U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2009
SCREENING-LEVEL HAZARD CHARACTERIZATION
TV-Methylphthalimide
(CASRN 550-44-7)
The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary
initiative aimed at developing and making publicly available screening-level health and
environmental effects information on chemicals manufactured in or imported into the United
States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsored chemicals; sponsorship
entailed the identification and initial assessment of the adequacy of existing toxicity
data/information, conducting new testing if adequate data did not exist, and making both new
and existing data and information available to the public. Each complete data submission
contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2)
endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the
environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is
evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored
chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions.
They are not intended to be definitive statements regarding the possibility of unreasonable risk of
injury to health or the environment.
The evaluation is performed according to established EPA guidance2'3 and is based primarily on
hazard data provided by sponsors; however, in preparing the hazard characterization, EPA
considered its own comments and public comments on the original submission as well as the
sponsor's responses to comments and revisions made to the submission. In order to determine
whether any new hazard information was developed since the time of the HPV submission, a
search of the following databases was made from one year prior to the date of the HPV
Challenge submission to the present: (ChemID to locate available data sources including
Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.) and Science Direct. OPPT's focus on these specific sources is based on their being
of high quality, highly relevant to hazard characterization, and publicly available.
OPPT does not develop HCs for those HPV chemicals which have already been assessed
internationally through the HPV program of the Organization for Economic Cooperation and
Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment
Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are
presented in an international forum that involves review and endorsement by governmental
1	U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2	U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3	U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
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Hazard Characterization Document
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authorities around the world. OPPT is an active participant in these meetings and accepts these
documents as reliable screening-level hazard assessments.
These hazard characterizations are technical documents intended to inform subsequent decisions
and actions by OPPT. Accordingly, the documents are not written with the goal of informing the
general public. However, they do provide a vehicle for public access to a concise assessment of
the raw technical data on HPV chemicals and provide information previously not readily
available to the public.
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Hazard Characterization Document
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Chemical Abstract Service
Registry Number
	(CASRN)	
550-44-7
Chemical Abstract Index
Name
H-Isoindole-l,3(2H)-dione, 2-methyl-
Structural Formula
o
H3C.
-A
/to
Summary
CASRN 550-44-7 is a solid with moderate water solubility and moderate vapor pressure. It is
expected to possess high mobility in soil. Volatilization of this chemical is considered low
based on its Henry's Law constant. The rate of hydrolysis is considered negligible under acidic
conditions, moderate at basic pH, and slow under neutral conditions. The rate of atmospheric
photooxidation is considered moderate. CASRN 550-44-7 is expected to have low persistence
(PI) and low bioaccumulation potential (Bl).
The acute toxicity of CASRN 550-44-7 is low via the oral (rats) and dermal (rabbits) routes of
exposure. Repeated oral exposure of rats to CASRN 550-44-7 for 30 days showed effects on
body weight and liver at 250 mg/kg-bw/day and above, with a NOAEL of 125 mg/kg-bw/day. In
an one-generation reproductive toxicity study in rats, the LOAEL for systemic toxicity was 600
mg/kg-bw/day (highest dose tested) based on effects on body weight, liver and kidneys. The
LOAEL for reproductive toxicity was 50 (males) to 150 (females) mg/kg-bw/day based on
delayed puberty in F1 pups; the NOAEL for reproductive toxicity for males was not established
and for females it was 150 mg/kg-bw/day. In the same study, the LOAEL for developmental
toxicity was 50 (males) to 150 (females) mg/kg-bw/day based on decreased post-weaning body
weights. The NOAEL for developmental toxicity for male pups was not established and for
females it was 150 mg/kg-bw/day. In the prenatal developmental toxicity study in rabbits, no
effects on maternal or developmental parameters were seen at 500 mg/kg-bw/day (only does
tested). CASRN 550-44-7 did not induce gene mutations in bacteria or chromosomal aberrations
in mammalian cells in in vitro tests.
The measured 96-hour LC50 of CASRN 550-44-7 for fish is 110 mg/L. The measured 24-hour
EC50 of CASRN 550-44-7 for aquatic invertebrates is 112 mg/L, and the measured 72-hour EC50
for aquatic plants is 57 mg/L.
No data gaps were identified under the HPV Challenge Program.	
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The sponsor, General Electric (GE), submitted a Test Plan and Robust Summaries to EPA for N-
methylphthalimide (CASRN 550-44-7) on December 31, 2002. EPA posted the submission on
the ChemRTK HPV Challenge website on January 30, 2003
(http://www.epa.gov/hpv/pubs/summaries/nmethylp/cl4220tc.htm). EPA comments on the
original submission were posted to the website on June 16, 2003. Public comments were also
received and posted to the website. The sponsor submitted updated/revised documents on
August 5, 2003 and November 30, 2005, which were posted to the ChemRTK website on
September 5, 2003 and January 10, 2006, respectively.
1. Chemical Identity
1.1	Identification and Purity
The HPV submission4 for this chemical did not include information on purity in the Test Plan
(2003). However, in response to EPA comments, GE Plastics indicates that the purity of the test
material was consistently > 99% and usually ~ 99.9% (August 2003).
1.2	Physical-Chemical Properties
The physical-chemical properties of/V-methylphthalimide are summarized in Table 1.
A-Methylphthalimide is a solid with moderate water solubility and moderate vapor pressure.
Table 1. Physical-Chemical Properties of A-Methylphthalimide1
Property
Value
CASRN
550-44-7
Molecular Weight
161.16
Physical State
Solid
Melting Point
136-137°C (measured)
Boiling Point
275°C (measured)
Vapor Pressure
0.000385 mm Hg at 24.15°C (measured)
Water Solubility
420 mg/L at 22.6°C (measured)
Dissociation Constant (pKa)
Not applicable
Henry's Law Constant
2.2x 10"8 atm-m3/mole (estimated)2
Log Kow
1.29 (measured)
General Electric Company. December 1, 2005. Revised Robust Summary and Test Plan for A-Methyl-
phthalimide. http://www.epa.gov/chemrtk/pubs/summaries/nmethvlp/cl4220tc.htm.
2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. United States
Environmental Protection Agency, Washington, DC, USA.
http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
4General Electric Company (2003). Robust Summary N-methylphthalimide CASRN 550-44-7.
http://www.epa.gov/chemrtk/pubs/summaries/nmethylp/cl4220tc.htm
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2. General Information on Exposure
2.1	Production Volume and Use Pattern
A-Methylphthalimide had an aggregated production volume in the United States of 1 million to
10 million pounds during calendar year 2005.
Non-confidential information in the IUR indicated that the industrial processing and uses of the
chemical include processing as an intermediate in other basic organic chemical manufacturing.
The HPV submission for this chemical states that it is primarily used as a site-limited
intermediate in the production of a high molecular weight polyetherimide polymer.
2.2	Environmental Exposure and Fate
No quantitative information is available on releases of this chemical to the environment.
The environmental fate properties are provided in Table 2. A'-M ethyl phthali mi de is a solid with
moderate water solubility and moderate vapor pressure. It is expected to possess high mobility
in soil. Volatilization of iV-methylphthalimide is considered low based on its Henry's Law
constant. The rate of hydrolysis is considered negligible under acidic conditions, moderate at
basic pH, and slow under neutral conditions. The rate of atmospheric photooxidation is
considered moderate. A-Methylphthalimide is expected to have low persistence (PI) and low
bioaccumulation potential (Bl).
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Hazard Characterization Document
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Table 2. Environmental Fate Characteristics of jV-Methylphthalimide1
Property
Value
Photodegradation Half-life
15.7 hours (estimated)
Hydrolysis Half-life
10,148 hours at pH 4 and 25°C (measured);
88 hours at pH 7 and 25°C (measured);
2.2 hours at pH 9 and 25°C (measured)
Biodegradation
77% in 23 days (readily biodegradable)
Bi oconcentrati on
BCF = 2 (estimated)2
Log Koc
1.1 (estimated)2
Fugacity
(Level III Model)2
Air = 5.3%
Water = 44.4%
Soil = 50.2%
Sediment = <0.1%
Persistence3
PI (low)
•>
Bioaccumulation
Bl (low)
General Electric Company. December 1, 2005. Revised Robust Summary and Test Plan for A'-Mcthyl-
phthalimide. http://www.epa.gov/chemrtk/pubs/summaries/nmethYlp/cl4220tc.htm.
2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. United States
Environmental Protection Agency, Washington, DC, USA.
http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
3Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances.
Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
3. Human Health Hazard
The human health hazard data are summarized in Table 3.
Acute Oral Toxicity
Male Spartan rats (2/dose) were administered N-methylphthalimide in corn oil via gavage at 500
or 5000 mg/kg-bw and observed for 14 days following dosing. Mortality occurred at 5000
mg/kg-bw.
LD50 > 500 mg/kg-bw < 5000 mg/kg-bw
Acute Dermal Toxicity
New Zealand White rabbits (1/sex/dose) were administered N-methylphthalimide dermally at
200 or 2000 mg/kg-bw to clipped intact skin under occluded conditions for 24 hours. Following
exposure animals were observed for 14 days. No mortality was reported.
LD50 > 2000 mg/kg-bw
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Repeated-Dose Toxicity
Sprague-Dawley rats (10/sex/dose) were administered N-methylphthalimide via the diet at 0,
0.25, 0.5 or 1.0% (approximately 0, 125, 250 or 500 mg/kg-bw/day) for 30 days. One male rat in
the low-dose level died on day 26 of the study. Marked decreases in relative body weights
occurred in the 250 and 500 mg/kg-bw groups, in both males (6 and 18%, respectively) and
females (4 and 11%, respectively). Mean food consumption was sporadically decreased
compared to controls throughout the study. Gross pathology showed no treatment-related effects
at any dose. Mean relative liver weight was increased in both sexes and mean relative kidney
weight was increased in males at the high-dose level. Microscopic evaluation revealed
compound-related centrilobular to diffuse hepatocellular enlargement in rats of both sexes in the
mid- and high-doses. The severity of chronic progressive nephropathy was increased slightly in
male rats at the high-dose. There were no compound-related findings in the tissues of low-dose
males or females.
LOAEL ~ 250 mg/kg-bw/day (based on decreased body weight and liver effects)
NOAEL ~ 125 mg/kg-bw/day
Reproductive/Developmental Toxicity
In the one-generation reproductive toxicity study, Sprague-Dawley rats (10 sex/dose) were
administered N-methylphthalimide in corn oil via gavage at 0, 50, 150 or 600 mg/kg-bw/day. F0
males were dosed for 4 weeks (beginning 2 weeks prior to breeding and continuing for 2 weeks
during breeding) and females were dosed for 10 weeks (2 weeks pre-breeding, 2 weeks during
mating, 3 weeks during gestation, 3 weeks during lactation). F1 litters were culled on postnatal
day (pnd) 4 to five per sex. At pnd 21, at least one male and female from each litter was selected
to continue treatment from pnd 22 until at least 70 days of age. Four unscheduled deaths
occurred in high-dose F0 females. No other treatment-related deaths were reported. Clinical
signs of toxicity in F0 male rats included ataxia, audible breathing and piloerection at the high
dose. Absolute and relative liver weight and brain weights were significantly increased in high-
dose males, and absolute and relative prostate weight was significantly decreased.
Histopathological findings included centrilobular hepatocellular hypertrophy in livers of the
high-dose animals of both sexes and hyaline droplets in kidney in males which is consistent with
alpha 2|i-globulin nephropathy. Pre-coital interval was markedly decreased at the high-dose.
There was a significant reduction in mean body weight during gestation and lactation in high-
dose females. No effects were observed on gestational length or reproductive indices. Total
number of implantation sites per litter and the number of total and live pups per litter at birth
were decreased at the high dose. In F1 offspring, there were significant reductions in body
weight, body weight gain and food consumption in males at all doses and in females at the two
highest doses from postnatal days 22-71. The absolute and adjusted acquisition of puberty was
significantly delayed in all F1 male groups and high-dose F1 females. In F1 males, hemoglobin
was significantly increased in high-dose males, platelet count was significantly decreased in mid-
and high-dose males and mean platelet volume was significantly decreased at all doses. In F1
females, total cholesterol was significantly increased at the high dose. Histological findings in
high-dose F1 animals consisted of centrilobular hepatocellular hypertrophy in both sexes and
hyaline droplets in male kidneys which is consistent with alpha 2|i-globulin nephropathy. In
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offspring sacrificed at pnd 21, absolute spleen weights were significantly decreased in males and
relative brain and epididymal weights were significantly increased in high-dose males. In female
offspring sacrificed at pnd 21, relative brain weight was significantly increased, and absolute
spleen and thymus weights were significantly decreased at the high-dose level.
LOAEL (systemic toxicity) = 600 mg/kg-bw/day (based on decreased body weight, liver and
kidney effects)
NOAEL (systemic toxicity) = 150 mg/kg-bw/day
LOAEL (reproductive toxicity - male/female) = 50/150 mg/kg-bw/day (based on delayed
puberty in F1 pups)
NOAEL (reproductive toxicity- male/female) = Not established/50 mg/kg-bw/day
LOAEL (developmental toxicity- male/female) = 50/150 mg/kg-bw/day (based on reduced
post-weaning body weights)
NOAEL (developmental toxicity - male/female) = Not established/50 mg/kg-bw/day
Developmental Toxicity
Female New Zealand White rabbits (16/dose) were administered N-methylphthalimide in 0.5%
carboxymethyl cellulose via gavage at 500 mg/kg-bw/day on days 6 through 18 of gestation.
There was no maternal or developmental toxicity.
NOAEL (maternal toxicity) = 500 mg/kg-bw/day (only dose tested)
NOAEL (developmental toxicity) = 500 mg/kg-bw/day (only dose tested)
Genetic Toxicity — Gene Mutation
In vitro
(1)	Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed
to N-methylphthalimide at concentrations of 0, 1, 10, 100, 500, 1000, 2500, 5000 or 10,000
Hg/plate in the presence and absence of metabolic activation. Positive and solvent controls were
tested concurrently and responded appropriately. The cytotoxic concentration was 10,000
Hg/plate for TA1537. The test substance did not exhibit mutagenic activity in any tested strain.
N-Methylphthalimide was not mutagenic in this assay.
(2)	S. typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 and Saccharomyces
cerevisiae strain D4 were exposed to N-methylphthalimide at concentrations of 0, 0.1, 1, 10, 100
and 500 |j,g/plate in the presence and absence of metabolic activation. Positive and solvent
controls were tested concurrently and responded appropriately. Cytotoxicity was observed at
500 |j,g/plate in strains TA1535, TA1537, TA1538 and TA98. The test substance did not exhibit
mutagenic activity in any tested strain.
N-Methylphthalimide was not mutagenic in this assay.
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Genetic Toxicity — Chromosomal Aberrations
In vitro
Chinese Hamster Ovary (CHO) cells were exposed to N-methylphthalimide at concentrations
of 0, 201.25, 402.5, 805 or 1610 |Jg/mL in the presence or absence of metabolic activation. In
the absence of metabolic activation, tests were conducted with exposure periods of 4 and 20
hours; in the presence of metabolic activation, tests were conducted with an exposure period
of 4 hours. Solvent and positive controls were tested concurrently and responded
appropriately. The cytotoxic concentration was >1610 |Jg/mL. The test substance was
negative for the induction of structural and numerical chromosome aberrations in Chinese
hamster ovary cells.
N-Methylphthalimide did not induce chromosomal aberrations in this assay.
Conclusion: The acute toxicity of CASRN 550-44-7 is low via the oral (rats) and dermal
(rabbits) routes of exposure. Repeated oral exposure of rats to CASRN 550-44-7 for 30 days
showed effects on body weight and liver at 250 mg/kg-bw/day and above, with a NOAEL of 125
mg/kg-bw/day. In one-generation reproductive toxicity study in rats, the LOAEL for systemic
toxicity was 600 mg/kg-bw/day (highest dose tested) based on effects on body weight, liver and
kidneys. The LOAEL for reproductive toxicity was 50 (males) to 150 (females) mg/kg-bw/day
based on delayed puberty in F1 pups. The NOAEL for reproductive toxicity for males was not
established and for females it was 150 mg/kg-bw/day. In the same study, the LOAEL for
developmental toxicity was 50 (males) to 150 (females) mg/kg-bw/day based on decreased post-
weaning body weights. The NOAEL for developmental toxicity for male pups was not
established and for females it was 150 mg/kg-bw/day. In the prenatal developmental toxicity
study in rabbits, no effects on maternal or developmental parameters were seen at 500 mg/kg-
bw/day (only dose tested). CASRN 550-44-7 did not induce gene mutations in bacteria or
chromosomal aberrations in mammalian cells in in vitro tests.
4. Hazard to the Environment
The environmental hazard data are summarized in Table 3.
Acute Toxicity to Fish
Rainbow trout (Oncorhynchus mykiss) were exposed to A-methylphthalimide at measured
concentrations of 0, 34.6, 100.3 and 293.3 mg/L under static conditions for 96 hours. At the
higher concentration, seven fish were dead. Total mortality was 0, 0, 0, 33.3, 100 and 100% for
the control, 40, 68, 116, 200 and 293 mg/L, respectively.
96-h LC5o= HO mg/L
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Acute Toxicity to Aquatic Invertebrates
Daphnia magna were exposed to A-methylphthalimide at measured concentrations of 26.9, 126.0
and 313.7 mg/L under static conditions for 24 hours. At 126 mg/L, 75% immobilization occurred
and 100% immobilization occurred at the two highest concentration levels.
24-h LC5o= 112 mg/L
Toxicity to Aquatic Plants
Green algae (Pseudokirchneriella subcapitata) were exposed to A-methylphthalimide at
measured concentrations of 0, 27.6, 80.4 and 360.2 mg/L for 46, 110 and 400 mg/L under static
conditions for 72 hours. Control samples produced a satisfactory cell increase during the
exposure period. Mean relative cell growth rates were 100, 84, 75, 7, 1, 0 and -1% for the
control, 46, 70, 110, 170, 260 and 400 mg/L samples, respectively.
72-h EC50 (growth) = 57 mg/L
Conclusion: The measured 96-hour LC50 of CASRN 550-44-7 for fish is 110 mg/L. The
measured 24-hour EC50 of CASRN 550-44-7 for aquatic invertebrates is 112 mg/L, and the
measured 72-hour EC50 for aquatic plants is 57 mg/L.
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Table 3. Summary Table of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
N-Methylphthalimide
(550-44-7)
Summary of Human Health Data
Acute Oral Toxicity
LD5o (mg/kg-bw)
> 500,< 5000
Acute Dermal Toxicity
LD50 (mg/kg-bw)
>2000
Repeated-Dose Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
(30-day)
NOAEL = 125
LOAEL = 250
Reproductive/Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Systemic Toxicity
NOAEL = 150
LOAEL = 600
Reproductive/Developmental Toxicity
Male/Female
NOAEL = Not established/50
LOAEL = 50/150
Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Maternal Toxicity
(Rabbits)
NOAEL = 500 (odt)
Developmental Toxicity
NOAEL = 500 (odt)
Genetic Toxicity - Gene Mutation/n vitro
Negative
Genetic Toxicity - Chromosomal Aberrations
In vitro
Negative
Summary of Environmental Effects - Aquatic Toxicity Data
Fish
96-h LCS0 (mg/L)
110
Aquatic Invertebrates
48-h ECso (mg/L)
112 (24-h)
Aquatic Plants
72-h ECso (mg/L)
(growth)
57
odt = only dose tested;
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