methacrylate. The
data presented serve to summarize older studies assessing the toxicity of
methyl mctacrylate at the whole organism level. For most of the studies
cited, specific Information regarding concentrations of test solutions and
dosing were unavailable In the reports and, thcrfore, the toxicity values
are presented as they were reported.
Innes and Tansy (1981) studied the central nervous system effects of
methyl methacrylate exposure on male Sprague-Dawley rats. Following
Implantation of electrodes for monitoring electroencephalograph^ (EEC) and
multlunlt activity (MUA), rats were exposed to 400^20 ppm methyl meth-
acrylate for 60 minutes. Sham-exposed controls were exposed to room air.
Of the 10 areas of the brain studied, only the lateral hypothalamus and the
ventral hippocampus exhibited altered (rapid, reversible reduction In
neuronal discharge rates) neuronal activity.
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TABLE 6-1
Acute Toxicity Values for Methyl Hethacrylate
Species
Route
LD50, LC50 or lt50
Reference
Rat
oral
0000 mg/kg
Litchfield,
1978
Rat
oral
7.8 g/kg bw
Oelchmann, 1941
Rat
oral
10.0 mi/kg
Spealman
el al.. 1940
Rat
oral
>B.O to <6.0 ml/kg
Lawrence
et al.. 1974
House
oral
5.61 ml/kg
Lawrence
et al., 1974
House
oral
5.5 ml/kg
Schwach and
Hofer, 1970
House
oral
51.97 mmol/kg
Tan 11 and
Hashimoto, 19B2
Dog
oral
5.0 ml/kg
Spealman
et al., 1945
Guinea pig
oral
6.3 ml/kg
Spealman
et al., 1945
Rabbit
oral
6.6 g/kg bw
Oelchmann, 1941
Rabbit
oral
6000 mg/kg
Litchfield,
1978
Rat
Inhalation
19 mg/i, 8 hours
Delchman, 1941
Rat
Inhalation
7093 ppm (29,045 mg/m»)
4-hour exposure
Tansy et al.,
1980a
House
Inhalation
164.22 mg/l,
26.95 minutes
Lawrence and
Autlan, 1972
House
Inhalation
115.03 mg/l,
55.82 minutes
Lawrence and
Autlan, 1972
House
Inhalation
55 mg/l, 3 hours {LT50)
Oelchmann, 1941
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TABLE 6-1 (cont.)
Species
Route
lo50' lc50 or lt50
Reference
House
Inhalation
13.1 mg/i, 2 hours (LT50)
Karpov, 1954
Rabbit
Inhalation
19 mg/l, 8 hours
Delchmann, 1941
Guinea pig
1. p.
2.8 ml/kg
Lawrence
et al., 1974
Rat
1.p.
1.20 mi/kg
Lawrence
et al., 1974
House
I.p.
1.13 g/kg bw
Autlan, 1975
House
s.c.
6.36 g/kg bw
CastelUno and
Col1cch1o, 1969
Rabbit
s.c.
7.68 g/kg bw
CastelUno and
ColIcchlo, 1969
Rabbit
percutaneous
>B ml/kg
Lawrence
el al., 1974
0490d
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Following an acute, accidental Inhalation exposure to methyl meth-
acrylate (used to repair acrylic holding chamber) an adult, male rhesus
monkey (Hacaca mulatta) was found 1n a comatose state 22 hours after being
placed 1n the chamber (Kessler et al., 1977). Attempts to revive the monkey
were unsuccessful and the animal died 1.5 hours later. Necropsy revealed a
diffusely mottled liver, pulmonary edema and atelectasis. Biochemical
parameters were also Indicative of hepatotoxlc and pulmonary effects. Ihe
exposure concentration was not provided.
An abstract by Miller et al. (19B2) reported adverse renal effects
(significantly elevated BUN values, and Inflammation of the kidneys) In
Sprague-Dawley rats given methyl methacrylate (100 or 200 vit s.c. dally
for 34 days, or 200 pi methyl methacrylate dally for 42 days. It was
noted that the Inflammatory processes correlated with the elevated DUN
values.
A dose-related Increase In pulmonary microvascular permeability was
detected In sheep administered methyl methacrylate at l.v. doses of 12
mg/kg. The compound Induced pulmonary hypertension at 12 mg/kg but not al 2
mg/kg (Falrman et al., 1984}.
In a study by Va1n1otalo et al. (1904) male VIIstar rats were exposed to
thermal (300°C) decomposition products of polymethacrylate, the main
component of which was monomer 1c methyl methacrylate. Rats were exposed for
6 hours/night for 1, 5 or 10 exposures, which produced serious toxicologic
effects as determined by biochemical and histological alterations In the
lungs. The contribution of other decomposition products was not assessed.
Acute Inhalation exposure studies using male Sprague-Dawley rots
(100-150 g) provided an LC^q value of 7093 ppm for 4 hours of continuous
exposure (Oberly and Tansy, 1985). Exposure of rats to 110 ppm methyl
0490d
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methacrylate 4 hours/day for 32 days failed to produce significant differ-
ences In body or tissue weights, blood chemistry values, gross metabolic
performance or small Intestine motor activity relative to control (sham-
exposed) rats.
Raje et al. (1985) reported pulmonary damage (Interalveolar congestion
and hemorrhage, pulmonary vasodilation, and edema) In male rats following
Inhalation exposure to 100 ppm methyl methacrylate for 2, 3 or 4 hours but
not for a 1-hour exposure. No hlstopathologlcal changes were observed In
the brains of any of the exposed rats.
An Investigation by Ghanayem et al. (1986) Indicated that methyl
methacrylate (a structural analogue of the carcinogen ethyl acrylate) did
not Increase the Incidence or severity of forestomach cell proliferation In
rats relative to rats In the control group. In this short-term study, male
FIscher rats were administered methyl methacrylate (100 or 200 mg/kg) dally,
5 days/week for 2 weeks by gavage. The control group received equivalent
volumes of the Hazola corn oil vehicle.
A reduction In spontaneous motor activities of the gastrointestinal
tract of laboratory species was reported by several Investigators (Tansy et
al., 1976, 1977). further studies using guinea pigs and Isolated sections
of the Ileum Indicated that this effect was due, in part, to a direct action
of methyl methacrylate on the contractile mechanism of the Intestines
(Martin and Tansy, 1981). An Increase in the Intercontractlle Interval was
measured for rats exposed to methyl methacrylate at near 1LV concentrations
for 7 hours/day, 5 days/week for 10 days (Tansy and Kendall, 1987). Born et
al. (1988) using isolated rat uterus, demonstrated a calcium channel
blockade for methyl methacrylate, an effect that also explains the Inhibi-
tory action of the compound on smooth muscle activity.
0490d
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Methyl methacrylate administered Intradermally to guinea pigs was shown
to be a moderate sensitizer compared with other methacrylates (van der Walle
et al., 1982}.
Methyl methacrylate (>99% purity) applied lo tails of Wlstar rats for 8
weeks {3 hours/day} Induced local dermatotoxlc and neurotoxic effects
(Verkkala et al., 1903; Kanerva and Verkkala, 1986). Effects rioted In these
studies Included abnormal muscle responses to stimulation of motor nerves In
the tall, and hlstopathologlcal alterations Including spongiosis, vacuoliza-
tion, edema and cytolysls. Additionally, myelin figures, Indicative of
nerve degeneration, were observed In <10% of the axons.
6.2. CARCINOGENICITY
6.2.1. Inhalation Exposure.
6.2.1.1. HUMAN STUDIES — Two epidemiologic studies on the mortality
of workers exposed to methyl methacrylate were found; one study showed
unexplained excess deaths from colorectal cancer (Monroe, 1984), whereas the
other did not show excess cancer at any tissue site {Collins et al., 1969).
The first study Involved a cohort of 3934 white males working at the Rohm
Haas Bristol Plant, Bristol, PA (which makes and uses ethyl acrylate and
methyl methacrylate), between January 1, 1933 and December 31, 1945; no
limitations were placed on the duration of employment (Monroe, 1904). The
cohort consisted of those who had ever been exposed (70% of the cohort) and
those with no exposure to acrylates/methacrylates. Follow-up of this cohort
extended to December 31, 1981. The SHR was calculated from the observed and
expected deaths using U.S. white males as the reference. Specific causes of
death were coded according to the 8th Revision of the ICO. Relative
exposure levels were used, because data on actual exposure levels In the
plant were not available.
049Od
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At the end of the follow-up period, 1528 workers had died, 1925 were
alive, and the status of 461 was unknown. For deaths from all causes, the
SHR for the entire plant was only 62, and for those exposed to
acrylates/methacrylates, H was 84, The SHR for deaths from all cancers was
92 for the entire plant and 95 for the exposed group. However, a
statistically significant excess of deaths from cancers of the colon and
rectum were noted, with SMRs of 167 and 171, respectively, for the two
sites. Of the 52 deaths from colorectal {colon or rectum combined) cancer,
51 were found among the exposed group. Among workers who had been employed
for at least 1 year, 43 deaths from colorectal cancers were recorded (SHR -
210), and 38 of these deaths occurred 10 years or more after Initial
exposure to acrylates/methacrylates. Using the male population In
Pennsylvania or New Jersey (high background for colorectal cancer) as the
reference still resulted 1n a significant excess deaths, but lower SHRs, for
colorectal cancer. According to the author there was no clear relationship
between deaths from colorectal cancer and the Intensity of exposure, cumula-
tive exposure, or duration of exposure. Nevertheless, regardless of the
cumulative exposure or Intensity of exposure, almost all deaths from
colorectal cancer occurred at least 10 years after Initial exposure.
Honroe (1984) also reported that excess deaths from digestive cancer
were not found among workers at the Rohm Haas Houston plant, but they stated
that the level of exposure may have been lower at the Houston plant than at
the Pennsylvania plant. A significant confounding factor 1n this study,
however. Is the exposure to ethyl acrylate, which Is classified as a 2B
carcinogen by IARC {1967), which Induces squamous cell papillomas and
carcinomas In mice and rats by the oral route.
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In the other study, Collins et al. (1989) studied a cohort consisting of
2671 males workers at the American Cyanamld Company at the Fortler and Santa
Rosa plants. This cohort consisted of those who started work at the Fortler
plant In 1951 and the Santa Rosa In 1957 and worked until January 1974 and
followed up until December 31, 19B3. The Fortler plant manufactures methyl
methacrylate and the Santa Rosa plant uses methyl methacrylate to make
acrylic fibers. The 8-hour TWA concentration at the Fortler plant ranged
from 0-7.83 ppm (0-32.06 mg/m3), and at the Santa Rosa plant, the concen-
tration ranged from 0.05-11.5 ppm (0.2-47.03 mg/m3). A total of 1561
workers were in the exposed category and had cumulative exposures >0.1 ppm;
1971 were unexposed {<0.1 ppm). Cumulative exposure was defined as the
product of the number of days 1n the Job and the estimated average exposure
{In ppm) divided by 365. No significant excess deaths from all causes or
from any specific cause were noted 1n this cohort. The SHRs were 0.67 (all
causes), 1.04 {all cancers) and 0.39 (cancer of the large Intestine) for the?
exposed workers, and 0.79, 1.01 and 0.87, respectively, for the unexposed
group. The test for trends In relative risk for four exposure categories
(0, <0.19, 0.20-2.0 and >2.0 ppm) showed no statistical significance when
risk was based on Indirect or Internal standardization, which took Into
account age, calendar year, race, latency, and smoking history. Therefore,
the results from this study did not confirm those of Monroe (1984). Collins
et al. (1989) stated that, In the Rohm Haas study, the exposures were
probably higher, the latency and duration of exposure were longer, and the
plant was located In an area where the background for colorectal cancer 1s
high. They further stated that these factors could account for differences
In results, but It Is unlikely, because there was no increase In risk with
increasing dose.
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6.2.1.2. ANIMAL STUDIES — Long-term Inhalation exposure studies have
been conducted In three animal species. Hore details of these studies are
presented In Section 6,1.2.1.2. Neoplastic lesions did not develop at any
site in male or female Lakevlew golden hamsters (53-59/sex/dose) exposed to
methyl methacrylatc at concentrations of 0, 25, 100 or 400 ppm (0, 102, 409
or 163B mg/m3} for 6 hours/day, 5 days/week for 7B weeks (Hazelton
Laboratories, 1979a). Neoplastic lesions also did not develop In male and
female F344 rats (70/sex/dose) exposed to methyl methacrylatc at the same
concentrations for 102-106 weeks (Hazelton Laboratories, 1979b).
NTP (1986) exposed F344 rats and B6C3F1 mice to methyl melhacrylate for
102 weeks. Hale rats and male and female mice were exposed to 0, 500 or
1000 ppm (0, 2047 or 4094 mg/m3) and female rats to 0, 250 or 500 ppm (0,
1024 or 2047 mg/m3), 6 hours/day for 5 days/week. The overall incidence
of mononuclear leukemia in female rats was 11/50 (2?X), 13/50 (26%) and
20/50 (40%) for the three exposure groups, respectively. The Increase was
significant by the Incidental Tumor Test, Fischer Exact Test, and the
Cochran-Armltage Trend Test, but not by the more appropriate Life Table
Test. The Incidence of neoplastic lesions was not Increased In male rats or
In male and female mice at any site. Unexplained statistically signifi-
cant negative associations were noted for pituitary gland and preputial
gland adenomas or carcinomas In male rats, hepatocellular adenomas or
carcinomas In male and female mice, alveolar/bronchlolar adenomas or
carcinomas In male mice, and pituitary gland adenomas or carcinomas and
uterine adenocarcinomas 1n female mice. This study was also reported by
Chan et al. (1988).
6,2.2. Oral Exposure. One study on long-term oral exposure to methyl
methacrylate was located In the literature. The results showed that male
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and female rats exposed to methyl methacrylate for 2 years at concentrations
of 0, 6.85 (1WA), 68.46 (TWA) or 2000 ppm In drinking water did not develop
neoplastic lesions at any site (Borzelleca el al., 1964). Weight-normalized
doses were 0, 1.1, 11.4 and 332.2 mg/kg for male rats and 0, 1.6, 15.7 and
457.9 rag/kg for female rats. More details of this study can be found In
Section 6.1.2.2.2.
In the same study, male and female purebred beagle dogs (2/sex/dose)
were administered (p.o.) gelatin capsules containing methyl methacrylate
dissolved In corn oil. The substance was administered Just before feeding
each day for 2 years at doses constituting 0, 10, 100 or 1000 ppm (raised to
1500 ppm at the ninth week) {1WA dose * 1460 ppm) of dietary Intake. The
weight-normalized doses were 0, 0.25, 2.5 and 36.7 mg/kg/day. No neoplastic
lesions were found.
6.2.3. Other Relevant Information. Thompson and Entln (1969) reported
that a 60-year-old female developed a chondrosarcoma In the supraclavicular
area 18 years after an extrapleural plombage on the right side using luclle
spheres (polymethyl methacrylate} as treatment for tuberculosis. The tumor,
which had invaded the adjacent areas and metastasized to the lungs, did r«l
have a skeletal primary site. The spheres were encapsulated by fibrous
tissue, and one sphere actually contained necrotic tumor tissue. Some
others were filled with fluid. The authors stated that the Intimate asso-
ciation of the tumor with the lucUe spheres suggested that the plastic
material may have acted as a carcinogenic agent.
In animal studies, fibrosarcomas have been found at the site where
polymethyl methacrylate films were embedded In the subcutaneous tissues of
rats (Oppenhelmer et al., 1955) and mice (Laskln et al., 1954). In
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addition, Oppenhelmer et al. {1955} reported that neither skin nor systemic
tumors developed In 10 rats receiving topical applications of methyl
methacrylate 3 times/week for 4 months.
6.3. GENOTOXICITY
Poss et al. (1979) reported that methyl methacrylate tested at concen-
trations of 0, 10, 50 and 100 mM in the presence and absence of rat liver S9
induced mutations In Salmonella typhlmur turn strain TH677 (8-azaguan1ne
sensitive). Positive results were observed at 50 and 100 mH. Poss et al.
(1979) also reported that similar results were obtained for Induction of
resistance to azetldinecarboxyl1c acid and 5-fluorouracll. Methyl meth-
acrylate did not Induce reversion 1n Salmonella strains TA1535, TA1537,
TA1538, TA98 and TA100 or E,. coll strain HP2 In the presence or absence of
rat or hamster S9 using the plate Incorporation method or the liquid pre-
incubation test {Anderson et al., 1979; Lljlnsky and Andrews, 1980; Smith,
1980; Hachltanl et al., 19B1; Waegemaekers et al., 1983b; Waegemaekers and
Benslnk, 1984). Concentrations up to 10 mg/plate were tested. Hethyl
methacrylate gas at concentrations up to 9000 ppm (36,846 mg/m3) In air
was also negative In the plate Incorporation test {Smith, 1980). Hoore et
al. {1988) conducted tests with the mouse lymphoma cell line, L5178Y^K+/-»
and showed a significant Increase {2-fold over controls) In the number of
mutant colonies. The majority of the colonies were small, Indicating that
methyl methacrylate was clastogenlc rather than mutagenic. Analysis of the
cells for chromosomal aberrations showed a significant Increase in the
chromatid breaks and rearrangements, total number of aberrations, and the
percentage of cells with aberrations. The frequency of chromosome breaks
and rearrangements was not significantly Increased.
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Other lests showed that methyl methacrylate was negative In mammalian
cell transformation assays (Anderson et al.p 1979; SmUh, 1980). The bone
marrow mlcronucleus test In mice receiving 1.13, 2.26 or 4.52 mg/kg (p.o.)
as a single dose or four doses of 1.13 mg/kg was negative (HacMtanl et al.,
1981). In rats exposed by Inhalation to 0, 100, 1000 or 9000 ppm (0, 409,
4094 or 36,846 mg/m®) of methyl methacrylate for 2 hours or for 5 hours/
day for 5 days, a small significant Increase In chromosome aberrations in
bone marrow cells was noted at >1000 (single exposure) or at 9000 ppm
(multiple exposures) (Smith, 1980}. A repeat test using concentrations or
100-1000 ppm showed a significant Increase In aberrations at 100 ppm, but no
definitive dose-response relationship was established. A dominant lethal
test using CD1 male mice exposed to methyl methacrylate at concentrations of
1, 100, 1000 or 9000 ppm, 6 hours/day for 5 days and mated weekly for 8
weeks showed no Indications of prelmplantatlon or post implantation losses;
therefore, no dominant lethal effects on any stage of spermatogenesis were
noted (Smith, 1980). Anderson el al. (1979) also reported that methyl
methacrylate was negative In the mouse dominant lethal test.
6.4. DEVELOPMENTAL TOXICITY
Studies addressing the developmental/teratogenlc effects of methyl
methacrylate are reviewed In the following sections.
6.4.1. Humans. Splelmann (1906) reported an evaluation of embryoloxlc
properties of Industrial chemicals- Exposure during pregnancy to methyl
methacrylate at or below the HAK (maximum admissible concentration) was not
considered to be embryoloxlc in humans. However, because of what was
considered an Incomplete data base, officials from countries other than
Germany were not as definitive In this conclusion as was the MAK-Corrm1ss1on.
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6,4.2. Animals. The developmental toxicity of methyl methacrylate admin-
istered to pregnant Sprague-Davley rats (175-225 g) on gestation days 5, 10
or 15 was studied by Singh et al. (1972). Methyl methacrylate was admin-
istered l.p. at doses corresponding to a tenth (0.1328 mi/kg), a fifth
(0.2656 ml/kg), or a third (0.4427 mi/kg) of the acute LD5Q (1.3280
ma/kg). Controls received 0.822 mi/kg of cottonseed oil, distilled
water, or normal saline although none of these were used as vehicles for
test substance administration. No significant, compound-related differences
1n number of resorptions, fetal deaths, or numbers of live fetuses were
detected. However, a significant decrease (p<0.01) in fetal weight was
observed for all doses of methyl methacrylate. Additionally, the two
highest doses of methyl methacrylate produced a significant Increase
(p<0.05) In fetal gross hemangiomas (8,0 and 16.1% vs. 054 for controls). No
skeletal abnormalities were noted for the methyl methacrylate exposures.
McLaughlin et al. (1978) conducted Inhalation studies on pregnant ICR
mice (22 g). The mice were exposed to methyl methacrylate (1330 ppm) for 2
hours, twice dally on days 6 through 15 of gestation. A slight but signifi-
cant Increase In average fetal weight was noted for the exposure group. No
explanation for this effect could be offered nor were any other signs of
toxicity observed.
The embryotoxlc and fetotoxlc effects of maternal Inhalation exposure of
methyl methacrylate on Sprague-Dawley rats (250 g) was studied by Nicholas
et al. (1979). Pregnant rats were exposed to methyl methacrylate (109
mg/s,) for 17.2 or 54.2 minutes/day on days 6 through 15 of gestation. The
longer exposure duration resulted In maternal toxicity as evidenced by
decreased food consumption and decreased weight gain (even after normaliza-
tion to controls). Fetal body weights and crown-rump lengths In both
exposure groups were significantly (p<0.05) less than those of controls.
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Delayed ossification of sternebrae (p<0.05) was observed for fetuses In both
exposure groups, and delayed ossification of vertebrae (p<0.05) was noted in
the fetuses of the longer-term exposure group only. Incidences of hematomas
and early fetal deaths were also significantly higher {p<0.00) In the
fetuses of the longer term exposure group.
Korhonen et al. {1983) used 3-day-old chicken embryos (30/dose) to study
the embryotoxlc effects of a number of compounds Including methyl meth-
acrylate. The doses of methyl methacrylate Injected Into the eggs were 2.3,
4.5, 9, 18 or 36 pmol/egg. An EDgg of 22.0 |imol/egg was derived. Ihe
highest dose resulted In a 43% early (<5 days after Injection) death rate,
20% malformed survivors, and an overall 67% affected level. The lowest dose
produced no adverse effects on the embryos. The remaining doses produced
early death percentages ranging from 7-10% (dose-related), malformed
survivor percentages of 10-20% (not dose-related), and overall affect
percentages of 20-30% (not dose related).
An abstract by Luo et al. (1986) reported a significant (p<0.Dl)
Increase In the Incidence of resorptions following inhalation exposure (2
hours/day, every 3 days) of pregnant rats to 4.48 mg methyl mcthacrylate/8.
on days 6 through IB. Delayed ossification 1n fetuses from this exposure
group was also noted. A low exposure group (0.52 mg/i) did not exhibit
significant differences 1n these parameters relative to controls. No
exposure related differences were observed In maternal weight, fetal weight,
or crown-rump length.
6.5. OTHER REPRODUCTIVE EFFECTS
6.5.1. Humans. Two Russian studies reported sexual disorders (decreased
sexuality) for men (Hakarov, 1984) and women (Hakarov et al., 1984)
chronically exposed to methyl methacrylate. An Increase In serum serotonin
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levels and myometrium contractile activity was reported by Frlgo et al.
(1981) for a female worker exposed to methyl methacrylate.
6.5.2. Animals. Continuous Inhalation of methyl methacrylate (54
mg/m*) by female rats for 1-4 months resulted 1n Increased estrogenic
functions of the ovaries (English abstract of Smlrnova arid Blagodatln,
1977). Specifically, an Increase In estrogen secretion by the ovaries was
noted, and thought to be a function of Increased follicle-stimulating
activity of the pituitary.
Nesbltt et al. (1988) administered methyl methacrylate subcutaneously to
a group of seven male Noble rats dally for 10 weeks. There were no treat-
ment related effects on accessory organ weight, testicular organ weight, or
body weight compared with saline controls. No other specific data were
provided In this abstract.
6.6, SUMMARY
Epidemiologic studies provide little evidence of serious toxicity
resulting from long-term Inhalation exposure to methyl methacrylate.
Various symptoms Including headache, fatigue, memory loss and Irritability
were reported for Individuals occupatlonally exposed to methyl methacrylate
vapor for periods approximating 10 years (Blagodatln et al., 1971; Kuzelova
et al., 1985). Monroe et al. {1981) noted that chronic bronchitis could not
be attributed to the occupational exposure to methyl methacrylate 1f smoking
habits of the workers were considered. Delia Torre et al. (1982) reported
mucosal Irritation and minor nervous system disorders In workers exposed to
methyl methacrylate for -12 years. Chronic exposure to methyl methacrylate
did not result in Increased mortality according to a report by Collins et
al. (1989).
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Chronic animal studies using various species (rats, mice, hamsters)
provide evidence of toxicity from Inhalation exposure to methyl mcth-
acrylate. The 2-year NTP (1986) study Indicated that Inhalation exposure to
methyl methacrylate at all exposure levels produced an Increase In nasal
cavity Inflammation and degeneration of olfactory epithelium, but had no
effect on survival of the rats or mice used In the study. Minor reductions
(5-10%) In body weight gain were noted for rats and mice. Hlld rhinitis
observed In rats could not be definitively attributed to the chronic
exposure to methyl methacrylate (Hazelton Laboratories, 1979b). Equivocal
results were obtained for hamsters In that a 2-fold Increase In mortality
was observed for male but not female golden hamsters exposed to methyl
methacrylate for 78 weeks (Hazelton Laboratories, 1979a).
Although no subchronlc human Inhalation exposure data are available,
subchronlc Inhalation exposure studies have been conducted using rats arid
mice. As with the chronic studies, reduced body weight gain was reported by
several Investigators for rats exposed to methyl methacrylate for periods
ranging from 3-6 months {Tansy et al., 1976, 1980b; NTP, 1986). Exposure to
high levels of methyl methacrylate {2000-5000 ppm) In the BNH Laboratories
experiments resulted In reduced weight gain and deaths of rats before
termination of the experiment (NTP, 1986). However, studies conducted by
IBT for NTP (1986) failed to demonstrate any signs of toxicity In rats
exposed to methyl methacrylate at concentrations up to 1000 ppm for 14
weeks. In the BNW Laboratories study, all male and female mice exposed to
methyl methacrylate at concentrations ranging from 500-5000 ppm exhibited
metaplasia of the nasal epithelium, and deaths occurred In the 2000, 3000
and 5000 ppm exposure groups (NTP, 1986).
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Other exposure-related effects have also been reported Including liver
and kidney lesions (Motoc et al., 1971; Lomonova et al., 1980), histopatho-
logic changes 1n various levels of the respiratory tract (Hotoc et al.,
1971; Tansy et al-, 1976, 1980b; NTP, 1986), cardiovascular effects
(Lomonova et al., 1900; Blanchet et al., 1982), and reduced motility of the
small Intestine {Tansy et al., 1976).
No studies were located addressing human chronic or subchronlc oral
exposure to methyl methacrylate.
Chronic oral exposure studies conducted by Borzelleca et al. {1964)
demonstrated that methyl methacrylate administered 1n the drinking water
(6.85 or 68.46 pptn) for 104 weeks failed to produce any significant toxic
effects in male and female Wlstar rats.
Subchronlc, oral exposure animal studies using rats, mice or dogs have
been conducted by various investigators. Hale and female beagle dogs given
dietary methyl methacrylate for 1 year exhibited no significant signs of
toxicity based on gross pathology and histopathologic findings (Borielleca
et al., 1964). Methyl methacrylate orally administered to rats over periods
ranging from 3-8 months resulted In exposure-related Increases In histo-
pathologic alterations of the liver, Increased serum enzyme activity levels,
and a duration related increase 1n the severity of ulcerations of the
glandular epithelium of the stomach (Hotoc et al., 1971). Husaln et al.
(1985) reported altered behavior and biogenic amine levels In rats given
methyl methacrylate In olive oil over a 21-day period.
The results of acute exposure to methyl methacrylate by various routes
have been reported by a number of authors. These reports Include both human
case reports and results of animal studies. Occupational asthma from methyl
methacrylate exposure was reported for dental assistants and orthopedic
nurses. A systemic reaction to Inhaled methyl methacrylate vapor by
0490d
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an operating room nurse was characterized by headache, dyspnea, hyper-
tension, tachycardia and extreme lethargy (Scolnlck and Collins, 1986).
Seppalalnen and Rajn1em1 {1904} evaluated the neurotoxic effects of denial
technicians routinely exposed to methyl methacrylate, and noted a signifi-
cant reduction In distal sensory conduction velocity In methyl methacrylate-
exposed Individuals. Additionally, a number of contact dermatitis reports
Involving methyl methacrylate exposure are available {Pegum and Hedburst,
1971; Kassis et al., 1984; Conde-Salazaar et al.t 1988; Van Joost et al.,
1908j Kanzakl et al., 1989).
Hethyl methacrylate was not considered to be embryotoxlc to humans
(Splelmann, 1986}, but animal studies have provided evidence for teratogenic
potential (fetal gross hemangiomas} following Intraperitoneal administration
of methyl methacrylate to pregnant rats (Singh et al., 1972). McLaughlin et
al. (1978) reported a significant increase 1n fetal weight In the offspring
of mice exposed to methyl methacrylate vapor, and developmental effects
(delayed ossification of sternebrae) following Inhalation exposure of
pregnant rats to methyl methacrylate. Hethyl methacrylate Injected Into
3-day-old chick embryos at doses of 2.3-36 ymol/egg resulted In an
Increase in early deaths and malformations which were not dose related. Luo
et al. (1906) showed that Inhalation exposure of pregnant rats to 4.40
mg/l (2 hours/day every 3 days) resulted In a significant Increase In
resorptions, and delayed ossification 1n the fetuses.
Studies from the Russian literature reported sexual disorders {decreased
sexuality) in men (Hakarov, 1984} and women (Makarov et al., 1984) following
chronic exposure to methyl methacrylate. Fr1 go et al. (1981) Indicated an
Increase in serum serotonin and Increased myometrium contractile activity in
a woman exposed to methyl methacrylate.
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There Is no convincing evidence that methyl methacrylate Is a potential
carcinogen for humans. One epidemiology showed excess deaths from
colorectal cancer In workers who were exposed to ethyl acrylate In addition
to methyl methacrylate at a Rohm Haas plant In Pennsylvania (Monroe, 1984).
These results were not confirmed by a study of workers at a Rohm Haas plant
In Houston, Texas (Monroe, 1984) or by a study of workers at two American
Cyanamld plants whore methyl methacrylate was manufactured or used {Collins
et al., 1989}.
Studies using laboratory animals exposed by Inhalation to methyl meth-
acrylate showed that the compound was not carcinogenic In hamsters exposed
to concentrations up to 400 ppm for 78 weeks (Hazelton Laboratories, 1979a)
or In rats exposed under the same conditions for 102-106 weeks (Hazelton
Laboratories, 1979b), A study by NTP (1986) showed that methyl methacrylate
was not carcinogenic In male and female mice and rats administered the
compound by Inhalation at concentrations up to 1000 ppm (up to 500 ppm for
female rats) for 102 weeks. An Increase 1n the Incidence of mononuclear
leukemia was noted In female rats, but this Increase was Judged to be
statistically nonsignificant according to the Life Table Test.
Statistically significant unexplained decreases in the Incidences of tumor
at other sites were noted. One study on oral exposure of male and female
rats to methyl methacrylate In drinking water showed no Induction of
neoplasms at concentrations up to 2000 ppm (Borzelleca et al., 1964).
Topical application of methyl methacrylate for 4 months did not Induce skin
or systemic tumors (Oppenhelmer et al.. 1955). A study using humans showed
that a chondrosarcoma developed In the supraclavicular area 18 years after
extrapleural plombage of polymethyl methacrylate spheres (Thompson and
Entln, 1969). Another study showed that fibrosarcomas can be Induced at the
0490d
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site where polymethyl methacrylate films are subcutaneously embedded in
laboratory animals (Laskln et al.f 1954; Oppenhelmer et al., 1955).
Genotoxldty tests showed that methyl methacrylate does not Induce
hlstldlne reversion In Salmonella typhimurium using the plate Incorporation
or liquid preincubation lest In the presence or absence of rat or hamster
liver S9, but Poss et al. (1979} reported that 8-azaguanlne resistance can
be Induced In Salmonella strain 7H677 (not confirmed). Methyl methacrylate
Induced chromosome aberrations In mouse lymphoma cells (Hoore et al., 1908}.
In vivo genotoxtclty tests showed that methyl methacrylate administered p.o.
did not induce mlcronucle! In bone marrow cells In mice (Anderson et al.,
1979; Smith, 1980). Methyl methacrylate administered by Inhalation was
negative In the dominant lethal test In rats and positive for Inducing
chromosome aberrations 1n bone marrow cells In rats (Smith, 1980).
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUHANS
OSHA (1989b) has established a final rule 0-hour TWA of 100 ppm (410
mg/m3). The American Conference of Governmental Industrial Hyg1 en 1sis
recommended a TIV of 100 ppm (410 mg/m3), and considered this sufficiently
low to protect against discomfort from irritation and that this was well
below the level giving rise to any systemic effects (ACGIH. 1980). A STEL
of 125 ppm (510 mg/m'} Is also Indicated (ACGIH, 1980). Hethyl meth-
acrylate is considered hazardous under the Resource Conservation and
Recovery Act (RCRA) of 1976 and listed 1n 40 CFR Section 261 Subpart 0
(Dixon and Rlssman, 19B5).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms
regarding the toxicity of methyl methylmethacrylate were not found 1n the
searched literature.
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8. RISK ASSESSMENT
B.I. CARCINOGENICITY
8.1.1. Inhalation.
8.1.1,1. HUMAN STUDIES — Two epidemiologic studies were found In the
literature. Mortality was studied 1n a cohort consisting of 3934 workers
who were hired between January 1 , 1933 and December 31, 1945 at a plant
manufacturing and using ethyl acrylate and methyl methacrylate and followed
up until December 31, 1981 (Monroe, 1984). SMRs were calculated using the
white male population as the reference. The SMRs for death from all causes
and deaths from all cancers were <100, whereas the SMRs for cancers of the
colon and rectum In the entire cohort and In the exposed group (ever exposed
to acrylat.es/methacry1ates) showed a significant excess In deaths. Among
those employed for at least 1 year, 43 deaths were due to colorectal cancer,
3B occurred 10 years or more after the Initial exposure to
acrylates/methacrylates. Although the populations In Pennsylvania and Hew
Jersey had high backgrounds for colorectal cancer, the SMRs were still
significant when compared with these groups. However, the relationship
between death from colorectal cancer, Intensity of exposure, cumulative
exposure, or duration of exposure could not be clearly established.
Furthermore, results were not confirmed by the second study of workers
exposed to acrylates/methacrylates at the Rohm Haas Houston plant. This
study, however. Is not considered valid for evaluating the potential
carcinogenicity of methyl methacrylate In humans. The study Is considered
Inadequate for the following reasons: the workers were also exposed to ethyl
acrylate; smoking history was not presented; dietary factors, which can
Influence digestive cancer, were not evaluated; exposure levels were not
adequately documented; too few deaths were recorded for adequately
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evaluating factors such as latency, Intensity of exposure, and duration of
exposure; and the statistical tests employed were not described.
In the other epidemiologic study, workers were exposed to methyl meth-
acrylate at two plants of the American Cyariamld Company (Collins et al.,
1989). No excess deaths from any cause, including colorectal cancer were
observed. The SHRs for deaths from all causes, all malignant neoplasms, and
for specific neoplasms among the exposed workers were similar to those of
unexposed workers, neither of which was significantly higher than that of
the reference population (U.S. male population) or was less than the
reference. The trends for relative risk based on the observed/expected
ratio for different disease categories and standardized for age, time
period, race, latency, and smoking history were not significant. Therefore,
the data regarding mortality experience 1n workers exposed to methyl
methacrylate do not Indicate a positive association between exposure to
methyl methacrylate and cancer. The reference population for calculating
the SHRs was not specified; the U.S. male population, however, was assumed.
Because the confounding factors were accounted for, this epidemiologic study
Is Judged adequate for evaluating the potential carcinogenicity of methyl
methacrylate.
B.l .1.2. ANIHAL STUDIES — Several long-term Inhalation studies were
found In the literature. Hale and female hamsters were exposed to vapors of
methyl methacrylate at concentrations ranging from 25-400 ppm (102-1638
mg/rn®}, 6 hours/day, 5 days/week for 76 weeks (Hazelton Laboratories,
1979a}, and male and female rats were exposed to the same concentrations for
102-106 weeks (Hazelton Laboratories, 1979b). No neoplastic lesions were
Induced In either species. The strengths of these studies are the numbers
of animals per dose, the relevant route of exposure (Inhalation), duration
of exposure for rats (somewhat Inadequate for hamsters) and the complete set
049 2d
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of endpolnts examined (body and organ weights, clinical signs,
ophthalmoscopic examination, hematology tests, clinical chemistry,
urinalysis, and gross and microscopic examination of major organs and
tissues). The major weakness of these studies 1s that the dose levels were
too low for Induction of nonneoplastic effects (the mild rhinitis observed
1n rats receiving 400 ppm of methyl methacrylate could not be directly
related to treatment), Indicating that the HTD was not reached. Therefore,
these studies are Inadequate for evaluating the potential carcinogenicity of
methyl methacrylate in humans.
The NTP (1986) conducted long-term Inhalation studies using male and
female F344 rats and B6C3F1 mice. Male rats and male and female mice were
exposed to 0, 500 or 1000 ppm (0, 2047 or 4094 mg/ma) of methyl
methacrylate vapors and female rats to 0, 250 or 500 ppm (0, 1024 or 2047
mg/m3). A dose-related Increase In the Incidence of mononuclear leukemia
was observed In female rats; the Increase was not statistically significant
according to the Life Table Test, In addition, statistically significant
unexplained decreases In the Incidences of neoplasms at several sites 1n
both sexes of both species were also noted. The strengths of this study are
the selection of dose levels (the HTD was reached as Indicated by the
Induction of nonneoplastic lesions In the upper respiratory tract), adequate
numbers of animals per dose, duration of exposure, relevant route of
exposure (Inhalation), and gross and microscopic examination of major
tissues and organs. Therefore, this study was chosen for evaluating the
potential carcinogenicity of methyl methacrylate to humans.
8.1.2. Oral. Hale and female rats exposed for 2 years to 0, 6.85 (IWrt),
68.46 (TWA) or 2000 ppm of methyl methacrylate In drinking water did not
develop neoplastic lesions (Borzelleca et al., 1964). No treatment-related
nonneoplastic effects were found, Indicating that the HTD was not reached.
0492d
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11/07/90
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Therefore, this study was not adequate for evaluating the potential carcino-
genicity of methyl methacrylate in humans. A similar study was performed
with dogs In which dally dietary equivalents of 0, 10, 100 or 1468 (TWA) pptn
of methyl methacrylate were administered for 2 years (Borzelleca et a!.,
1964). No neoplastic or nonneoplastic lesions were Found. This study was
also Inadequate for evaluating the potential carcinogenicity of methyl
methacrylate, because the HTD was not reached and the 2-year duration of
treatment was not sufficient for Induction of neoplasms 1n dogs.
8.1.3. Other Routes. One human study showed that extrapleural plombage
of polymethyl methacrylate spheres may have been Involved In the development
of a chondrosarcoma 1n the supraclavicular area of a 60-year-old woman 18
years later {Thompson and Entln, 1969). Embedding polymethyl methacrylate
films subcutaneously 1n mice and rats results In fibrosarcomas at the site
(Laskln et al., 1954; Oppenhelmer el al., 1955), and topical applications of
methyl methacrylate 3 times/week for 4 months did not result In skin or
systemic tumors In rats {Oppenhelmer et al., 1955). The development of
fibrosarcomas at the site where solid materials are embedded Is not a true
measure of carcinogenicity; therefore, these studies do not reflect a
carcinogenic response and cannot be used to evaluate the potential carcino-
genicity of methyl methacrylate.
8.1.4. Height of Evidence. IARC classifies methyl methacrylate as Group
3 based on no data for humans and insufficient data for animals {IARC, 1987).
One epidemiologic study presented data Indicating that occupational
exposure of workers to methyl methacrylate at two American Cyanamld plants
was not associated with deaths from cancer {Collins et al., 1989). Another
epidemiologic study of workers at a plant operated by Rohm Haas 1n
Pennsylvania presented data suggesting that occupational exposure to methyl
0492d
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methacrylate may be associated with excess deaths from colorectal cancer
(Monroe, 1984). However, the excess deaths in this study could not be
correlated with Intensity of exposure, cumulative exposure, or duration of
exposure to methyl methacrylate; and excess deaths were not found among
workers at another Rohm Haas plant In Houston, Texas (Monroe, 1984). 1 he
statistical tests employed In this study were not described, and statistical
significance was reported under conditions where very few deaths were
reported during the follow-up period (for example, only five deaths observed
for <10 years of exposure), therefore casting doubt on the appropriateness
of the statistical tests. The only epidemiologic study considered adequate
(Collins et al.» 1989} was negative and the results were unconfirmed by a
second well-conducted study, thus precluding a firm assessment of "no
evidence of carcinogenicity* based on epidemiologic data.
The two oral studies In laboratory animals (rats and dogs) were not
adequate for evaluating the potential carcinogenicity of methyl methacry-
late, because the MTD was not reached and exposure duration for the dogs was
not sufficient for evaluating neoplastic effects (Borzelleca et al., 1964).
Therefore, based on EPA's guidelines for Carcinogen Risk Assessment (U.S.
EPA, 1986a), methyl methacrylate 1s classified as welght-of-evldence Group D
"not classifiable as to human carcinogenicity" for oral exposure.
The Inhalation studies 1n hamsters and rats performed by Hazelton
Laboratories (1979a,b} were not adequate for evaluating the potential
carcinogenicity of methyl methacrylate, because the the absence of
nonneoplastic effects Indicated that the MTD was not reached. The
Inhalation studies performed by HTP (1966) In male and female F344 rats and
B6C3F1 mice, however, showed an Increase In mononuclear cell leukemia 1n
female rats, which was not significant by the Life Table Test; statistically
0492d
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significant negative associations with tumor incidences at other sites In
rats and mice were observed. The NTP study was adequate For evaluating the
potential carcinogenicity of methyl methacrylate, showing that the compound
is not carcinogenic 1n rats or mice of either sex.
Genotoxlclty test showed that methyl methacrylate was not mutagenic 1n
Salmonella typhimurluro except strain TH677. Hethyl methacrylate was
negative In the bone marrow mkronucleus test In mice (p.o.J, negative 1n
the dominant lethal test (Inhalation), and positive In the bone marrow
chromosome aberration tests In rats (Inhalation) (Anderson et al., 1979;
Smith, 1980). A positive response was observed for the mouse lymphoma test
In which chromosome aberrations were Induced (Hoore et al., 1908).
Therefore, data regarding genotoxlclty of methyl methacrylate Indicate that
this compound Is not mutagenic, but It may be clastogenlc.
Based on EPA's Guidelines for Carcinogen Risk Assessment {U.S. IPA,
1986a), methyl methacrylate Is classified as welght-of-evldence Group E,
"evidence of noncarclnogenklty for humans' for Inhalation exposure. The
Group E classification requires two well-designed and well-conducted studies
in two species; these requirements were satisfied by the studies conducted
by NTP {1986) using rats and mice. The Group E classification Is supported
by limited human data that showed no association of occupational exposure
with deaths from cancer. With regard to oral exposure, methyl methacrylate
Is classified as Group 0, "not classifiable as to human carcinogenicity."
8.1.5. Quantitative Risk Estimates.
8.1.5,1. INHALATION ~ Hethyl methacrylate 1s classified as
welght-of-evldence Group E {evidence of noncarclnogenklty for humans).
Therefore, methyl methacrylate does not receive a quantitative evaluation.
~49 2d
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8.1.5.2. ORAL — Data were not available for quantitative evaluation
of the potential carcinogenicity of methyl methacrylate by oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFITIHE EXPOSURE — No human studies were identi-
fied In the available literature suitable for quantitative risk assessment
of subchronlc, Inhalation exposure to methyl methacrylate.
A summary of dose and effect level data from pertinent studies of short-
term Inhalation exposure to methyl methacrylate Is presented In Table 0-1.
A number of animal studies examined the effects of short-term, Inhala-
tion exposure to methyl methacrylate. Hotoc et al. {1971) exposed 50 rats
to methyl methacrylate (49 mg/m»} for 3, 5 or 8 months. Histopathologic
alterations of the lungs, liver and kidneys were observed, but details of
the exposure protocol were not provided. Tansy et al. (1976) reported a
decrease 1n body weight gain, decrease In visceral fat content, decreased
lung and spleen weights, and gross pathological changes In the upper respi-
ratory tract for male Sprague-Dawley rats exposed to methyl methacrylate at
475 mg/m3 for 8 hours/day, 5 days/week for 3 or 6 months. Rats 1n the
6-month exposure groups also exhibited a decrease In small Intestine
motility. In a later study (Tansy et al., 1980a), a slight Increase In
total cholesterol and a decrease In total bilirubin was noted for rats
exposed to the same concentration of methyl methacrylate for 7 hours/day, 5
days/week for 77 days. Tansy et al. (1900b) also reported equivocal data
regarding hepatic enzyme alterations 1n rats and mice exposed to methyl
methacrylate for short periods of 56 hours and 160 hours, respectively.
Electrophysiological alterations of the myocardium, enlargement of the
kidneys and liver, and hlstopathologlcal changes In the heart and
0492d
11/07/90
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TABLE 0-1
Summary of Dose and Effect Level Data from Pertinent
Studies of Short-Term Inhalation Exposure to Methyl Hethacrylate
Species
Description
Effect Level lmq/ma)
NOAEL LOAEL FEL
Reference
Rat
180-day
475
Tansey
et al., 1976
Rat
120-day
115
Lomonova
et al., 1980
Rat
42-day
311,149*
Blanchet
et al., 1982
Rat
98-day
4094
NTP, 1986
(1ST)
Rat
98-day
2047 4094 8188
NTP, 1986
-------
kidneys were noted by Lomonova et al. (1980} for rats exposed to methyl
methacrylale (115 mg/m3) for 3 hours/day, 6 days/week for 4 months. These
effects were not observed for rats In a 6 hours/day, 3 days/week protocol,
but behavioral changes were noted for this group of rats. Changes in fCG
were also reported by Blanche! et al. (1982) for female rats exposed to
methyl methacrylale at concentrations of 311,149 mg/m3 for 20 minutes/day
for 21 days. Exposure for 42 days resulted In ECG changes indicative of
heart block, an Increase in systolic blood pressure, and abnormal respira-
tory patterns. NTP (1986) conducted extensive Inhalation exposure studies
using male and female F344 rats and B6C3F1 mice. Studies were conducted by
both Industrial Blotest Laboratories (1BT) and Batelle Pacific Northwest
(BNW). In the IBT studies, groups of 10 male and 10 female rats and mice
were exposed to methyl methacrylale at concentrations of 0, 63, 12S, ?f>0,
500 or 1000 ppm, 6 hours/day, 5 days/week for 14 weeks. No gross or
microscopic signs of toxicity were observed. The BNH studies used the same
exposure durations but employed methyl methacrylale concentrations of 0,
500, 1000, 2000, 3000 or 5000 ppm. In these experiments, 80% and 100%
mortalities were observed for mice and rats, respectively, following
exposure to 5000 ppm. Relative to controls (OX mortality), Increased
mortality was also reported for the 3000 ppm (rats: 10% for males, 90% for
females; mice: 40% for males) and 2000 ppm (rats: 10% for males, 30% for
females; mice: 20% for males, 10% for females) groups. Ho effects were
observed for the rats In the 500 ppm group or for male rats In the 1000 ppm
group. Ten percent of female rats In the 1000 ppm group exhibited an
Increase over controls In the severity of Inflammation and necrosis of the
nasal cavity and loss of olfactory epithelium. Mice In all groups exhibited
a decrease In body weight relative to controls and had metaplasia of the
nasal epithelium.
0492d
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For derivation of the RfCc, several studies were examined. Evaluation
of these studies was based on magnitude of effect and the adjusted animal
dose producing the effect, and the overall quality of the study. One such
study was by Tansy et al. (1976), 1n which 25 male Sprague-Dawley rats were
exposed to methyl methacrylate at a concentration of 116 ppm (475 mg/m3)
for 100 days. Following adjustment for conversion from discontinuous to
continuous exposure, a LOAEL^j of 113.095 mg/mJ was obtained. At this
exposure, the rats were found to exhibit a decreased visceral fat content,
decreased weight of the lungs and spleen, and focal hemorrhage and
denudation of cilia of the tracheal mucosa. An adequate number of animals
was used, and a sham-exposed control group was also incorporated into the
study. Based on a comparison of human and rat alveolar ventilation rates,
body weights, and dally air Intake, the LOAEL^ derived from this study
Is 252.20 mg/m®. Application of an uncertainty factor of 1000 (10 for
extrapolation from a L0AEL value, 10 for Interspecies extrapolation, and 10
for protection of sensitive populations) results 1n an RfC$ of 0.252
mg/m' (5.0 mg/day based on a 24-hour ventilatory volume of 20 m* for a
70 kg human}.
The study by Lomonova et al. (1980} was also examined for derivation of
an RfCs that was due to the severity of effects following exposure to a
relatively low (115.0 mg/ma) concentration of methyl methacrylate
(corresponding to a L0AELADJ of 12.32 mg/ma). In this study, rats
(number per group, age, strain and sex not specified} were exposed to methyl
methacrylate vapor for 3 hours/day, 6 days/week for 120 days. In reporting
the results, reference to a control group was made, but the nature of this
group was not Indicated In the experimental protocol. The authors reported
an Increase in ECG alterations (decreased voltage of R-S complex and
0492d
8-10
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extrasytoles) at days 40 and 130 of exposure. Additionally, hlstcpathologl-
cal changes 1n the kidneys, liver and myocardium were noted for the exposure
group. Although the data from this study {L0AELA0J of 27.07 mg/m9; UF
of 1000} would provide a very conservative RfC$ of 0.027 mg/ma, the
confidence level for this study 1s low. The report was difficult to follow,
which was due In part to possible translatlonal artifacts, and often used
confusing terminology (for example, liver diuresis function, catechln amide
content of the blood, no definition of "summation threshold level") and made
conjectural Interpretations of the data. Although treated rats exhibited a
significant Increase 1n the Incidence of altered ECGs, experimental details
regarding these measurements and the number of animals 1n which they were
observed were lacking and thus not used.
The study by Blancbet et al. (198?) also reported alterations 1n
electrophysiologic parameters of the heart. In this study, four female
Sprague-Dawley rats were exposed to methyl methacrylate at a concentration
of 311,149 mg/m3 (76,000 ppm) for 20 minutes/day for 21 or 42 days. A
control group was exposed to compound-free air. An alteration In ECG
patterns and respiration were observed In the rats following 21 days of
exposure. Following 42 days of exposure, all animals exhibited Increases 1n
systolic blood pressure, increased heart and respiratory rate, abnormal
respiratory patterns, and ECG changes Indicative of heart block, ihc
exposure-adjusted animal dose corresponding to these effects was 103,716.33
mg/m3. Based on the ratio of rat and human alveolar ventilation, body
weight, and dally air Intake, a L0A£L^c of 291.49 mg/m3 Is obtained.
The resulting RfC$ Is 291.49 mg/m' and reflects adjustment by an
uncertainty factor of 1000, which accounts for extrapolation from a L0AEI,
protection of sensitive Individuals, and Interspecies extrapolation.
049 2d
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The various studies (BNW and 1ST studies) conducted by NTP (1986) using
mice also provided results considered for derivation of the RfC$. The JBT
studies (NTP, 1986) were not considered because NOftEL values considerably
exceeded LOAEL values of the other studies, a situation suggesting that the
toxicity ondpolnt used to obtain the NOAEL was not sensitive enough. The
BNW study (NTP, 1986) provided a LQAELadJ of 365.54 mg/m> for male mice
exposed to 500 ppm (2047.03 mg/m3) methyl methacrylate 6 hours/day, 5
days/week for 98 days. The L0AEL^c Is 1663.21 mg/m3 which, after
application of an uncertainty factor of 1000 (animal-to-human extrapolation,
use of a LOAEL, and protection for sensitive populations), results in an
RfC$ of 1.66 mg/m* (33.26 mg/day).
The RfCs (1.66 mg/ma) derived from the BNW Laboratories study (NTP,
1986) appears to be the most tenable of those derived from the subchronlc
rat studies. Both the Lomonova el al. (1980) and the Blanche! et al. (1982)
study Identify cardiac effects following short-term Inhalation exposure of
rats to methyl methacrylate vapor but the exposure levels and resulting
adjusted animal doses vary considerably, thereby reducing confidence In
determining the actual exposure concentration. Furthermore, the LOAEL
values derived are not consistent with other dose-response data, making them
questionable for derivation of an RfC$ (U.S. EPA, 1988).
8.2.1.2. CHRONIC EXPOSURE — A number of epidemiology studies regard-
ing occupational exposure to methyl methacrylate were reviewed. Blagodatln
et al. (1971) conducted a retrospective study of 152 workers exposed to
methyl methacrylate at concentrations ranging from 2-200 mg/m51. Subjec-
tive reports by the workers Indicated that they experienced a variety of
symptoms including headaches, pain in the extremities, fatigue,
irritability, memory loss, and sleep disturbances. The report did not
provide specific exposure details during the 10-year study period.
0492d 8-12 11/13/90
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Monroe et al. (1901) reported the results of a survey of chemical plant
workers who were exposed to methyl methacrylate vapor. Workers were
compared on the basis of sex, age, smoking habits, work history and length
of service. There was no correlation between length of service and
respiratory disorders when smoking habits were considered. No methyl
methacrylate exposure levels were provided.
A clinical investigation of workers from a factory producing polymethyl
methacrylate sheets concluded that exposure to methyl methacrylate at levels
ranging from 20-736 mg/ma produced moderate nervous sytem disorders and
mucosal Irritation (Delia Torre et al., 1982). Exposure groups were defined
; based on exposure to low (20-342 mg/ma) or high (472-736 mg/m*) levels
' of methyl methacrylate vapor. Specific exposure concentration and duration
data, and Identification of a reference group were not provided.
Jedrychowskl (1982) assessed the effects of Inhalation exposure to
methyl methacrylate and styrene and found that such exposure produced a
>2-fold Increase In lung obstruction compared with a reference group matched
for age and smoking habits. Methyl methacrylate levels ranged from
0.2-382.2 mg/m9 (mean^ll.06 mg/ma) but were concurrent with varying
levels of styrene (0.06-31.81 mg/ma), which confound the Issues when
assessing compound-specific effects.
A group of 63 workers (35 men and 28 women) exposed to methyl
methacrylate concentrations ranging from 30-300 mg/ma for an average of 10
years were reported to have a 50% incidence of nervousness, headache and
weakness, and a 41.2% Incidence of undefined neurotic symptoms (Kuzolova et
al., 1985). No exposure-specific details were provided nor was mention made
of a reference group.
Another study (Hakarova and Hakarenko, 1983) from the Russian literature
reported altered hormonal levels In 51 workers exposed to methyl
0492d 8-13 11/07/90
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methacrylate In a plastic glass factory. No details regarding exposure
concentration or duration were provided.
After considering the effects of smoking habits, age, specific
employment period, race and latency, Collins et al. (1989) found no
Increased risk of mortality from methyl methacrylate exposure In workers
from two American Cyanamld plants. The Q-hour TWA values at these plants
were 0.13-0.69 and 0.72-1.00 ppm. Specific exposure duration data were not
available, but no Individuals were exposed for greater than a 22-year period.
The effects of methyl methacrylate on several species Including rats,
mice and hamsters were Investigated 1n some chronic animal studies. NTP
(1986} conducted 102-week Inhalation exposure studies using male and female
F344 rats, and B6C3F1 mice exposed to methyl methacrylate at concen-
trations of 0, 500 or 1000 ppm, 6 hours/day, 5 days/week {except female rats
that were exposed to 0, 250 or 500 ppm). Exposure to all concentrations of
methyl methacrylate resulted In Inflammation of the nasal cavities and
degeneration of olfactory sensory epithelium both rats and mice. Survival
of compound-exposed rats and mice was not affected, but rats In the exposure
groups exhibited a slight decrease (5-11%) 1n body weight relative to
controls, and mice had body weights that were 10-10% less than controls.
Additionally, male and female mice from all exposure groups exhibited cyto-
plasmic Inclusions 1n the respiratory epithelium, and epithelial hyperplasia
of the nasal cavity.
Hazelton Laboratories (1979b) exposed male and female Fisher rats to 0,
25, 100 or 400 ppm methyl methacrylate for 6 hours/day, 5 days/week for 104
weeks. female rats of the highest exposure group exhibited a slight
decrease In body weight relative to controls. Mild rhinitis was observed 1n
all methyl methacrylate exposure groups, but could not be definitively
0492d
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attributed to the compound. Hazelton Laboratories (1979a) also examined the
effects of Inhaled methyl methacrylate on male and female golden hamsters
using the same experimental protocol as that used In the rats studies except
for a 78-week exposure duration. A 2-fold Increase In mortality was noted
for male hamsters In the 400 ppm exposure group. No toxic efreels were
noted for any hamsters in any of the other exposure groups.
Several studies examining the developmental toxicity potential of methyl
methacrylate by exposing rats and mice to the compound during gestation are
considered In assessing chronic effects of methyl methacrylate exposure.
These exposures are considered chronic relative to the fetus and develop-
mental processes. McLaughlin et al. (1978}, In an Inhalation study, exposed
pregnant ICR mice to 1330 ppm of methyl methacrylate for 2 hours, twice
dally on days 6 through 15 of gestation. With the exception of a slight
Increase In average fetal weight, no toxic effects were observed.
Nicholas et al. (1979) exposed pregnant Sprague-Dawley rats to methyl
methacrylate at a concentration of 109 mg/2. for 17.2 or 54.2 minutes/day
on days b through 15 of gestation, lhe longer exposure duration produced
evidence of fetal toxicity in the presence of maternal toxicity. lhe
shorter duration exposure resulted In developmental toxicity (lower fetal
body weight, decreased crown-rump length, delayed ossification of
sternebrae) without maternal toxicity.
Luo et al. (1986) administered methyl methacrylate (0.52 or 4.48 my/i)
to pregnant rats for 2 hours/day, every 3 days on days 6 through 10 of
gestation. The low exposure group did not exhibit any signs of
developmental toxicity relative to controls. Increased Incidence of
resorptions and delayed ossification in the fetuses were observed for the
high exposure group. There was no evidence of maternal toxicity.
0492d
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Several animal studios were considered for deriving the RfC for methyl
methacrylate; these data are presented 1n Table 8-2. The retrospective
epidemiologic studies regarding Inhalation exposure to methyl methacrylate
were not considered useful for quantitative risk assessment. The studies by
McLaughlin et al. (1978), Nicholas et al. {1979) and Luo et al. (1986) were
given Initial priority because of the gestational exposure. The mouse study
by McLaughlin et al. (1978} exposed pregnant ICR mice to methyl methacrylate
(5445.11 mg/m*) for 2 hours, twice dally on days 6 through 15 of
gestation. No observable effects were noted for this exposure, thus
resulting In a free-standing NOAEL^ of 907.52 mg/m» and a M0AELH£C
of 4129,19 mg/ma. Application of an uncertainty factor of 100 (10 for
interspecies extrapolation and 10 for protection of sensitive populations)
results In an RfC of 41.29 mg/m1 (825.84 mg/day). Data from the Nicholas
et al. (1979) study provided only a free-standing FEL value and, therefore,
was not used 1n deriving an RfC. The study by Luo et al. (1986) used
exposure protocols resulting In both a N0AEL and FEL based on developmental
toxicity endpolnts. The exposure of pregnant rats to 0.52 mg/i (520
mg/m3}, 2 hours/day, every 3 days on days 6 through 18 of gestation
produced no significant effect, resulting In a NOAEL^j of 12.38 mg/m3.
However, the same exposure protocol using 4.48 mg/i (4480 mg/m3)
resulted In a significant Increase In the number of resorptions, and delayed
ossification In the fetuses. Adjusting for differences In ventilatory
volume between rats and humans results In a NOAEL^ of 27.61 mg/m*.
Application of an uncertainty factor of 100 (10 for Interspecies
extrapolation and 10 for protection of sensitive populations) results 1n an
RfC of 0.276 mg/m" (5.52 mg/day). In the NTP (1986) study, exposure of
female rats to 250 ppm methyl methacrylate for 6 hours/day, 5 days/week for
0492d
8-16
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TABLE 8-2
Summary of Dose and Effect level Data from Pertinent
Studies of Chronic Inhalation Exposure to Methyl Methacrylate
Effect Level [mg/ma)
Spectes
Description
NOAEL
LOAEL
FEL
Reference
Rat
714-day
—
2017 (H)
1023 (F)
—
NTH, 1906
Rat
Days 6-18
of gestation
520
—
4,480
Luo et al.,
1986
Rat
Days 6-15
of gestation
—
—
109,000
Nicholas
et al., 1979
Rat
728-day
1636
Hazelton
Laboratories
1979b
House
Days 6-15
of gestation
5445
—
HcLaughlin
et al,, 1978
House
714-day
500
—
NTP, 1906
Hamster
546-day and
714-day
409
1,638
Hazelton
Laboratorles
1979a
0492d
8-17
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714 days resulted 1n 1nflammatlon of the nasal cavity and degeneration of
olfactory epithelium, and can be assigned LOAEl status. The resulting
L0AELadj Is 182.77 mg/ifi3 and the LQAEL^ Is 407.58 mg/ma.
Application of an uncertainty factor of 1000 (10 for Interspecies
extrapolation, 10 for protection of sensitive populations, and 10 for LOAEL
to NOAEL extrapolation) results 1n an RfC of 0.41 mg/m3 (8.15 rag/day).
Based on U.S. EPA (1988) methodologies, the NTP (1986) 2-year study was
selected for derivation of the RfC (0.41 mg/m5, 8.15 mg/day). Although
the gestational exposure study by Luo el al. (1986) provided a somewhat more
conservative RfC (0.28 mg/m», 5.5 mg/day), the study was reported only In
abstract form and lacked experimental detail. Furthermore, It employed an
unconventional exposure protocol (every 3 days during gestation), the
rationale for which was not provided. The HcLaughlIn et al. (1978) study
was not given further consideration because the NOAEL value was considerably
greater than LOAEL and F£l values of other studies.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE — No studies In human subjects
regarding the subchronlc oral toxicity of methyl methacrylate were located.
A summary of dose and effect level data from pertinent animal studies of
short-term and chronic oral exposure to methyl methacrylate 1s presented in
Table 8-3.
In an animal study by Hotoe et al. (1971), rats were administered methyl
methacrylate orally for periods of 3, 5 or 8 months. The total dosage
during these periods was 2750, 5500 and 8125 mg/kg, respectively. Compound-
evidenced hlstopathologlcal alterations of the liver and Increases in serum
enzyme activity levels were reported. An exposure duration-related Increase
In severity of ulcerations 1n the glandular epithelium of the
0492d
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TABLE 8-3
Summary of Dose and Effect Level Data from Pertinent Studies of
Short-Term and Chronic Oral Exposure to Methyl Hethacrylate*
Species
Description
Effect Level (ppm)
NOAEL LOAEL fEL
Rat
728-day;
68.46 2000
drinking water
Dog
365-day; dietary
1473
(considered sub-
chronic exposure
for dog}
~Source: Borzelleca et al., 1964
049 2d
8-19
06/^7/90
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stomach was also noted. A 21-day gavage study Indicated that dally
administration of methyl methacrylate (In olive oil} at 500 mg/kg produced
behavioral changes and Increased levels of biogenic amines in the pons-
mcdulla and hippocampus regions of the brain (Husaln et al., 1985). In a
1-year dog study, Borzel1eca et al. (1964} found only a reduction In
spleen-to-body weight ratio (of equivocal biological significance). The
dogs had received dietary methyl methacrylate at 0, 10, 100 or 1000 ppm, the
latter being upwardly adjusted to provide a TWA of 1473 ppm for the exposure
period. The 36.825 mg/kg/day exposure level (1473 ppm) in the dog study may
be assigned N0AEL status. Application of an uncertainty factor of 1000 {10
for interspecies extrapolation, 10 for protection of sensitive populations,
and 10 for a deficient data base) results 1n an RfDs of 0.037 mg/kg/day.
8.2.2.2. CHRONIC EXPOSURE — No studies were available that examined
the effects of chronic, oral exposure of humans to methyl methacrylate.
The only chronic, oral exposure study Identified was that of Borzelleca
et al. (1964) wherein male and female rats were administered methyl meth-
acrylate in the drinking water for a period of 104 weeks. The exposure
concentrations were 0, 6, 60 or 2000 ppm (0, 24.6, 245.6 or 8188 mg/m3,
respectively). The low and medium concentrations were upwardly adjusted at
the fifth month to provide a TWA exposure of 6.85 ppm (28.0 mg/ma) and
60.46 ppm (280.3 mg/m3), respectively. There was an increased kidney-to-
body weight ratio In female rats of the 2000 ppm group. No compound-related
effects were observed.
The study by Borzelleca et al. (1964) was of sufficient exposure
duration for consideration In deriving a chronic RfD. The exposure groups
consisted of adequate numbers of male and female Wlstar rats (25 of each sex
per group), and reflected a wide range of compound exposure. Based on the
049?d
8-20
11/07/90
-------
negative findings for the low and medium exposures and the altered
kidney-to-body weight ratio observed for female rats of the high exposure
group, a NOAEI^qj (15.67 mg/kg/day) and LOAEL^j (457.94 mg/kg/day) are
calculated using a drinking water factor of 0.049 a/day. Ho toxic effects
were observed for male rats In the high (2000 ppm) group and, therefore, a
NOAEL^pj could be assigned to the 332.20 mg/kg/day dose calculated for
this group. However, the experimental protocol and data derived from this
study are not sufficient to demonstrate with certainty, a sex-dependent
effect. For this reason and in order to provide a more conservative assess-
ment of the RfD, the dose (15.68 mg/kg/day, for female rats) from the medium
exposure (68.85 ppm) group Is being assigned N0AEL status. Application of
an uncertainty factor of 1000 (10 for protection of sensitive populations,
10 for interspecies extrapolation, and 10 for a deficient data base) results
1n an oral RfD value of 0.016 mg/kg/day. This value corresponds to 1.12
mg/kg/day for a 70 kg human.
0492d
B-21
11/07/90
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Toxicity summaries and composite scores For Inhalation exposure to
methyl methacrylate are presented In Tables 9-1 and 9-2, respectively.
Toxicity summaries and composite scares for oral exposure to methyl meth-
acrylate are presented In Tables 9-3 and 9-4, respectively.
Several studies can be considered for deriving the RQ for methyl
methacrylate. In the study by Lomonova et al. (1980), discontinuous exposure
(3 hours/day, 6 days/week) of rats to 115.0 mg/m3 methyl methacrylate for
120 days resulted In ECG alterations. Based on the transformed animal dose
of 3.925 mg/kg/day and an RVd of 7, a composite score (CS) of 31.44 Is
obtained. This Is the highest CS obtained from any of the studies, and
represents an RQ of 100. The Delia Torre et al. (19B2) study reported minor
nervous system disorders in humans occupatlonally exposed to methyl meth-
acrylate at concentrations of 20 or 736 mg/m3 over a period of -12 years.
These effects were assigned an RV of 6 and resulted In a CS of 17.90 and
c
an RQ of 1000. The 98-day mouse study conducted by DNW Laboratories (NTH,
19B6) Indicated that discontinuous exposure to methyl methacrylate at a
concentration of 2000 ppm (957.977 mg/kg/day) resulted in 20% mortality
(RV^IO). These data result in a CS of 14.52 and an RQ of 1000. However,
the most appropriate study is the 714-day, chronic rat study by BNH
Laboratories (NTP, 1986) wherein male and female rats were exposed to methyl
methacrylate at concentrations ranging from 250-1000 ppm. The study
Identifies a L0AEL of 250 ppm (transformed animal dose of 127.32 mg/kg/day
and a human HED of 19.89 mg/kg/day). Based on an RV& of 6.00 for
histological alterations of the nasal cavity and the olfactory epithelium, a
CS of 6.00 and RQ of 1000 are obtained for these data.
0493d
9-1
11/07/90
-------
TABU 9-1
Inhalation Toxicity Sumary for Hethyl Kethacrylatc*
Species/
Strain
Sex/
Hvabtr
Average
Height
(kg)
Purity
Exposure
Transforncd
Animal Dose61
(ng/kg/day>
equivalent
Hunan NED*
99% 63 ppn (257.93 rag/n*J, 11.46?
r/10 0.142,e >95* 125 ppa {511.76 »g/a»|, 34.656
r/10 0.142<*.e 6 hours/day, 5 days/week 39.257
for 98 days
H/10 O.PQ?11-* >99* 250 ppra (1023 wj/n»|, 7I.3BI
r/10 0.1420.* 6 hours/day, 5 days/week 78.515
for 9B days
N/10 0.20^-e >99X SOD ppn (?047 138.674
f/10 0.M2
HIP, 1986
(IBIJ
KIP. 198£>
Uaij
-------
TABLE 9-1 (carl.)
Species/
Strain
S ex/
N water
Average
Weight
(k9)
Purity
Exposure
Transforoed
Anlnal Doseb
(mg/kg/day)
Equivalent
Hunan HEDC
(tag/kg/day]
Response
Reference
Bat/f 344
N/10
F/10
0.20799X
1000 ppa (4094 rag/m1}.
6 hours/day, 5 days/week
For 98 days
277.248
314.0S9
3.979'
3.976*
No signs of toxicity
HTP, 19B6
(IBT)
N/10
r/io
D.?59d'e
0.159d»e
>99X
500 ppn {2047 tag/a1),
f> hours/day, 5 days/week
for 98 days
129.14
151.735
1.997f
1.994'
No signs of toxicity
KIP, 1986
(BUM)
N/10
0.2S9d.*
>99*
1000 ppa (4094 rag/a1},
6 hours day. 5 days/week
for 98 days
2SB.2B
3.995'
Ho signs of toxIcHy
NIP. 1986
(BKH)
r/io
o.i59d'c
>99X
i
1000 ppn (4094 rag/n1),
6 hours day, 5 days/week
for 9B days
606.941
7.978'
Inflammation and necrosis
of nasal cavity
NIP. 1986
IBHW}
N/10
0.2S9d«e
>99X
2000 ppn {B,1B8 ag/ia*},
6 hours/day, 5 days/week
for 9B days
516.560
7.989'
10X mrtallty
NIP. 19B6
(BKW)
r/io
0.159d-e
>99X
20D0 ppn, 6 hours/day
5 days/week, for 9B days
606.941
7.978'
30X mortality
NIP, 19B6
(BKW)
H/10
0.259d'e
>9W
3000 ppa (12,282 ng/*»).
6 hours/day. 5 days/week
for 9B days
744.840
11.984'
10X mortality
HTP, 19B6
(SHU)
r/io
0.15Sd-e
>99X
3000 ppa. 6 hours/day.
S days/week for 98 days
910.411
11.96B'
9OX raorUIUy
KTP. 1986
(BHWJ
h/10
r/io
0.259d»*
0.159d«*
>99X
>99X
5000 ppa (20,470 ng/n»),
6 hours/day, 5 days/week
for 98 days
1291.400
1517.351
19.974'
19.946'
100X aortallty
NTP, 1986
99X
102 ng/n', 6 hours/day,
S days/week for 728 days
11.111
13.57B
1.986
1.989
Mild rhinitis
Haielton
Laboratories
1979b
N/70
r/70
0.396d^
0.217d»e
>99X
409 ng/a*. 6 hours day,
S days/week for 728 days
44.633
54.524
7.953
7.950
Mild rhinitis
Haielton
Laboratories
1979b
N/70
r/70
Q.396d«e
0.?17d»c
>99X
1636 mq/Pt*. 6 hours/day.
S days/week for 728 days
178.532
219.790
32.311
31.899
HUd rhinitis
Reduced body weight
Haielton
Laboratories
1979b
-------
TABLE 9-1 (conl.)
o
VD
U
a.
Species/
Sir jln
Sc*/
Number
Average
Wright
(kg)
Purity
Exposure
transformed
An In] 1 0(HCb
(ng/kg/djy)
Equivalent
Itumn H£DC
{ng/kg/day>
Response
Reference
Rat/f344
f/70
0.267''.e
>99X
250 ppa. 6 hours/day,
5 days/week for 714 days
127.324
19.694
Pathological and histo-
logical effects on nasal
epithelium, decreased
body weight
NTP. 1986
Rat/f344
H/70
r/70
0.448d.®
0.?699X
SOD ppa, 6 hours/day,
S days/week for 714 days
214.594
2S6.1S8
39.842
39.873
Pathological and histo-
logical effects on nasal
eplthellun, decreased
body weight
NTP. 1986
K/70
0.44D"'.®
>99X
1000 ppn. 6 hours/day,
5 days/week for 714 days
216.003
39.864
Pathological and histo-
logical effects on nasal
eplthcllun, decreased
body weight
HIP, 1986
Rats
r
0.3SQS
NS
520 ppa (2129 «g/n*).
2 hours/day, every 3 days
during gestational days 6-18
3.944
0.674
No Ddternal or fcto-
loxlclty
Luo et al.,
1906
r
D.3S09
NS
4480 ppfii (IS.341 ng/n').
2 hours/day. every 3 days
during gestation days 6-10
33.981
5.811
Increased Incidence of
resorptions, delayed
ossification In fetuses
Luo et al..
1906
Ral/Sprague-
Ojwley
F
0.2Sd
NS
109 mq/frt {109,000 ng/n').
0.287 hours/day. 7 days/
week gestation days 6-1S
464.03
70.929
Teratogenic effects with
no maternal toxicity
Nicholas
et al.. 1979
r
D.2S"3
KS
109 mg/t (109.000 mg/n').
0.903 hours/day, 7 days/
week gestation days 6-15
1455.12
15.569.56
Teratogenic effects,
fetal death with oatemal
toxicity
Nicholas
el al.. 1979
House/
B6C3fl
M/l ~
f/10
0.027d.c
0.22*.*
>99X
63 ppa {257.9 mg/»«>.
6 hours/day, 5 days/week
for 98 days
33.497
30.706
0.22B'
0.224'
Ko toxic effects
NTP. 1986
(IBT)
M/l 0
r/io
0.027d»c
0.022d»®
>99X
125 ppa (409.8 iag/n>),
6 hours/day, 5 days/week
for 90 days
60.924
66.463
0.443'
0.452'
No toxic effects
06/VL/lL
M/l 0
r/io
H/10
r/to
0.027^.*
a.D??d-<>
D.^
>99X
>99X
250 ppa {102.4 ng/n'|.
6 hours/day, 5 days/week
for 98 days
iOD ppci {204/ rnj/ra»|,
t> hours/day, S days/week
for 98 days
121.840
132.925
243.696
26S.05O
0.807'
0.904'
1.774'
1.aoa'
No toxic effects
No toxic effects
-------
TABLE 9-1 (coril.)
C3
S Species/
Strain
Sc*/
Nuixber
Average
Height
(NJ
Purity
Exposure
Transformed
Animal Dose11
93* 1000 ppsi (4094 iag/ia'J, 487.39?
0.022<^e 6 hours/day, 5 days/week 531.700
for 98 days
0.029*.e >99* 500 ppm 12,017 «g/ra»K 239.494
0.024d>e 6 hours/day. 5 days/week 258.927
for 98 weeks
D.024d.* >99X 1000 ppm {4094 «g/«,K 47B.988
0,02499* 2000 ppn (B188 ng/"*h 957.977
0.024tf-e 6 hours/day, 5 days/week 1035.707
for 98 days
0.02911'* >99* 3000 ppn (12,282 ag/a*}. 1436.965
i hours/day. S days/week
for 9B days
0.024«5.e >99* 3000 ppra {12,282 p*q/n»l. 1553.361
6 hours/day, 5 days/week
for 98 days
0.029d.° >99* 5000 ppa (20,470 rag/a*), 2436.958
0.023*1.« 6 hours/day. 5 days/week 2860.777
for 9B days
0.033d.p >99* 500 ppm, f> hours/day, 232.619
0.03ld.f 5 days/week for 714 days 235.B3S
0.033^»c >99* 1000 pfm. 6 hours/day, 432.006
0.031b.d 5 days/week for 714 days 471.669
0.022".* >99* 1330 ppa, {5445 «g/n>), 660.01?
4 hours/day, 7 days/week
on days 6-IS of gestation
0.11B
-------
TABLE 9-1 (cont.)
o
-------
TABLE 9-2
Composite Scores for Inhalation Exposure to Kethyl Hclhacrylate
558.484^
838.901b
837.726b
1,398.16Bb
1.396.203b
3.05
3.OS
3.13
4.49
1.00
3.63
3.63
3.19
3.19
2.72
2.74
2.28
2.28
1.83
1.83
2.28
2.28
1.83
1.38
1.38
1.38
1.11
1.12
1.00
1.00
Decreased fat content; decreased weight;
tracheal Irritation
Decreased visceral and subcutaneous fat
content; decreased weight; tracheal
Irritation
Increased cholesterol; decreased bili-
rubin; tCG alterations;
Enlarged liver and kidneys; htstopatho-
loglcal changes
Abnormal cardiac function; increased
respiratory rate and pattern; Increased
blood pressure
No
slgnj
of
toxicity
No
signs
of
toxicity
No
signs
of
toxicity
Xo
signs
of
toxicity
No
signs
of
toxicity
No signs of toxicity
Xo signs of toxicity
Inflamation and necrosis of nasal
cavity; loss of olfactory epithelium
10% mortality
30* ewrtallty
10X mortality
90* mortality
100X Mortality
10W Mortality
4
12.19
1000
Tansy et al..
1976
4
12.19
1000
Tansy el al.,
1976
1
3.13
5000
Tansy el al..
1980a
7
31.44
100
Looonova
et al., 1980
7
7.00
1000
Blanche!
et al.. 1982
1
3.63
5000
NIP, 1986
1
3.63
5000
UBTJ
1
3.19
5000
1
3.19
5000
1
Z.72
5000
1
2.74
5000
1
2.28
5000
1
2.28
5000
1
1.63
SOOO
1
1.83
5000
1
2.28
SOOO
NIP, 19B6
1
2.28
5000
(8NM)
1
1.83
5000
6
8.28
1000
10
13.79
1000
10
10.80
1000
10
11.14
1000
10
11.15
1000
10
10.00
1000
10
10.00
1000
-------
Transformed
Spectcs/ Anlnat Dose Himun MED3 RVj
Strain {«g/*g/day) (og/
-------
TABU 9-2 (cont.)
Species/
Strain
Transformed
Antiaal Dose
(Big/kg/day)
KuiWfi KE0»
(i*q/day >
R*d
Effect
RVe
CS
m
Reference
Hoitse/86C3FI
H
957.977
499.904b
1.45
20% (sociality
10
14.52
1000
HIP, 1986
r
1035.707
507.426b
1.44
10% mortality
10
14.42
1000
[BKMJ
H
1436.965
749.B55b
1.19
4OX mortality
10
11.83
1000
F
1553.561
761.139b
t.ia
Reduced body weight gain
6
7.07
1000
H
24 36- .958
1,241.7S2b
1.00
BOX oortallty
10
10.00
1000
F
2060.777
1,391.B43b
1.00
00% curtailty
10
10.00
1000
H
232.619
1,267.306
l.OO
111stopathology of naial cavity
4
4.00
5000
F
235.835
1,256.327
1.00
Reduced body weight gain
4
4.00
5000
N
432.006
2,353.568
1.00
Hlstopathology oF naial cavity
4
4.00
5000
F
471.669
2,516.654
1.00
Reduced body weight
4
4.00
5000
House/ICR
660.OT7
3,141.193
1.00
Slight Increase in fetal weight
1
1.00
5000
Mclaughlin
et al., I97B
Hamster H
a.442
70.326
2.73
Nq toxic effects
1
2.73
5000
tlJzrl ton
r
8.514
70.726
2.73
No toxic effects
1
2.73
5000
Laboratories,
N
34.055
202.905
1.8?
No toxic effects
1
1.02
5000
1979a
F
33.858
285.218
1.9?
No toxic effects
1
1.02
5000
N
136.220
1,131.620
1.00
?-Fold Increase In mortality
10
10.00
1000
F
136.046
1,123.699
1.00
No toxic cfFects
1
1.00
5000
Kununs
3.401
23S.095
1.93
Subjective neuropsychological
6
11.61
1000
BlagodatIn
et al.. 1971
Hununs
0.660
47.619
2.98
Minor nervous systen disorders
6
6.00
1000
Delia Torre
25.034
1,752.381
1.00
Minor nervous sysUm disorders
6
17.90
1000
et al,, 19B?
a|[unun equivalent dose (ng/kg/dayj fron Table 9-1 multiplied by 70 kg to express M£0 Irt nq/dajr far TO kg hunun
bIndudes correction by uncertainty factor of 10 for extrapolation Iron subchronk exposure data
-------
TABLE 9-3
Oral Toxicity Sumary for Hethyl MethacryTate*'1'
Species/
Strain
Sex/
Nunber
Average
Weight'
(kg}
Vehicle/
Physical
State
Exposure
Transformed
Anlnal Dose"1
(ng/kg/day)
Equivalent
Huwn HEDe
(ng/kg/day)
Response
Rat/Wlstar
K/25
f/25
0.295*
0.214'
solution
(water)
6.650 ppn In drinking water; con-
tinuous exposure for 72B days
1.138
1.56B
0.184
0.228
No toxic effects
N/2S
f/25
0.295'
0.214'
solution
(water)
6B.460 ppei In drinking water; con-
tinuous exposure for 728 days
11.371
15.675
1.837
2.275
No toxic effects
N/25
J725
0.295'
0.24'
solution
(water)
2000 ppn in drinking water; con-
tinuous exposure for 728 days
332.203
457.944
53.659
66.464
No toxic effects
Dog/beagle
M/2
F/2
9.47
dietary
10 pps In food; contlnous exposure
for 36S days
0.250
0.0139
Increased kidney-to-
body weight ratio
h/2
r/2
9.47
dietary
100 ppn in food; continuous exposure
for 365 days
2.5
0.1289
No toxic effects
N/2
r/2
9.47
dietary
1473 ppst (tlne-welghtcd average)
In food; continuous exposure for
365 days
36.825
1.899
No toxic effects
'Source: Borzelleca ct a1., 1964
bIhe purUy of the compound was not reported.
cAuthor data
^Drinking factors: rats ¦ 0.049 t/day; food factor: dogs = 0.025 (U.S. EPA, 1906b]
'Calculation: transferred animal dose (tag/kg/day) x [anlnal body weight (kg)/rcfcrcnce huwn body weight]*'3
'[stlrated weight at aldpotnt of study; based on authors data
^Includes correction by uncertainty factor of 10 for extrapolation from subchrontc exposure data
-------
TABU 9-4
Composite Scores for Orally Administered Methyl Hethacrylate3
Species/
Strain
Sex
Transformed
Animal Oose
(mg/kg/day)
Human HEDb
(nig/day)
RVd
Effect
RVe
CS
RQ
Rat/Wlstar
H
1.13B
12.865
3.84
No
toxic effects
1
3.84
5000
F
I.56B
15.935
3.70
No
toxic effects
1
H
11.371
128.573
2.34
No
toxic effects
1
2.34
50 DO
F
15.675
159.254
2.20
No
toxic effects
1
2.20
5000
H
332.203
3756.154
1.00
No
toxic effects
1
1.00
5000
F
457.944
4652.456
1.00
No
toxic effects
4
4.00
5000
Dog/beagle
H&F
0.250
Q.B98C
5.57
Increased kldney-to-
1
5.57
5000
body weight ratio
H&F
2.500
8.9a4c
4.07
No
toxic effects
1
4.07
5000
H&F
36.825
132.330c
2.32
No
toxic effects
1
2.32
5000
aSource: Borzelleca et al., 1964
bHuman equivalent dose {mg/kg/day) from Table 9-3 multiplied by 70 kg to express MED In mg/day for 70 kg
human
cIncludes correction by uncertainty factor of 10 for extrapolation from subchrorilc exposure data
-------
Although the lomonova et al. {1980) study provides the highest CS
(31.44) and lowest RQ (100), confidence In this study is low (see Section
8.2.1.1.) and, therefore, not selected for deriving the RQ for methyl
methacrylate. Both the Delia Torre et al. (1982) and NTP (1986) provide
similar CS values and RQ values of 1000. When compared with the other
animal studies or the retrospective epidemiologic studies, both NTP studies
provided greater detail of exposure protocol and greater precision and
thoroughness In reporting experimental procedures and data. However,
because of 1 ts chronic exposure protocol, the 714-day NTP (1986) study was
selected for determining the chronic RQ (1000) for methyl methacrylate.
9.2. BASED ON CARCINOGENICITY
The available data did not allow for derivation of a reportable quantity
for methyl methacrylate based on carcinogenicity.
0493d
9-12
11/07/90
-------
10. REFERENCES
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285.2(83).
Amoore, J.E. and E. Hautala. 1983. Odor as an aid to chemical safety: Odor
thresholds compared with threshold limit values and volatilities for 214
Industrial chemicals In air and water dilution. 3. Appl. Toxicol. 3:
272-290.
Anderson, 0., E. longstaff and J, Ashby. 1979. An assessment of the
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Apol, A.G. and S.O. Helgerson. 1984. Swedish Hospital, Seattle, WA. HETA
83-153-1510. NI0SH, Cincinnati, OH.
Autlan, J. 1975. Structure-activity relationships of acrylic monomers.
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Bailey, li.C., O.H.W. Liu and H.A. Javltz. 1985. T1me/tox1c1ty relation-
ships In short-term static, dynamic, and plug-flow Moassays. In: Aquatic
Toxicology and Hazard Assessment: Eighth Symposium. Proc. of Symp., Fort
Mitchell, KY, April 15-17, 1984, sponsored by ASTH Committee E-47. ASTM
Special Technical Publ. 891. ASTH, Philadelphia, PA. p. 193-212.
0494d
10-1
07/02/90
-------
Baker, S., S.C. Brooks and D.H. Walker. 1988. The release of residual
monomer 1c methyl mcthacrylate from acrylic appliances In the human mouth: An
assay for monomer In saliva. J. Dent. Res. 67: 1295-1289.
Blagodatln, V.M., L.N. Chernova, I.A. Golova, E.Sh. Gronsberg and A.A.
Russklkh. 1971. Hygenlc evaluation of the working conditions and stale of
the health of workers 1n continuous production of methyl methacrylalc. Gig.
Tr. Prof. Zabol. 15: 48-49.
Blanchet, 1.3., O.C. Bowman and H.D. HcReynolds. 1982. Effects of methyl
methacrylate monomer vapors on respiration and circulation In unanesthetUed
rats. J. Prosthct. Dent. 48: 344-34B. (Cited 1n U.S. EPA, 1985}
Bcrchard, U. 1982. Pharmacology, toxicology, and clinical actions of mono-
merle and polymeric methylmelhacrylate. Ijn: Systemic Aspects of Blocumpal-
IbHUy, Vol. 2., D.F. Williams, Ed. CRC Press, Inc., Boca Raton, fL.
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Relnhalt. luft. 32: 1-11. (Cited in I ARC, 1979)
0494d
10-19
01/18/91
-------
Schwach, 6.H. and H. Hofer. 197B. Determination of the oral acute toxicity
of methcrylales and vlnylpyrrolodone in mouse. Ber. Oesterr. Studienges
Atomenerg. SGAE Ber. No. 3004: 1-15.
Scolnlck, B. and J. Collins. 1986. Systemic reaction to methylmethacrylate
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Seppalalnen, A.M. and R. Rajanleml. 1984. Local and neurotoxicUy of
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Singh, A.R., W.H. Lawrence and J. Autlan. 1972. Embryonic-fetal toxicity
and teratogenic effects of a group of methacrylate esters in rats. 3.
Dental Res. 51s 1632-1639.
Singh, H.B., M.H, Jaber and J.E. Davenport. 1984. ReactlvUy/Volat 11 Uy
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Slave. T. et al. 1974. Title not given. Rev. Chem. 25: 666-670. (Cited
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Slozewlcz, A.G., A.G. Davison, A. Hopklrk ct al. 19B5. Occupational asthma
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Q494d
10-20
11/07/90
-------
Smith, J.N. 1980. Letter on review of toxicology of methyl methacrylate.
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Smith, J.H., G. Cruzan, J.A. Drees, H.F. Tansy, W.B. Coate and F.E. Reno.
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0494d
10-21
11/07/90
-------
Tansy, H.F. and F.H, Kendall. 1987. Endocrinological considerations of the
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GI motor inhibition associated with acute exposure to methyl methacrylatc
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Chronic biological effects of methyl methacrylatc vapor. II. Body and
tissue weights, blood chemistries, and gross metabolic performance In the
rat. Environ. Res. 21: 108-116.
Tansy, H.F., F.J. Hohenleltner, O.K. White, R. Oberly, W.E. landln and F.H.
Kendall. 1980b. Chronic biological effects of methyl methacrylate vapor.
III. Hlstopathology, blood chemistries, and hepatic and ciliary function in
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0494d
10-22
11/07/90
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U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
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Chronic Toxicity Oata. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for Methyl Meth-
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Syracuse Research Corporation, Syracuse, NY under Contract No. 67-03-3228
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U.S. EPA. 1986c. Methodology for Evaluating Reportable Quantity Adjust-
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0494d
10-23
11/07/90
-------
U.S. EPA. 1987. An ongoing study prepared for the Office of Hater Regu-
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U.S. EPA. 1908. Interim Methods for Development of Inhalation Reference
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Water Quality Criteria for the Protection of Aquatic Organisms and 7he 1 r
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Chemicals - U.S. Production/Sales, p. 267. (CUed In HSOB, 1989)
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Savolalnen. 1984. Toxicity of polymethacrylate thcrmodegradatlon products.
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OermatH. 8: 223-235.
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97-99.
0494d
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11/07/90
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Verkkala, £., R. Rajan1cm1 and H. Savolalnen. 1903. local neurotoxicity of
methyl methacrylate monomer. Toxicol. Lett. 18; 111-114.
Waegcmaekers, T.H.J.H. and H.P.H. Benslnk. 1904. Non-mutagen*city of 27
aliphatic aerylate esters In the Salmonella-microsome test. Mutat. Res.
137; 95-102.
Waegemaekers, T.H.J.H., E. Seutter, J.A.C.J. den Arend and K.E. Halten.
l9B3a. Permeabll1ty of surgeons' gloves to methyl methacrylate. Acta
Orthop. Scand. 54; 790-795.
Haegemaekers, T.H.J.H., K.E. Halten and 1. Benslnk. 1983b. NonmutagenlcUy
of a series of aerylate esters In the Ames Salmonella/mlcrosome test.
Hutat. Res. 113: 317-31B.
Weast R.C. and H.J. Aslle, Ed. 19B5-19Q6. Handbook of Data on Organic
Compounds, Vol. I. CRC Press, Boca Raton, FL. p. B36.
Wonzel H.t A. Garbe and H. Mowak. 1973. Untersuchungen zur pharroakoklnetlk
von monomethylmethacrylat. 1st Int. Koogr. Prothesentecknok funkt. RehabH.
Wlen. (CUed In Borchard, 1982)
Wlllert, H.-G., H.-A. Freeh and A. Bechtel. 1973. Measurements of the
quantity of monomer leaching out of acrylic bone cement Into the surrounding
tissues during the process of polymerization. Am. Chem. Soc. Dlv. Org.
Coat. Plast. Chem. Pap. 33: 370-370g.
0494d
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASR online
TOXLINE
TOXLIT
TQXUT &5
RTECS
OHM TADS
SRC Environmental Fate Data Bases
AQUIRE
TSCAPP
HTIS
Federal Register
CAS ONLINE
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted In July, 1989, and the following secondary
sources were reviewed;
ACGIH (American Conference of Government Industrial Hyglenlsts).
1988-1909. TLVs. Threshold Limit Values and Biological Exposure
Indices for 1986-19B7. Cincinnati, OH.
ACGIH (American Conference of Government Industrial Hyglenlsts).
1986. Documentation of TLVs and BEIs for Substances In Workroom
Air Adopted by ACGIH for 1985. Cincinnati, OH.
Battelle's Columbus Laboratories. 1971. Water quality Criteria
Data Book. Vol. 3. Effects of Chemicals on Aquatic Life. Selected
Data from the Literature through 1966. Prepared for the U.S. EPA
under Contract No. 68-01-0007.
Callahan, H.A., H.W. Sllmak, N.H. Gabel et al. 1979. Water-
Related Environmental Fate of 129 Priority Pollutants, Vols. I and
II. U.S. Environmental Protection Agency, Washington, DC.
EPA-440/4-79-029a.
0495d
A-l
07/Q?/9Q
-------
Chemical Hazard Response Information System (CHRIS). 1985. Volume
II.
Daubert, T.I. and R.P Danner. 1905. Data Compilation Tables of
Properties of Pure Compounds. Department of Chemical Engineering,
Pennsylvania State University, University Park, PA.
Grayson, H. and D. Eckroth, Ed. 197B-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John-Wiley and Sons, New
York.
IARC (International Agency for Research on Cancer). 1974-1986.
IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals
to Man, Vols. 1-39. World Health Organization, Lyon, France.
ITII (international Technical Information Institute). 1986. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Disposal with Toxicity and Hazard Data, International Technical
Information Institute, Tokyo,
Johnson, W.W. and M.T. Flnley. I960. Handbook of Acute Toxicity
of Chemicals to fish and Aquatic Invertebrates. U.S. Dept. of the
Interior, Washington, DC. Fish and Wildlife Service/Resource Publ.
137.
Keith, L.H. 1975. Identification and Analysis of Organic
Pollutants In Water. Ann Arbor Science Publishers, Inc., Ann
Arbor, HI,
Keith, L.H. 1981, Advances 1n the Identification and Analysis of
Organic Pollutants In Hater, Vols. 1 and 2. Ann Arbor Science
Publishers, Inc., Ann Arbor, HI.
Kemp, H.T., R.L. Little, V.L. Holoman and R.L. Darby. 1973. Hater
Quality Criteria Data Book. Vol. 5. Effects of Chemicals on
Aquatic Life. U.S. Environmental Protection Agency, Washington,
DC. EPA 1805QHLAQ9/73. NTIS PB 234 435.
Kent, J.A., Ed. 1974. Relgel's Handbook of Industrial Chemistry,
7th ed. Van Nostrand and Relnhold Company, New York.
Konasewlch D., W. Traversy and H, Zar. T97B. Great Lakes Water
Quality. Great Lakes Hater Quality Board.
Macklson, F.W., R.S. strlcoff and L.J. Partridge, Ed. 1981.
NIOSH/OSHA occupational health guidelines for chemical hazards.
U.S. Department of Health and Human Services, Washington, DC.
HcKee, J.E. and H.W. Wolf, Ed. 1963. Water Quality Criteria, 2nd
ed. Prepared for the Resources Agency of California, State Hater
Quality Control Board. Publ. No. 3-A.
NAS (National Academy of Sciences). 1977-1983. Drinking Water and
Health. NAS, Washington, DC.
0495d
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07/02/90
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QSHA (Occupational Safety and Health Administration). 1989. Table
Z-l-A. Limits for Air Contaminants. Federal Register. 54(12};
2923-2958,
Overcash, H.R., Ed. 19B1. Decomposition of Toxic and Nontoxic
Organic Compounds 1n Soils. Ann Arbor Science, Ann Arbor, HI.
Plmentel, D. 1971. HCPA. In; Ecological Effects of Pesticides on
Non-Target Species. Dept. of Entomology and Limnology, Cornell
University, Ithaca, NY. p. 112-113, 131-136.
Plunkett, E.R. 1976. Handbook of Industrial Toxicology. Chemical
Publishing Company, New York.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Oata. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA. Washington, OC. EPA 540/9-79-003. NTIS PB 80-196876.
Shackelford, H.M. and L,H. Keith. 1976. frequency of Organic
Compounds Identified in Hater. Office of Research and Development,
U.S. Environmental Protection Agency, Athens, GA. EPA-600/4-76-062.
Shackelford, W.M., D.H. CUne, L. faas and 6. Kurth. 1983.
Evaluation of automated spectrum matching for survey Identification
of wastewater components by gas chromatography-mass spectrometry.
NTIS P883-1B2931. U.S. Environmental Laboratory. Anal. Chlm.
Acta. 146(1): 15-27.
SHtlg, H. 1975. Environmental sources and emissions handbook.
Noyes Data Corporation, Park Ridge, NJ.
U.S. EPA. 1979. Toxicology Handbook, Mammallan and Aquatic Data,
Books 1 and 2. U.S. Environmental Protection Agency, Washington,
DC. EPA-540/9-79-003 Bk 1, Parts 1 and 2, and Bk 2. NTIS PB 80
196B84.
Verschueren, K. 19B3. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Company, New York.
Wlndholz, H., Ed. 1983. The Merck Index. An Encyclopedia of
Chemicals and Drugs, 10th ed. Merck and Company, Rahway, NJ.
In addition, the following compendia of aquatic toxicity data were
reviewed:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Vol. 3. Effects of Chemicals on Aquatic Life. Selected
Data from the Literature through 1968. Prepared for the U.S. EPA
under Contract No. 68-01-0007.
0495d
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-------
Brook, L.T., D.J. Call, D.L, Gelger and C.E. Northcott, Ed. 1984.
Acute Toxicities of Organic Chemicals to Fathead Minnows (Flme-
phales promelash Vol. 1, Center for Lake Superior Environmental
Studies, University of Wisconsin.
Gelger, D.L., S.H. Polrler, L.T. Brook and 0.3. Call, Ed. 1986.
Acute Toxicities of Organic Chemicals to Fathead Hlnnows (Plme-
phales promelasl. Vol. 3. Center for Lake Superior Environmental
Studies, University of Wisconsin.
Gelger, D.L., 0.3. Call and L.T. Brooks. 1988. Acute Toxicities
of Organic Chemicals to Fathead Hlnnows (Plmephales promelash Vol.
4. Center for Lake Superior Environmental Studies, University of
Wisconsin.
Gelger. D.L., C.E. Northcott. D.J. Call and L.T. Brook. Ed. 1985.
Acute Toxicities of Organic Chemicals to fathead Hlnnows (Plme-
phales promelasl. Vol. 2. Center for Lake Superior Environmental
Studies, University of Wisconsin.
Johnson. W.H. and H.T. Flnley. I960. Handbook of Acute Toxicity
of Chemicals to Fish and Aquatic Invertebrates. U.S. Dept. of the
Interior, Washington, DC. Fish and Wildlife Service/Resource Publ.
137.
Mayer, f.L. and M.R. Ellersleck. 1986. Manual of Acute Toxicity:
Interpretation and Database for for 410 Chemicals and 66 Species of
Freshwater Animals. U.S. Dept. of Int., Washington, DC. Fish and
Wildlife Service Resource Publ. 160.
McKee, J.E. and H.W. Wolf, Ed. 1963. Water quality Criteria, 2nd
ed. Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmentel, 0. 1971. MCPA. In; Ecological Effects of Pesticides on
Non-Target Species. Dept. of Entomology and Limnology, Cornell
University, Ithaca, New York. p. 112-113, 131-136.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington. DC. EPA 540/9-79-003. NTIS PB B0-196B76.
id
A-4
07/02/90
-------
o
tn
Cl
APPENDIX B
Sunmary Table for Xethyl Hethacrylate
Species
Exposure
Effect
RfD. RfC or q|*
Reference
Inhalation Etposure
Subchronlc raouse
Chronic rat
Carcinogenicity HD
500 ppn, 9B days
250 pp«. 714 days
NO
Inflamitlon and
necrosis of nasal cavity
Inf lawaitlon and
necrosis of nasat cavity
NO
1,6$ »g/«,a
0,41 i»g/B*a
ND
NIP, 1986
-------
APPENDIX C
DQSE/DURATION-RESPONSE GRAPHS FOR EXPOSURE TO METHYL HETHACRYLATE
C.I. DISCUSSION
Dose/duratloiwesponsc graphs for oral and Inhalation exposure to methyl
mothacrylate generated by the method of Crockett et al. (1985> using the
computer software by Durkln and Heylan (1988} under contract to ECAO-
dnclnnatl are presented In Figures C-l and C-2. Data used to generate
these graphs are presented In Section C.2. In the generation of these
figures, all responses are classified as adverse (FEt, AEl or LOAEL) or
nonadvcrse (NOEL or NOAELJ for plotting. The ordinate expresses dosage as
human equivalent dose {mg/day). The animal dosage in mg/kg/day Is
multiplied by the cube root of the ratio of the animal:human body weight to
adjust for species differences in basal metabolic rate (Mantel and
Schneldcrman. 1975). The result Is then multiplied by 70 kg, the reference
human body weight, to express the human equivalent dose as mg/day for a 70
kg human.
The boundary for adverse effects (solid line) is drawn by identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point an Infinite
line Is extended upward parallel to the dose axis. The starting point 1s
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process 1s continued
to the lowest adverse effect dose or concentration. From this point a line
Is extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
0496d
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00
a.i i
HUMAN EQUCU DURATION ENVELOP NEIHOP
Key: - NOEL
n - NOAEL
I - LOAEL
A » A EL
r - FEL
Solid line - Adverse Effects Boundary
Dashed Line - No Adverse Effeces Boundary
FIGURE C-l
Dose/Durat1on-Response Graph for Inhalation Exposure to Acetone
CyanohydMn: Envelope Hethod
0496d
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X089QB
a
i
f
\
*
I
o
a
»
looaa
1009
iaa
10
r
I
E
h
rfl
m
a
rut
* ¦ i~
o.
r>
N
70
Q.ot a.i i
HUMAN EOUIU DURATION (fmatian lirtip«nJ
:0f*J A Inhalation Exposure) CENSOREB CftTft METHOD
J
Key: V, - N'OEL
n - :;oael
L - 10AEL
A - AEL
f - FEL
Solid line - Adverse Effects Boundry
Dashed Lino - No Adverse Effects Boundary
FIGURE C-2
Oose/OuratIon-Response Graph for Oral and Inhalation Exposure to Acetone
Cyanohydrln: Censored Data Hethod
Q4S6d
C-3
07/05/90
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The boundary for no adverse effects (dashed line) Is drawn by Identify-
ing the highest no adverse effects dose or concentration. From this point,
a line parallel to the duration axis 1s extended to the dose or concentra-
tion axis. The starting point Is then connected to the next no adverse
effect dose or concentration of equal or lower magnitude at a longer
duration of exposure. When this process can no longer be continued, a line
Is dropped parallel to the dose or concentration axis to the duration axis.
The region of no adverse effects lies below the no adverse effects boundary.
At either end of the graph between the adverse effects and no adverse
effects boundaries are regions of ambiguity. The area resulting from the
Intersections of the adverse effects and no adverse effects boundaries Is
defined as the region of contradiction. A censored graph Is drawn so that
the no adverse effects boundary does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results
1n the most conservative definition of the no adverse effects region.
In both graphs, the Inhalation data points appear within a box In order
to distinguish them from the oral data. In Figure C-l, drawn by the
envelope method, the boundary for adverse effects Is defined by several
Inhalation data points: FELs for offspring of female rats administered 109
mg/i (Nicholas et al., 1979) or 4.48 mg/n (Luo et al., 1906) during
pregnancy, a LOAEl of 475 mg/ma administered to rats for 90 days, an AIL
of 100 mg/m3 during occupational exposure for 10 years (Blagodatln el al.,
1971), and an AEL of 115 mg/m3 administered to rats for 120 days (Lomonova
et al., 1980). The boundary for no adverse effects Is defined by a NQAEl of
2000 ppm administered In drinking water to rats for 104 weeks (Borzelleca et
al., 1964). From this point the graph drops through several NOAELs and
NOELs to the duration axis. The subchronlc oral and Inhalation HfOs fall
0496d
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11/00/90
-------
within the region of contradiction. The chronic oral and Inhalation RfDs
and the chronic RQ all He on the no adverse effects boundary.
In figure C-2, drawn by the censored data method, the adverse effects
boundary remains the same, but the no adverse effects boundary Is defined by
several Inhalation data points: a NOAEL of 1330 ppm administered to pregnant
rats for 10 days (McLaughlin et al., 1970), a NOAEL of 116 ppm administered
to rats for 77 days (Tansy et a 1., 1980aJ. a NOEL of 125 ppm administered to
mice for 14 weeks In the study by the IBT Laboratories {NTP, 1986), HOELs of
63 ppm administered to mice or rats for 14 weeks in the IBT Labs study (NTP,
1986), and a NOEL of 6.85 ppm administered to male or female rats for 104
weeks (Borzelleca et al., 1964).
€.2. DATA USED TO GENERATE OOSI/DURATION RESPONSE GRAPHS
Chemical Name: Methyl Hethacrylate
CAS Number: 80-62-6
Document Title: Health and Environmental Effects Document For Methyl
Hethacrylate
Document Number: ECAO-CIN-124
Document Date: 1990
Document Type: HEED
CPBasaiftliXSeSSCBailDCXfiBSSSZaBEKtlSCtSXSBKVPBaBSieiBfieBf S6B*DtlKIIBeB??BBKBS:&SeCX3BBl
RECORD #1
Comment:
Citation:
Species: Rats Body Height: 0.15 kg
Sex: Male Reported Dose: 475 mg/m®
Effect: LOAEL Converted Dose: 113 mg/m®
Route: Inhalation Exposure Period: 90 days
Duration Observation: 90 days
Molecular Height: 100.10
Inhalation hours/day: 8.00
Inhalation days/week: 5.00
# Inhal. ixp. days:
Number Exposed:
25
25
25
25
25
Number Responses:
25
25
25
25
25
Type of Effect:
HGTDC
HGTDC
WGTOC
HGTDC
HISTO
Site of Effect:
BODY
FAT
LUNG
SPLEN
PULMN
Severity Effect:
4
4
4
4
4
Body weights supplied by authors
Tansy et al, 1976
04l6d
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07/05/90
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RECORD #2:
Species: Rats Body Weight: 0.15 kg
Sex: Hale Reported Dose: 475 mg/m3
Effect: LQAEl Converted Dose: 113 mg/m3
Route: Inhalation Exposure Period: 180 days
Duration Observation: 180 days
Molecular Height: 100.10
Inhalation hours/day: 8.00
Inhalation days/week: 5.00
§ Inhal. Exp. days:
Number Exposed: 25 25 25 25 25
Number Responses: 25 25 25 25 25
Type of Effect: WGTDC WGTDC WGTDC WGTDC H1ST0
Site of Effect: BODY FAT LUNG SPLEN PULMN
Severity Effect: 4 4 4 4 4
Comment:
Citation:
Tansy et al, 1976
RECORD #3:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
NOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 46
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: LIVER
Severity Effect: 1
Body weight supplied by authors
Tansy et al., 1980a
0.195 kg
116 ppm
98.8 mg/m'
77 days
77 days
100.10
7.00
5.00
0496d
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07/05/90
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RECORD #4:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
AEL
Inhalation
0ody Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: NR NR NR
Number Responses: NR NR NR
Type of Effect; NEURB WGTIN HGTIN
Site of Effect: HEART UVER KJONY
Severity Effect: 7 4 4
0.35 kg
115 rag/m'
12.3 mg/mJ
120 days
120 days
100.10
3.00
6.00
NR
NR
HISTO
HEART
7
90 rats total, number per group not specified.
Lomonova et al., 1980
RECORD #5:
Comment*.
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
AEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: NR
Number Responses: NR
Type of Effect: BEHAV
Site of Effect: CNS
Severity Effect: 7
See previous record.
lomonova et al., 1980
0.35 kg
115 mg/m»
12.3 mg/m3
120 days
120 days
100.10
6.00
3.00
0496d
C-7
07/05/90
-------
RECORD #6:
Comment;
Citation:
Species;
Sex;
Effect:
Route;
Rats
female
AEL
Inhalation
Body Weight:
Reported Dose:
Converted Oose:
Exposure Period:
Duration Observation;
Molecular Height;
Inhalation hours/day:
Inhalation days/week:
i Inhal. Exp. days:
Number Exposed: 4 4 4
Number Responses: NR NR NR
Type of Effect: NEURP STIHU FUNS
Site of Effect: HEART CARDV PULHH
Severity Effect: 7 7 7
Blanchct et al.( 1982
0.35 kg
311,149 mg/m*
4200 mg/m3
42 days
42 days
100.10
0.33
7.00
RECORD #7:
Comment:
Citation:
Species:
Sex:
Effect;
Route;
Rats
Hale
NOEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inha1. Exp. days:
0.207 kg
63 ppm
46.1 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
Number Exposed: 10
Number Responses: 10
Type of Effect; NOS
Site of Effect: UODY
Severity Effect: 1
Male and female F344/N rats exposed to 0, 63,
or 1000 ppm. Body weights supplied by authors,
NTP, 1986 (IBT)
125, 250. 500
0496d
c-a
1]/08/90
-------
RECORD #8;
Comment:
Citation:
Species;
Sex:
Effect:
Route:
Rats
female
HOEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect; 1
See previous record.
NTP, 19B6 (1BT)
0.142 kg
63 ppm
45.1 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #9:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
NOEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.207 kg
125 ppm
91.4 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 {1BT>
0496d
C-9
11/08/90
-------
RECORD #10:
Comment:
Citation:
Spectes;
Sex:
Effect:
Route:
Rats
Female
NOEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Holecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp, days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0.142 kg
125 ppm
91.4 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #11
Comment:
Citation:
Species: Rats Body Height: 0.20? kg
Sex: Hale Reported Dose: 250 ppm
Effect: NOEL Converted Dose: 183 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Holecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
8 Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0496d
C-10
11/00/90
-------
RECORD #12; Species; Rats Body Height: 0.142 kg
Sex; Female Reported Dose: 250 ppm
Effect; NOEL Converted Dose; 183 tng/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
§ Inhal. Exp, days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NDS
Site of Effect: BODY
Severity Effect: 1
Comment: Sec previous record.
Citation: IITP, 1906 (1BT)
RECORD #13;
Comment:
Citation:
Species: Rats Body Weight: 0.207 kg
Sex: Hale Reported Dose: 500 ppm
Effect: NOEL Converted Dose: 366 mg/m3
Route; Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
§ Inhal. Exp. days:
Number Exposed: 10
Number Responses; 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1906 (IBT)
0496d
C-ll
11/08/90
-------
RECORD #14:
Comment:
Citation;
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Inhalation
Body Weight: 0.142 kg
Reported Dose: 500 ppm
Converted Dose: 366 mg/m3
Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Jnhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: N0S
Site of Effect: 800Y
Severity Effect: 1
See previous record.
NTP, 19B6 {IBT)
RECORD #15:
Comment:
Citation:
Species: Rats Body Height: 0.207 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: NOEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height; 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed; 10
Number Responses: 10
Type of Effect; NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0496d
C-12
11/08/90
-------
RECORD #16;
Comment;
Citation:
Species: Rats Body Weight: 0.142 kg
Sex: Female Reported Dose: 1000 ppm
Effect; NOEL Converted Dose: 731 mg/m»
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 10
Number Responses; 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect; 1
See previous record.
NTP, 1986 (1BT)
RECORD #17;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
H1ce
Hale
NOEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Holecular Height:
Inhalation hours/day;
Inhalation days/week;
# Inhal. Exp. days:
0.027 kg
63 ppm
46.1 mg/ms
14 weeks
14 weeks
100.10
6.00
5.00
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
Hale and female B6C3F1 mice exposed to 0, 63, 125, 250, 500
or 1000 ppm. Body weights supplied by authors.
NTP, 1986 (1BT)
0496d
C-13
11/08/90
-------
RECORD #18:
Carmen I;
Citation:
Species;
Sex:
Effect:
Route:
H1ce
Female
NOEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Holecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NQS
SUe of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0.022 kg
63 ppm
46.1 mg/ms
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #19:
Comment:
CltaUon:
Species:
Sex:
Effect:
Route:
Mice
Hale
NOEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Holecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0.027 kg
125 ppm
91.4 mg/m*
14 weeks
14 weeks
100.10
6.00
5.00
0496d
C-14
11/00/90
-------
RECORD #20;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
NOEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: "I
See previous record.
NTP, 1986 (IBT)
0.022 kg
125 ppm
91.4 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #21:
Comment:
Citation:
Species: Mice Body Weight: 0.027 kg
Sex: Hale Reported Dose: 250 ppm
Effect: NOEL Converted Dose: 183 mg/m»
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Weight*. 100.10
Inhalation hours/day: 6.00
Inhalation days/week*. 5.00
# lnhal. Exp. days:
Number Exposed; 1G
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
0496d
C-15
1V0B/9Q
-------
RECORD #22:
Comment;
Citation:
Species; Mice Body Height; 0.022 kg
Sex; Female Reported Dost: 250 ppm
Effect: NOEL Converted Dose: 183 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation; 14 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week; 5.00
# Inhat. Exp. days;
Number Exposed: 10
Number Responses: 10
Type of Effect: NQS
SUe of Effect; BODY
Severity Effect: 1
See previous record.
NTP, 1966 (IDT)
RECORD #23: Species; Mice Body Weight: 0.027 kg
Sex: Hale Reported Dose: 500 ppm
Effect: NOEL Converted Dose: 366 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Weight; 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
§ Inhal. Exp. days:
Number Exposed: 10
Number Responses; 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
Comment: See previous record.
Citation; NTP, 1966 {IBT)
0496d
C-16
11/08/90
-------
RECORD #24;
Species: H1ce Body Height: 0.022 kg
Sex: Female Reported Dose: 500 ppm
Effect: NOEL Converted Dose: 366 mg/m*
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment:
Citation:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
NIP, 1986 (IBT)
RECORD #25;
Comment:
Citation:
Species: Mice Body Height: 0.027 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: NOEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
Sec previous record.
NTP, 19B6 (IBT)
0496d
C-17
11/08/90
-------
RECORD #26:
Comment;
Citation:
Species:
Sox:
Effect:
Route:
H1ce
Female
NOEL
Inhalation
Body Weight: 0.022 kg
Reported Dose: 1000 ppm
Converted Dose: 731 mg/m3
Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5,00
# Inhal, Exp. days:
Number Exposed: 10
Number Responses: 10
Type of Effect: NOS
SUe of Effect: BODY
Severity Effect: 1
See previous record.
NTP, 1986 (IBT)
RECORD #27:
Species: Rats Body Weight: 0.259 kg
Sex: Hale Reported Oose: 500 ppm
Effect: 10AEL Converted Dose: 366 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment:
Citation:
Number Exposed: 10
Number Responses: NR
Type of Effect: NECRO
SUe of Effect: NASAL
Severity Effect: 6
Hale and female F344/N rats exposed to 0, 500, 1000, 2000,
3000 or 5000 ppm.
NTP, 1986 (BMW)
0496d
C-18
11/08/90
-------
RECORD #28;
Comment:
Citation:
Species: Rats Body Weight: 0.159 kg
Sex: Female Reported Dose: 500 ppm
Effect: LOAEL Converted Dose: 366 mg/m*
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6,00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 10
Number Responses: NR
Type of Effect: NECRO
Site of Effect: NASAL
Severity Effect: 6
See previous record.
NTP, 19B6 (BNW)
RECORD #29;
Comment:
CUatlon:
Species: Rats Body Height: 0.259 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 10
Number Responses: NR
Type of Effect: NECRO
Site of Effect: NASAL
Severity Effect: 6
See previous record.
NTP, 1906 (BNW)
0496d
C-19
11/08/90
-------
RECORD #30;
Comment:
Citation;
Species: Rats Body Height: 0.159 kg
Sex: Fenale Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Weight: 100.10
Inhalation hours/day*. 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed;
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:
See previous record.
NTP, 1986 (BNW)
10
NR
NECRO
NASAL
6
RECORD #31
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
AEL
Inhalation
Body Height:
Reported Dose:
Converted Oose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 ID 10
Number Responses: NR NR 1
Type of Effect: NECRO HQ1DC DEATH
SUe of Effect: NASAL BODY BODY
Severity Effect: 6 4 10
See previous record.
NTP, 1906 (BNH)
0.259 kg
2000 ppm
1460 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
049M
C-20
11/0B/90
-------
RECORD #32;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
AEl
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR NR 3
Type of Effect: NECRO WGTDC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 4 10
See previous record.
MTP, 1986 (BNW)
0.159 kg
2000 ppm
1460 ing/m®
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #33:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
FEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR NR 1
Type of Effect: NECRO WGTDC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 6 10
See previous record.
NTP, 1986 (BNH)
0.259 kg
3000 ppm
2190 mg/ma
14 weeks
14 weeks
100.10
6.00
5.00
0496d
C-21
11/00/90
-------
RECORD #34:
Comment:
Citation:
Species: Rats Body Weight:
Sex: Female Reported Oose:
Effect: FEL Converted Dose:
Route: Inhalation Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR NR 9
Type of Effect: NECRO HGTDC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 6 10
See previous record.
NIP, 1986 (BNW)
0.159 kg
3000 ppm
2190 mg/ma
14 weeks
14 weeks
100.10
e.oo
5.00
10
NR
HEMOR
BRAIN
10
RECORD #35:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Hale
FEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR MR 10
Type of Effect: NECRO HGTDC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 6 10
See previous record.
NTP, 1986 {BNHJ
0.259 kg
5000 ppm
3660 mg/rn3
14 weeks
14 weeks
100.10
6.00
5.00
10
4
ATROP
SPLEN
4
10
e
A7KQP
BOflE
0496d
C—22
11/08/90
-------
RECORD #36;
Comment;
Citation:
Species;
Sex:
Effect;
Route;
Rats
Female
FEL
Inhalation
Body Height;
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
i Inhal. Exp. days;
Number Exposed: 10 10 10
Number Responses: NR NR 10
Type of Effect: NECRO HGTDC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 6 10
See previous record.
NTP. 1906 (BNW)
0.159 kg
5000 ppm
3660 rag/m3
14 weeks
14 weeks
100.10
6.00
5.00
10
NR
HEMOR
BRAIN
10
RECORD #37:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Hlce
Hale
LOAEL
Inhalation
Body Weight:
Reported Dose;
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day;
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed:
Number Responses;
Type of Effect:
Site of Effect;
Severity Effect;
ID 10
NR NR
METAP HGTDC
NASAL BODY
6 6
0.029 kg
500 ppm
366 mg/m5
14 weeks
14 weeks
100.10
6.00
5.00
Hale and female B6C3F1 mice exposed to 0, 500, 1000, 2000,
3000 or 5000 ppm.
NTP, 1906 (BNW)
Q496d
C-23
T1/0B/90
-------
RECORD #30:
Comment:
Citation;
Species: Hlce Body Height: 0.024 kg
Sex: Female Reported Dose: 500 ppm
Effect: L0AEL Converted Dose: 366 mg/ma
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Holecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 10 10
Number Responses: NR NR
Type of Effect: METAP WGT0C
Site of Effect: NASAL BODY
Severity Effect: 6 4
See previous record.
NTP, 1986 (BNW}
RECORD #39: Species: H1ce Body Height: 0.029 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Holecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10 10
NR NR
HETAP WGTUC
NASAL BODY
6 6
Comment: See previous record.
Citation: NTP, 1906 (BNH)
0496d
C-24
11/0B/9Q
-------
RECORD #40:
Comment:
Citation:
Species: Mice Body Height: 0.024 kg
Sex: Female Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 14 weeks
Duration Observation: 14 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
10 10
NR NR
METAP WGTDC
NASAL BODY
6 4
See previous record.
NTP, 1986 (BNW)
RECORD #41:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Male
PEL
Inhalation
Body Weight;
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
See previous record.
NTP, 1906 (BNW)
10
10
10
NK
NR
2
MET AP
WGTDC
DEATH
NASAL
BODY
BODY
6
6
10
0.029 kg
2000 ppm
1460 mg/in3
14 weeks
14 weeks
100.10
6.00
5.00
0496d
C-25
11/08/90
-------
RECORD #42:
Comment;
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
FEl
inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation;
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR MR 1
Type of Effect: HETAP HGTDC DEATH
Site of Effect: NASAL OOOY BODY
Severity Effect: 6 b 10
See previous record.
NTP, 1986 (BNW)
0.024 kg
2000 ppm
1460 mg/ffi3
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #43:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Halo
FEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR NR 4
Type of Effect: METAP WGTOC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect; 6 6 10
See previous record.
NTP, 19B6 (BNH)
0.029 kg
3000 ppm
2190 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
0496d
C-26
11/00/90
-------
RECORD #44:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
FEL
inhalation
Number Exposed:
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp, days:
10
10
NR NR
HE TAP HGTOC
NASAL 800V
6 6
See previous record.
NTP, 1986 (BNU)
0.024 kg
3000 ppm
2190 mg/m>
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #45:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Hlce
Kale
FEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
i? Inhal. Exp. days:
Number Exposed: 10 10 10
Number Responses: NR NR S
Type of Effect: HiTAP HGTOC DEATH
Site of Effect: NASAL BODY BODY
Severity Effect: 6 6 10
See previous reocrd.
NTP, 1906 (BNH)
0.027 kg
5000 ppm
3660 mg/m*
14 weeks
14 weeks
100.10
6.00
0496d
C-27
11/08/90
-------
RECORD #46:
Comment:
Citation:
Species:
Sex;
Effect:
Route:
Mice
Female
FEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: 10
Number Responses: NR
Type of Effect: METAP
Site of Effect: NASAL
Severity Effect: 6
See previous record.
NTP, 1986 (BNH)
10
NR
WGTDC
B00Y
6
10
8
DEATH
BODY
10
0.023 kg
5000 ppm
3660 mg/m3
14 weeks
14 weeks
100.10
6.00
5.00
RECORD #47:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Dogs
Both
NOEL
Food
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Number Exposed: 4
Number Responses: NR
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
Two male and two female beagle dogs
1473 ppm 1n food.
Bonrelleca et al., 1964
9.47 kg
10 ppm
0.25 mg/kg/day
52 weeks
52 weeks
exposed to 10, 100 or
RECORD #48:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Dogs
Both
NOAEL
Food
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Number Exposed: 4
Number Responses: NR
Type of Effect: WGTOC
Site of Effect: SPLEN
Severity Effect: 1
See previous record.
Borzelleca et al., 1964
9.47 kg
100 ppm
2.5 mg/kg/day
52 weeks
52 weeks
0496d
C-28
11/08/90
-------
RECORD #49:
Comment:
Citation:
Species;
Sex:
Effect:
Route;
Dogs
Both
WML
Food
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
9.47 kg
1473 ppm
36.8 mg/kg/day
52 weeks
52 weeks
Number Exposed: 4
Number Responses: NR
Type of Effect: NOS
Site of Effect: BOOY
Severity Effect: 1
See previous record; Reported dose Is a time-weighted average
of doses ranging from 1000-1500 ppm.
Borzelleca et al., 1964
RECORD #50:
Comment:
Species:
Sex:
Effect:
Route:
Humans
NR
Mi
Inhalation
Body Height:
Reported Dose:
Converted Dose;
Exposure Period:
Duration Observation:
Molecular Height;
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
70 kg
100 rag/m*
23.8 mg/in®
10 years
10 years
100.10
8.00
5.00
Number Exposed: 152
Number Responses: NR
Type of Effect: NEURB
Site of Effect: BRAIN
Severity Effect: 6
152 workers exposed to 2-200 mg/m* over a 10-year period.
Symptoms Included headaches, pain In the extremities,
excessive fatigue, sleep disturbances, memory loss,
Irritability.
Citation; Blagodatln et al., 1971
0496d
C-29
07/05/90
-------
RECORD m
Comment:
Citation;
Species:
Sex:
Effect:
Route:
Humans
NR
LOAEL
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Ixp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site Of Effect:
Severity Effect:
NR
NR
NR
NR
IRRIT NOS
NASAL CNS
4 6
70 kg
20 mg/m3
4,76 mg/m3
12 years
12 years
100.10
8.00
5.00
Occupational
for 12 years
exposure to 20-342 mg/m9 and 472-736 mg/m?
Delia Torre et al., 1982
RECORD #52:
Comment:
Citation:
Species: Humans Body Height: 70 kg
Sex: NR Reported Dose: 736 mg/m'
Effect: AEL Converted Dose: 175 mg/m'
Route: Inhalation Exposure Period: 12 years
Duration Observation: 12 years
Molecular Height: 100.10
Inhalation hours/day: 8.00
Inhalation days/week; 5.00
# Inhal. Exp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR NR
NR NR
IRRIT NOS
NASAL CNS
4 6
See previous record.
Delia Torre et al.. 1982
04S6d
C-30
07/06/90
-------
RECORD #53:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Humans
Hale
NOEL
Inhalation
Body Height;
Reported Dose:
Converted Dose;
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days;
70 kg
0.4 ppnt
0.39 mg/m'
20 years
20 years
100.10
8.00
5.00
Number Exposed; 1561
Number Responses: NR
Type of Effect: NOS
Site of Effect; BODY
Severity Effect: 1
1561 men occupatlonally exposed to 8-hour
average of 0.4 ppm for no more than 20 years.
Collins et al.» 1989
time-weighted
RECORD #54:
Comment:
Citation;
Species:
Sex:
Effect:
Route:
Hamsters
Kale
NOEL
Inhalation
Body Height:
Reported Dose:
Converted Dose;
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week;
# Inhal. Exp. days;
0.118 kg
25 ppm
18.3 mg/m3
78 weeks
78 weeks
100.10
6.00
5.00
Number Exposed; 56
Number Responses: 56
Type of Effect: NOS
Site of Effect; BODY
Severity Effect: 1
53-59 male or female Lakevlew golden hamsters exposed to 0,
25, 100 or 400 ppm for 78 weeks.
Hazelton laboratories, 1979a
0496d
C-31
07/05/90
-------
RECORD #55:
Comment.;
Citation:
Species: Hamsters Body Height:
Sex; Female Reported Dose:
Effect: NOEL Converted Dose:
Route: Inhalation Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Ixp. days:
Number Exposed: 5$
Number Responses; 56
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
Hazelton Laboratories, 1979a
O.l17 kg
25 ppm
18,3 mg/m3
78 weeks
78 weeks
100.10
6.00
5.00
RECORD #56:
Comment:
Citation;
Species:
Sex:
Effect:
Route:
Hamsters
Hale
NOAEL
Inhalation
Body Height;
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: 56
Number Responses: 56
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
Hazelton Laboratories, 1979a
0.117 kg
100 ppm
73.1 mg/m3
78 weeks
78 weeks
100.10
6.00
5.00
0496d
C-32
07/05/90
-------
RECORD #57:
Comment;
Citation;
Species:
Sex;
Effect;
Route;
Hamsters
Female
NOAEl
Inhalation
Body Height:
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:
Molecular Height:
Inhalation hours/day;
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 56
Number Responses: 56
Type of Effect: NOS
Site of Effect: 80DY
Severity Effect: 1
See previous record.
Hazelton Laboratories, 1979a
0.122 kg
100 ppm
73.1 mg/m'
78 weeks
78 weeks
100.10
6.00
5.00
RECORD #58:
Comment:
Citation:
Species: Hamsters Body Height: 0.117 kg
Sex: Hale Reported Dose; 400 ppm
Effect: FEL Converted Dose: 292 mg/m*
Route: Inhalation Exposure Period: 78 days
Duration Observation: 78 days
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week; 5.00
# Inhal. Exp. days:
Number Exposed; 56
Number Responses; NR
Type of Effect; DEATH
SUe of Effect: BODY
Severity Effect: 10
See previous record.
Hazelton Laboratories, 1979a
0496d
C-33
07/05/90
-------
RECORD #59:
Comment:
Citation:
Species: Hamsters Body Weight: 0.115 kg
Sex: Female Reported Dose: 400 ppm
EFfect: PEL Converted Dose: 292 mg/m3
Route: Inhalation Exposure Period: 78 days
Duration Observation: 78 days
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp, days:
Number Exposed: 56
Number Responses: 56
Type of Effect: NOS
Site Of Effect: BODY
Severity Effect: 1
See previous record.
Haaelton Laboratories, 1979a
RECORD #60;
Comment;
Citation;
Species:
Sex:
Effect:
Route:
Rats
Hale
NOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Holecular Weight:
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
0.4 kg
25 ppm
18.3 mg/m3
104 weeks
104 weeks
100.10
6.00
5.00
Number Exposed: 70
Number Responses: NR
Type of Effect: 1RR1T
Site of Effect: NASAL
Severity Effect: 1
Hale and female nsher rats exposed to 0, 25, 100 or 400 ppm
for 104 weeks. Body weights supplied by authors.
Hazelton Laboratories, 1979b
0496d
C-34
07/05/90
-------
RECORD #61:
Comment;
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
NPAEL
Inhalation
Body Weight;
Reported Dose;
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 70
Number Responses; NR
Type of Effect: IRRIT
Site of Effect; NASAL
Severity Effect: 1
See previous record.
Nazelton Laboratories, 1979b
0.22 kg
25 ppra
IB.3 mg/m»
104 weeks
104 weeks
100.10
6.CO
5.00
RECORD #62:
Comment:
Citation:
Species:
Sex;
Effect:
Route;
Rats
Hale
NOAEL
Inhalation
Body Weight:
Reported Dose;
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight;
Inhalation hours/day;
Inhalation days/week:
f Inhal. Exp. days:
Number Exposed: 70
Number Responses: NR
Type of Effect; IRRIT
Site of Effect: NASAL
Severity Effect: 1
See previous record.
Hazel ton Laboratories, 1979b
0.396 kg
100 ppm
73.1 mg/m"
104 weeks
104 weeks
100.10
6.00
5.00
0496d
C-35
07/05/90
-------
RECORD m-
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
NOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation;
Molecular Weight;
Inhalation hours/day:
Inhalation days/week:
§ Inhal. Exp. days:
Number Exposed: 70
Number Responses: NR
Type of Effect: 1RRIT
Site of Effect: NASAL
Severity Effect: 1
See previous record.
Hazelton Laboratories, 1979b
0.217 kg
100 ppm
73.1 mg/m*
104 weeks
104 weeks
100.10
6.00
5.00
RECORD #64:
Comment:
Citation:
Species: Rats Body Height: 0,396 kg
Sex: Hale Reported Dose: 400 ppm
Effect: NOAEL Converted Dose: 292 mg/m3
Route: Inhalation Exposure Period: 104 weeks
Duration Observation: 104 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal, Exp. days:
Number Exposed: 70
Number Responses: NR
Type of Effect: 1RRIT
Site of Effect: NASAL
Severity Effect: 1
See previous record.
Hazelton Laboratories, 1979b
0496d
C-36
07/05/90
-------
RECORD #65:
Comment:
Citation:
Species: Rats Body Weight: 0.214 kg
Sex; Female Reported Dose: 400 ppm
Effect: NDAEl Converted Dose: 292 mg/m3
Route: Inhalation Exposure Period: 104 weeks
Duration Observation: 104 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
70 70
NR NR
IRRIT HGTDC
NASAL BODY
1 4
See previous record.
Hazelton laboratories, 1979b
RECORD #66:
Species: Rats Body Weight: 0.267 kg
Sex: Female Reported Dose: 250 ppm
Effect: NOAEl Converted Dose: 183 mg/m®
Route: Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment:
Citation:
Number Exposed: 50
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 3
50 female F344/N rats exposed to 0, 250 or 500 ppm for 102
weeks. Body weights supplied by author.
NTP, 1986
0496d
07/05/90
-------
RECORD #67:
Comment:
Citation:
Species: Rats Body Weight: 0.264 kg
Sex: Female Reported Dose: 500 ppm
Effect: NOAEL Converted Dose: 366 mg/m3
Route: Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Height: 100.10
Inhalation hours/day: 6,00
Inhalation days/week: 5.00
# Inhal. Exp. days:
50
NR
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect: 1
See previous record.
NTP, 1986
50
NR
OEGEN WGTDC
NASAL BODY
RECORD #68:
Species: Rats Body Height: 0.448 kg
Sex: Hale Reported Dose: 500 ppm
Effect: NOAEL Converted Dose: 366 mg/m3
Route: Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment:
Citation:
Number Exposed: 50
Number Responses: NR
Type of Effect: DEGEN
Site of Effect: NASAL
Severity Effect: 3
50 male rats exposed to 0, 500 or
Body weights supplied by author.
NTP. 1986
1000 ppm for 102 weeks
Q496d
C—38
07/05/90
-------
RECORD #69;
Comment:
Citation:
Species: Rats Body Height: 0.44 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: LQAEl Converted Dose: 731 mg/ma
Route: Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.CO
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 50
Number Responses: NR
Type of Effect: DEGEN
SUe of Effect: NASAL
Severity Effect: 3
See previous record.
NTP, 1966
RECORD #70:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Hke
Hale
LQAEl
Inhalation
0.033 kg
500 ppm
366 mg/m3
102 weeks
102 weeks
100.10
6.00
5.00
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed: 50 50 50
Number Responses: NR NR NR
Type Of Effect: DEGEN IRRIT WGTDC
Site of Effect: NASAL NASAL BODY
Severity Effect: 4 4 4
50 male and 50 female B6C3F1 mice exposed to 0, 500 or 1000
ppm for 102 weeks. Body weights supplied by author.
NTP, 1986
0496d
C-39
07/05/90
-------
RECORD #71
Comment:
Citation;
Species: Wee Body Weight: 0.031 kg
Sex: Female Reported Dose: 500 ppm
Effect: LOAEL Converted Dose: 366 mg/m3
Route; Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Number Exposed: 50 50 50
Number Responses; NR NR NR
Type of Effect: IRRIT OEGEN HGTDC
Site of Effect: NASAL NASAL BODY
Severity Effect; 4 4 4
See previous record.
NTP, 19B6
RECORD #72:
Species: Mice Body Height: 0.033 kg
Sex: Hale Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m®
Route: Inhalation Exposure Period; 102 weeks
Duration Observation: 102 weeks
Molecular Height: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal, Exp. days;
Comment:
Citation:
Number Exposed; 50 50 50
Number Responses: NR NR NR
Type Of Effect: IRRIT OEGEN HGTDC
SUe Of Effect: NASAL NASAL BODY
Severity Effect: 4 4 4
See previous record.
NTP, 1986
0496d
C-40
07/05/90
-------
RECORD #73;
Species: Mice Body Height: 0.031 kg
Sex: Female Reported Dose: 1000 ppm
Effect: AEL Converted Dose: 731 mg/m3
Route: Inhalation Exposure Period: 102 weeks
Duration Observation: 102 weeks
Molecular Weight: 100.10
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:
Comment:
Citation:
Number Exposed: 50 50 50
Number Responses: NR NR NR
Type of Effect; IRRIT DEGEN WGTDC
Site of Effect; NASAL NASAL BODY
Severity Effect: 4 4 4
See previous record.
NTP, 1906
RECORD #74:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Hale
NOEL
Hater
Body Height:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.295 kg
6.85 ppm
1.01 mg/kg/day
104 weeks
104 weeks
Number Exposed: 25
Number Responses: NR
Type of Effect: NOS
Site of Effect: BODY
Severity Effect; 1
25 male and 25 female Wlstar rats exposed to 0, 6.85, 68,46
or 2000 ppm in drinking water. Body weights supplied by
authors.
Citation;
Borzelleca et al., 1964
RECORD #75: Species; Rats Body Height;
Sex: Female Reported Dose:
Effect: NOEL Converted Dose;
Route: Hater Exposure Period:
Duration Observation:
0.214 kg
6.85 ppm
1.09 mg/kg/day
104 weeks
104 weeks
Comment:
Citation:
Number Exposed: 25
Number Responses: NR
Type of Effect: NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
Borzelleca el al., 1964
0496d
C-41
07/05/90
-------
RECORD #76;
CommonI:
Citation:
Species:
Sex;
Effect:
Route:
Rats
Hale
HOE I
Hater
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation;
Number Exposed: 25
Number Responses: NR
Type of Effect: HQS
Site of Effect: BODY
Severity Effect: 1
See previous record,
Borzelleca et al., 1364
0.295 kg
68.46 ppm
11.4 mg/kg/day
104 weeks
104 weeks
RECORD #77:
Comment:
Citation:
Species: Rats Body Height:
Sex: Female Reported Dose:
Effect: NOEL Converted Dose:
Route: Hater Exposure Period:
Duration Observation:
Number Exposed: 25
Number Responses: NR
Type of Effect; NOS
Site of Effect: BODY
Severity Effect: 1
See previous record.
Borzelleca et al.. 1964
0.214 kg
68.46 ppm
15.7 mg/kg/ddy
104 weeks
104 weeks
RECORD #78:
Comment:
Citation:
Species:
Sex;
Effect:
Route:
Rats
Hale
NOEL
Hater
Body Height;
Reported Dose;
Converted Oose:
Exposure Period:
Duration Observation;
Number Exposed; 25
Number Responses; NR
Type of Effect; NOS
Site of Effect; BODY
Severity Effect: 1
See previous record.
Borzelleca et al., 1964
0.295 kg
2000 ppm
332 mg/kg/day
104 weeks
104 weeks
0496d
C-42
07/05/90
-------
RECORD #79;
Comment:
Citation;
Species: Rats Body Height:
Sex: Female Reported Dose:
Effect: NOAEL Converted Dose:
Route: Hater Exposure Period:
Duration Observation:
Number Exposed: 25
Number Responses; NR
Type of Effect: WGTIN
Site of Effect: KIDNY
Severity Effect: 4
See previous record.
Borzelleca et al., 196*
0.214 kg
2000 ppm
458 mg/kg/day
104 weeks
104 weeks
RECORO #80;
Comment:
CUatlon:
Species: H1ce Body Height: 0.22 kg
Sex: Female Reported Dose: 1330 ppm
Effect: NOAEl Converted Dose; 908 mg/m3
Route: Inhalation Exposure Period: 10 days
Duration Observation: 15 days
Molecular Weight: 100.10
Inhalation hours/day: 4.00
Inhalation days/week: 7.00
I Inhal. Exp. days;
Number Exposed; NR
Number Responses: NR
Type of Effect: HGTIN
Site of Effect: FETUS
Severity Effect; 4
Pregnant ICR mice exposed to 1330 ppm for 4 hours on days 6
through 15 of gestation. Body weight supplied by authors.
McLaughlin el a!., 1978
0496d
C-43
07/05/90
-------
RECORD #81;
Comment:
Citation:
Species:
Sex:
Effect;
Route:
Rats
Female
FEL
Inhalation
Body Weight;
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation;
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.025 kg
109 mq/i
1300 mg/m5
10 days
15 days
100.10
0.29
7.00
Number Exposed: NR
Number Responses: NR
Type of Effect: TERAP
Site of Effect: FETUS
Severity Effect: 9
Pregnant Sprague-Dawley rats expsoed to 109 mg/i on days &
through IS of pregnancy. Body weights supplied by authors.
Nicholas et a!., 1979
RECORD #82:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Female
FEL
Inhalation
Body Height:
Reported Dose:
Converted Dose;
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.025 kg
109 mq/i
1300 mg/m3
10 days
15 days
100.10
0.90
7.00
Number Exposed: NR
Number Responses: MR
Type of Effect: TERAP
Site of Effect: FETUS
Severity Effect: 10
See previous record. Maternal toxicity at this exposure
duration.
Nicholas et al., 1979
049&d
C-44
07/05/90
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RECORD #83;
Comment:
Citation:
Species;
Sex:
Effect:
Route:
Rats
Female
NOAEl
Inhalation
Body Weight;
Reported Dose:
Converted Oose:
Exposure Period;
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.35 kg
0.52 mg/fc
15.5 mg/m'
13 days
15 days
100.10
2.00
2.50
5.00
Number Exposed: HR
Number Responses; NR
Type of Effect: NOS
Site of Effect; FETUS
Severity Effect: 1
Rats exposed to 0.52 or 4.48 mg/l on days 6 through 18 of
pregnancy.
Luo et al., 1986
RECORD #84:
Comment:
Citation:
Species: Rats Body Height: 0.35 kg
Sex: female Reported Oose: 4.48 mg/l
Effect: PEL Converted Dose: 133 mg/m3
Route: Inhalation Exposure Period: 13 days
Duration Observation: 15 days
Molecular Height: 100.10
Inhalation hours/day: 2.00
Inhalation days/week: 2.50
# Inhal. Exp. days: 5.00
Number Exposed: NR
Number Responses: NR
Type of Effect: TOXDF
Site of Effect; FETUS
Severity Effect: 10
See previous record.
Luo et al., 1986
NR - Not reported
0496d
C-45
07/05/90
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