U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
SCREENING-LEVEL HAZARD CHARACTERIZATION
Cyclic Anhydrides Category
Hexahydrophthalic anhydride (HHPA)
Methylhexahydrophthalic anhydride (MHHPA)
Tetrahyrophthalic anhydride (THPA)
Methyltetrahydrophthalic anhydride (MTHPA)
Nadic methyl anhydride (NMA)
CASRN 85-42-7
CASRN 25550-51-0
CASRN 85-43-8
CASRN 34090-76-1/ 11070-44-3
CASRN 25134-21-8
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
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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U.S. Environmental Protection Agency
Hazard Characterization Document
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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
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)
85-42-7
25550-51-0
85-43-8
34090-76-1
11070-44-3
25134-21-8
Chemical Abstract Index Name
1,3-Isobenzofurandione, hexahydro-
1,3-Isobenzofurandione, hexahydromethyl-
1,3-Isobenzofurandione, 3a,4,7,7 a-
tetrahydro-
1,3-Isobenzofurandione, tetrahydro-5-
methyl-
1,3-Isobenzofurandione, tetrahydromethyl-
4,7-Methanoisobenzofuran-l,3-dione,
3a,4,7,7a-tetrahydromethyl-,
(3aR,4S,7R,7aS)-rel-]
Structural Formula
See Section 1
Summary
The cyclic anhydrides category contains both solid and liquid compounds that have moderate
vapor pressure. The water solubility of the cyclic anhydrides cannot be accurately determined
since the category members hydrolyze to their corresponding cyclic diacid rapidly. The cyclic
anhydrides are expected to have high mobility in soil, but would hydrolyze to the cyclic diacid
before traveling far. Volatilization of the cyclic anhydrides is expected to be low since these
compounds hydrolyze rapidly to their corresponding cyclic diacid, which exist as anions in the
environment. The rate of atmospheric photooxidation is considered rapid to moderate. The
cyclic anhydrides are expected to have low persistence (PI) and low bioaccumulation potential
(Bl).
The acute toxicity of the category members was low for the oral, dermal and inhalation routes.
A combined repeated-dose/reproductive/developmental toxicity study by the oral routes in rats
with CASRN 11070-44-3 showed histological changes in the forestomach at 300 mg/kg-bw/day;
the NOAEL for systemic and maternal toxicity was 100 mg/kg-bw/day. There was no evidence
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Hazard Characterization Document
September, 2009
of reproductive or developmental toxicity and the NOAEL was 300 mg/kg-bw/day. CASRN
34090-76-1 did not induce gene mutations or structural chromosomal aberrations when tested in
vitro. CASRNs 84-42-7, 85-43-8, 34090-76-1, and 25134-21-8 were slightly irritating to rabbit
skin and severely irritating or corrosive to rabbit eyes. CASRN 85-43-8 was a skin sensitizer in
guinea pigs. CASRNs 85-42-7 and 26590-20-5 were respiratory sensitizers in humans.
The 96-hour LC50 of the cyclic anhydride category members to fish is >86 mg/L, the 48-hour
EC50 to aquatic invertebrates is 130 mg/L, and the 72-hour EC50 to aquatic plants is 64 mg/L
(biomass) and 68 mg/L (growth rate). The 21-day chronic reproduction EC50 daphnia is 9.2
mg/L, and the NOEC and LOEC are 0.94 and 3.5 mg/L, respectively.
No data gaps were identified under the HPV Challenge Program.	
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U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
The sponsor, the International Health Foundation Cyclic Anhydrides Committee and its member
companies submitted a Test Plan and Robust Summaries to EPA for the cyclic anhydrides
category on March 28, 2001. EPA posted the submission on the ChemRTK HPV Challenge
website on April 17, 2001 (http://www.epa.gov/chemrtk/pubs/summaries/ihf/cl2983tc.htm).
EPA comments on the original submission were posted to the website on September 26, 2001.
Public comments were also received and posted to the website. The sponsor submitted
updated/revised documents on November 13, 2001, December 20, 2001 and December 16, 2003
which were posted to the ChemRTK website on January 23, 2002, January 11, 2002 and
February 24, 2004, respectively.
Category Justification
Four members (HHPA, MHHPA, THPA, and MTHPA) of the cyclic anhydride category are
bicyclic anhydrides, and NMA is a tricyclic anhydride. The category is based on similar
chemical structures, physical-chemical properties, and toxicological properties. Although
NMA's structure is more rigid than the other category members, the submitted physical and
chemical properties and mammalian and ecotoxicity did not show major differences between
NMA and the rest of the members. EPA considered this grouping acceptable for the purposes of
the HPV Challenge Program. Although treated as the same chemical in the HPV submission, for
inventory purposes, EPA considers the two chemicals CASRN 34090-76-1 (1,3-
isobenzofurandione, tetrahydro-5-methyl-) and CASRN 11070-44-3 (1,3-isobenzofurandione,
tetrahydromethyl-) as separate entities/isomers. 1,3-isobenzofurandione, tetrahydromethyl-
(CASRN 11070-44-3) has been evaluated under the OECD HPV Chemicals Program and
published under UNEP (http://www.chem.unep.ch/irptc/sids/QECDSIDS/11070443.pdf).
The IHF Consortium was contacted in August, 2009 to determine whether the testing proposed
in their 2002 revised test plan had occurred. EPA learned that the Consortium had disbanded
and was not planning on doing any further testing.
1 Chemical Identity
1.1 Identification and Purity
The following description is taken from the 2001 Test Plan and Robust Summary:
Chemicals in this category contain a bicyclic ring structure with the carboxylic acid anhydride
group as the single reactive moiety that hydrolizes to form the diacid in water. Two of the five
bicyclic ring structures are saturated and three are partially unsaturated. One of the saturated and
two of the partially unsaturated are substituted methyl derivatives. Compounds with the
substituted methyl groups may exist as several isomeric forms. Test substance purity, when
noted in the Robust Summaries, was given as > 99%. The chemical structures of the cyclic
anhydrides are depicted in Table 1.
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Table 1: Cyclic Anhydrides Category Sponsored Chemical Structures
Chemical Abstract Index
Name
CASRN
Structure
1,3 -Isob enzofurandi one,
hexahydro-
85-42-7
/
o
>
1,3 -Isob enzofurandi one,
hexahydromethyl-
25550-51-0
>
o
Ch|3 Position of the
methyl group is
unspecified
1,3 -Isob enzofurandi one,
3a,4,7,7a-tetrahydro-
85-43-8
/
o
/>
1,3 -Isob enzofurandi one,
tetrahydro-5-methyl-
34090-76-1
h3c^
o
-o
1,3 -i sob enzofurandi one,
tetrahydromethyl-
11070-44-3
h3c^
9
1Y°
-o
Position of the
methyl group is
unspecified
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Hazard Characterization Document
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4,7 -Methanoi sobenzofuran-1,3-
25134-21-8


dione, 3a,4,7,7a-tetrahydro-


\
methyl-, (3aR,4S,7R,7aS)-rel-


o Position of the
methyl group is
unspecified
1.2 Physical-Chemical Properties
The physical-chemical properties of the cyclic anhydrides category are summarized in Table 2.
Table 2. Physical-Chemical Properties Cyclic Anhydrides1
Property
Hexahydro-
phthalic
anhydride
Methylhexa-
hydrophthalic
anhydride
Tetrahydro-
phthalic
anhydride
Methyltetra-
hydrophthalic
anhydride
Nadic methyl
anhydride
CASRN
85-42-7
25550-51-0
85-43-8
34090-76-1
(11070-44-3)
25134-21-8
Molecular
Weight
154.16
168.19
152.15
166.17
178.18
Physical State
Glassy solid
Liquid
White
crystalline
powder2
Liquid
Colorless to light
yellow viscous liquid2
Melting Point
34-38°C
(measured)
37.5°C (cis,
measured)5
144°C (trans,
measured)5
-30°C
(measured)
99-102°C
(measured)
103-104°C (cis,
measured)5
186°C (trans,
measured)5
-38°C
(measured for
34090-76-1)
-5 to -3°C
(measured for
19438-59-6)5
<-20°C (measured)
Boiling Point
285-296°C
(measured)
158-160°C at 17
mm Hg (cis,
277°C N0M05)5
125-135°C at 0.02
mm Hg (trans,
390°C N0M05)5
299°C at 744
mmHg
(measured)
301°C
(measured)
283-290°C
(measured)
117-118°C at 2
mmHg
(measured for
19438-59-6,
281°C
NOM05)5
277°C at 743 mm Hg
(measured)
140°C at 10 mm Hg
(measured, 269°C
N0M05)4
Vapor Pressure
1.72xlO"3mmHg
at 20°C
(estimated)
5xl0"3 mmHg at
25°C (N0M05)
9.41><10"4mm
Hg at 20°C
(estimated);
5 mm Hg at
137°C
(measured)
(0.003 mmHg
NOM05)
1 37 x10 3 mm
Hg at 20°C
(estimated)
2xlO"3mmHg
at 25°C
(estimated)
3.5xlO"3 mm
Hg at 25°C
(NOM05)
9.88xlO"4mmHgat
25°C (estimated)
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U.S. Environmental Protection Agency	September, 2009
Hazard Characterization Document
Water
Solubility
290-367 mg/L at
20°C (measured,
hydrolyzes)
4700-1820
mg/L at 20°C
(measured,
hydrolyzes)
303-349 mg/L
at 20°C
(measured,
hydrolyzes)
> lOg/L at
10°C
(measured,
likely the
hydrolysis
product)
105-146 mg/L at
20°C (measured,
hydrolyzes)
Dissociation
Constant (pKa)
4.43 (estimated for
the cyclic diacid)3
4.43 (estimated
for the cyclic
diacid)3
4.43 (estimated
for the cyclic
diacid)3
4.43
(estimated for
the cyclic
diacid)3
4.14 (estimated for the
cyclic diacid)3
Henry's Law
Constant
2.1 / HP" atm-
m3/mole
(estimated)4
2.9xlO"5 atm-
m3/mole
(estimated)4
1.9xl0~5atm-
m3/mole
(estimated)4
l.OxlO"5 atm-
m3/mole
(estimated)4
1.5 x 10"5 atm-m3/mole
(estimated)4
Log Kow
2.17 (estimated)
2.59 (estimated)
1.96 (estimated)
4.0
(estimated)4
2.27 (estimated)
'The Industrial Health Foundation. Inc. Cyclic Anhydrides Committee. December 16, 2003. Revised Robust
Summary and Test Plan for the Cyclic Anhydrides Category.
http://www.epa.gov/chemrtk/pubs/summaries/ilif/cl2983tc.htm.
2HSDB. 2008. Hazardous Substances Data Bank. Accessed October 20, 2008. http://toxnet.nlm.nih.gov/cgi-
bin/sis/htmlgen?HSDB.
3SPARC. 2008. Online pKa and Property Calculator v. 4.2.1405-s4.2.1408. Accessed October 20, 2008.
http://ibmlc2.chem.uga.edu/sparc/.
4U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v3.20. United States
Enviromnental Protection Agency, Washington, DC, USA. http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
5Beilstein, EV, volume 17/11, pages 76, 83, 134, 199. EIII/IV, volume 17, pages 5931, 5943, 5996, 6003. EII, volume
17, pages 452, 457. 19438-59-6 is 1,3-Isobenzofurandione, 4,5,6,7-tetrahydro-5-methyl-.
2 General Information on Exposure
2.1 Production Volume and Use Pattern
The cyclic anhydrides category chemicals had an aggregated production and/or import volume in
the United States between 21.5 million pounds and 111.5 million pounds in calendar year 2005.
CASRN 85-42-7
CASRN 2550-51-0
CASRN 85-43-8
CASRN 34090-76-1
CASRN 11070-44-3
CASRN 25134-21-8
10 to 50 million pounds
<500,000 pounds
1 to 10 million pounds
10 to 50 million pounds
<500,000 pounds
500,000 to 1 million pounds
Non-confidential information in the IUR indicated that the industrial processing and uses of the
chemical include intermediates, adhesive and binding agents, coloring agents, dyes, and other.
Non-confidential information in the IUR indicated that the commercial and consumer products
containing the chemicals include adhesives and sealants, electrical and electronic products,
fabrics, textile and apparel, and other. The HSDB states that tetrahydrophthalic anhydride
(CASRN 85-43-8) is primarily used as a chemical intermediate for light-colored alkyds,
polyesters, plasticizers and adhesives, as an anti-scorching agent in the rubber industry, and in
the paints, lacquers and varnishes industry. Nadic methyl anhydride (CASRN 25134-21-8) is
used as a chemical intermediate for polyester resins and a curing agent for epoxy resins. The
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HPV submission states that these chemicals are primarily "destructive industrial use" chemicals
and are not sold in consumer markets. Anhydrides are mainly used as curing agents (also called
hardeners) in epoxy resin systems. Some of these chemicals are also used in the manufacture of
alkyd and polyester resins.
2.2 Environmental Exposure and Fate
Although there is no quantitative information available on releases of these chemicals to the
environment, there is potential for environmental releases to various media including water, land
and air.
The environmental fate properties are provided in Table 3. The cyclic anhydrides are expected
to have high mobility in soil, but will hydrolyze rapidly. The cyclic anhydrides were generally
not readily biodegradable; however, these tests likely measured the lack of biodegradability of
the hydrolysis products. Although the estimated Henry's Law constants suggest volatilization is
moderate for the cyclic anhydrides, these compounds hydrolyze rapidly to their corresponding
cyclic diacid, which exist as anions in the environment which do not volatilize. Due to the rapid
rate of hydrolysis, the cyclic anhydrides are expected to have low persistence (PI) and low
bioaccumulation potential (Bl).
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Table 3. Environmental Fate C
laracteristics of Cyclic Anhydrides1
Property
Hexahydro-
phthalic
anhydride
Methylhexa-
hydrophthalic
anhydride
Tetrahydro-
phthalic
anhydride
Methyltetra-
hydrophthalic
anhydride
Nadic methyl
anhydride
CASRN
85-42-7
25550-51-0
85-43-8
34090-76-1/
(11070-44-3)
25134-21-8
Photodegrada-
tion Half-life
37.7 hours
(estimated)
30 hours
(estimated)
1.04 hours
(estimated)
6.3
hours(estimated
on 34090-76-1)2
3.0
hours(estimated
on 11070-44-3 )2
1.04 hours
(estimated)





Hydrolysis Half-
life
<1 day at pH
4,7, and 9 at
25°C
(measured)
<1 day at pH
4,7, and 9 at
25°C
(measured)
<1 day at pH
4,7, and 9 at
25°C
(measured)
Hydrolyzes to
cyclic diacid
<1 day at pH 4,7,
and 9 at 25°C
(measured)
Biodegradation
1-6% after 28
days(not
readily
biodegradable)
0% after 28
days(not
readily
biodegradable)
0% after 28
days(not
readily
biodegradable);
21% after 21
days(not
readily
biodegradable)
No data
0% after 28 days
(not readily
biodegradable)
Bioconcen-
tration
BCF = 9
(estimated)2
BCF = 20
(estimated)2
BCF = 6
(estimated)2
BCF = 203
(estimated on
34090-76-1)2
BCF = 25
(estimated on
11070-44-3)2
BCF = 11
(estimated)2
Log Koc
1 (estimated)2
1.2 (estimated)2
1 (estimated)2
2.7 (estimated
on 34090-76-1)2
1.93 (estimated
on 11070-44-3 )2
1.5 (estimated)2
Fugacity
(Level III
Model)
Air
Water
Soil
Sediment
4.47%
40.6%
54.8%
0.145%
3.84%
38.2%
57.7%
0.229%
0.205%
43.9%
55.7%
0.127%
0.43%
40.3%
59.2%
0.09%
0.192%
41.7%
57.9%
0.166%
Persistence3
PI (low)
PI (low)
PI (low)
PI (low)
PI (low)
Bioaccumula-
tion
B1 (low)
B1 (low)
B1 (low)
B1 (low)
B1 (low)
'The Industrial Health Foundation, Inc. Cyclic Anhydrides Committee. December 16, 2003.
Summary and Test Plan for the Cyclic Anhydrides Category.
htto://www.era.eov/chemrtk/r>ubs/summaries/ihf/cl2983tc.htm.
Revised Robust
"U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v3.20. United States
Enviromnental Protection Asencv. Washington. DC. USA. httD:/A\\\\\ .CDa.ao\/oDDtintr/c\DOSurc/Dubs/cDisuitc.htin.
'Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal
Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
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3 Human Health Hazard
A summary of health effects data submitted for SIDS endpoints is provided in Table 4. The table
also indicates where data for tested category members are read-across (RA) to untested members
of the category.
Acute Oral Toxicity
Hexahydrophthalic anhydride (HHPA) (CASRN85-42-7)
Sprague-Dawley rats (5/sex/dose) were administered HHPA via gavage at 1500, 2027, 2739,
3700, and 5000 mg/kg-bw and observed for 14 days. Mortality rates were 0/5, 0/5, 2/5, 5/5, and
5/5 males; and 1/5, 0/5, 3/5, 4/5, and 5/5 females for the 1500, 2027, 2739, 3700, and 5000
mg/kg-bw dose groups, respectively.
LD50 3307 mg/kg-bw
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 34090-76-1)
Sprague-Dawley rats (5/sex/dose) were administered MTHPA via gavage at 0, 500, 1000, and
2000 mg/kg-bw and observed for 14 days. No mortality was seen at any dose.
LD50 > 2000 mg/kg-bw
Nadic methyl anhydride (NMA) (CASRN 25134-21-8)
Sprague-Dawley rats (5/sex/dose) were administered NMA via gavage at 650, 801, 987, 1217,
and 1530 mg/kg-bw and observed for 14 days. Mortality was 1/10, 2/10, 4/10, 9/10 10/10 at
650, 801, 987, 1217, and 1530 mg/kg-bw, respectively. All deaths occurred within 6 days post-
dosing.
LD50 = 958 mg/kg-bw
Acute Dermal Toxicity
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7)
New Zealand albino rabbits (5/sex) were administered HHPA dermally on abraded skin at 2000
mg/kg-bw under semi-occluded conditions for 24 hours and observed for 14 days. No rabbits
died.
LD50 > 2000 mg/kg-bw
Nadic methyl anhydride (NMA) (CASRN 25134-21-8)
TipRAIf rats (5/sex/group) were administered NMA dermally at 2000, 3000, 4000, and 5000
mg/kg-bw for 24 hours and observed for 14 days. Mortality was 0/10, 2/10, 3/10, and 5/10 at
2000, 3000, 4000, and 5000 mg/kg-bw, respectively.
LD50 = 4920 mg/kg-bw
Nadic methyl anhydride (NMA) (CASRN 25134-21-8)
New Zealand albino rabbits (5/sex) were administered NMA dermally at 2000 mg/kg-bw for 24
hours and observed for 14 days. No mortality occurred.
LD50 > 2000 mg/kg-bw
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Acute Inhalation Toxicity
Hexahydrophthalic anhydride (HHPA) (CASRN85-42-7)
Sprague-Dawley rats (5/sex/group) were exposed to HHP A aerosol for 4 hours at 1100 mg/m3
(1.1 mg/L), a maximum attainable concentration, and observed for 15 days. No mortality
occurred.
LC50 > 1.1 mg/L
Repeated-Dose Toxicity
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 11070-44-3)
In a combined repeated-dose/reproductive/developmental toxicity screening test, Sprague-
Dawley rats (number/sex/dose unspecified) were administered tetrahydromethyl-1,3-
isobenzofuranedione (CASRN 11070-44-3) via gavage at 0, 30, 100, and 300 mg/kg-bw/day for
49 days (males) or from 14 days prior to mating to day 3 of lactation (females). No changes
were observed for body weight or food consumption. The only clinical sign of toxicity observed
consisted of transient salivation at 300 mg/kg-bw/day. Hematology was unremarkable.
Decreases in total cholesterol and blood urea nitrogen, increases in triglycerides, and an increase
in adrenal weights (relative/absolute; p< 0.05) were reported at 300 mg/kg-bw/day in males only.
Histopathological examination revealed changes in the forestomach. Forestomach changes
characterized as moderate included squamous metaplasia of the forestomach observed in 10/12
males at 300 mg/kg-bw/day. Forestomach changes at 300 mg/kg-bw/day characterized as mild
included squamous metaplasia of the forestomach in females (9/12 females), mucosal thickening
of the forestomach in both sexes (10/12 males; 7/12 females), submucosal granulomatous
inflammation (10/12 males; 7/12 females), epithelial vacuolar change (10/12 males; females not
reported), edema (10/12 males; females not reported), cellular infiltration (1/12 males; 1/12
females), and erosion 1/12 males; 3/12 females). These details were found in the OECD
document for CASRN 11070-44-3 at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/1107Q443.pdf.
LOAEL (males/females) = 300 mg/kg-bw/day (based on histopathological changes in the
forestomach)
NOAEL (males/females) = 100 mg/kg-bw/day
Reproductive/Developmental Toxicity
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 11070-44-3)
In the combined repeated-dose/reproductive/developmental toxicity screening test previously
described, Sprague-Dawley rats were administered tetrahydromethyl-l,3-isobenzofuranedione
(CASRN 11070-44-3) via gavage at 0, 30, 100, and 300 mg/kg-bw/day. No statistically
significant effects were reported for any of the reproductive or developmental parameters/indices
including estrous cyclicity, numbers of corpora lutea, implantations, gestation length, litter size,
number of live newborns; and offspring sex ratios, body weight, viability, and gross external
examinations.
LOAEL (maternal) = 300 mg/kg-bw/day (based on histopathological changes in the
forestomach)
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NOAEL (maternal) = 100 mg/kg-bw/day
NOAEL (developmental toxicity) = 300 mg/kg-bw/day (based on no adverse treatment-related
effects at the highest dose tested)
NOAEL (reproductive toxicity) = 300 mg/kg-bw/day (based on no adverse treatment-related
effects at the highest dose tested)
Genetic Toxicity — Gene Mutations
In vitro
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN34090-76-1)
Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and in Escherichia coli Wp2
uvrA were exposed to MTHPA at 0, 62.5, 125, 250, 500, 1000, and 2000 |j,g/plate, without
metabolic activation and 0, 156, 313, 625, 1250, 2500, and 5000 |j,g/plate with metabolic
activation. Positive controls were run concurrently. Cytotoxicity was evident at 500 |ig/plate
(TA1535), 1000 |ig/plate (TA100, TA98, TA1537), and 2500 |ig/plate (E. coli Wp2 uvrA)
without activation, and at 5000 |ig/plate in TA100 and TA1537 with activation. Positive control
responses were not provided in the robust summary. No mutagenicity was observed.
MTHPA was not mutagenic in this assay.
Genetic Toxicity — Chromosomal Aberrations
In vitro
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 34090-76-1)
Chinese hamster lungs cells, CHL/IU, were exposed to MTHPA at 0.075, 0.15 and 0.30 mg/mL
by continuous treatment in the presence and absence of metabolic activation. In a short-tem
treatment assay without metabolic activation, the cells were exposed to MTHPA at 0.05, 0.10
and 0.20 mg/mL and at 0.11, 0.21 and 0.43 mg/mLwith metabolic activation. Positive controls
were used. Cytotoxic concentrations were 0.30 mg/mL for continuous treatment with activation,
0.40 mg/mL in short-term assay without metabolic activation, and 1.0 mg/mL with metabolic
activation. Structural chromosomal aberrations were not induced following 24 hours of
continuous treatment. Weak polyploidy was induced in short-term assays.
MTHPA did not induce structural chromosomal aberrations in this assay.
Additional Information
Skin irritation
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7)
Six New Zealand albino rabbits (sex not reported) were administered 6.25, 12.5, 25 and 50%
HHPA dermally and were scored at 24 and 72 hours according to the Draize scale. Minimal to
slight irritation was seen at < 50%.
HHPA was slightly irritating to rabbit skin.
Tetrahydrophthalic anhydride (THPA) (CASRN 85-43-8)
Rabbits (strain and number not stated) were administered THPA on to the skin. No irritation was
noted.
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September, 2009
THPA was not irritating to skin.
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN34090-76-1)
In one test in rabbits, MTHPA was shown to be slightly irritating to the skin. No other details
were provided.
MTHPA was slightly irritating to rabbit skin.
Nadic methyl anhydride (NMA) (CASRN 25134-21-8)
Two separate tests in rabbits with NMA, one using a 50% suspension and the other an undiluted
solution, showed slight to moderate irritation to the skin, respectively.
NMA was slightly to moderately irritating to rabbit skin.
Eye irritation
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7)
In a Draize test, 12 New Zealand white rabbits (sex not reported) were instilled with 100 mg
HHPA into the eyes. The eyes of six rabbits were not washed and the eyes of three rabbits each
were either washed for 4 or 30 seconds. Unwashed eyes and those washed at 30 seconds showed
severe irritation and corrosion with no recovery at 21 days. Rabbits at 4 seconds showed severe
but reversible irritation by 19 days.
HHPA was severely irritating or corrosive to rabbit eyes.
Tetrahydrophthalic anhydride (THPA) (CASRN 85-43-8)
In an acute eye irritation/corrosion study in rabbits, THPA was shown to be corrosive to the eyes.
No scores were calculated since only one test animal was used.
THPA was corrosive to rabbit eyes.
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 34090-76-1)
In a Draize test in rabbits, MTHPA was shown to be highly irritating to the eyes. No other
details were provided.
MTHPA was irritating to rabbit eyes.
Nadic methyl anhydride (NMA) (CASRN 25134-21-8)
In two tests, NMA was shown to be highly corrosive (no washout) or irritating (4 second
washout) to rabbit eyes.
NMA is corrosive to rabbit eyes.
Skin sensitization
Tetrahydrophthalic anhydride (THPA) (CASRN 85-43-8)
In a guinea pig maximization test, THPA was shown to be sensitizing, with 17/20 guinea pigs
showing a positive response.
THPA was a skin sensitizer in guinea pigs.
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U.S. Environmental Protection Agency
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Respiratory sensitization (These summaries reflect EPA reviews of the cited literature and not
the robust summaries provided in the HPV Challenge Program submission)
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7); Methyltetrahydrophthalic
anhydride (MTHPA) (CASRN 26590-20-5)4
A total of 110 workers (54 men, 56 women; 19-58 years old) employed at a medium-sized
company for an average of 8.1 years were investigated (Drexler et al., 1994). The employees
received extensive medical evaluations after 4 workers reported obstructive respiratory tract
diseases suggesting that some workers were sensitized to HHPA and/or MTHPA. The
reproductive status of the women was not reported in the study. The employees participated in
the study on a voluntary basis; 20% of workers chose to not participate in the investigation. No
reference is made regarding informed consent. The investigators collected information about the
workers' clinical symptoms related to allergies and/or respiratory problems (e.g. rhinitis,
rhinoconjuctivitis, dry cough, asthma symptoms). Sera were obtained and subsequently total IgE
levels and specific IgE to common allergens, HHPA, MTHPA, TMA or HAS conjugates of
phthalic anhydride (PA) were measured with the RAST assay. Skin prick tests were also
conducted with the following allergens: PA, histamine (positive control), acetone (negative
control), HHPA or MTHPA. An inhalation challenge test was performed with employees who
reported suspected clinical symptoms related to an occupational allergy and showed a positive
skin prick test and/or a RAST with PA conjugates. For the inhalation challenge, the employees
handled HHPA and MTHPA in a small room for about 10 min under conditions mimicking the
normal workplace environment. During the exposure, inhalation exposure was avoided and a
medical doctor monitored the workers. In addition, the physician provided a medical evaluation
after the exposure which included a whole-body plethysmography.
A total of 17 workers had specific IgE against HHPA and/or MTHPA. Six workers showed
clinically relevant symptoms (e.g. rhinitis, increased air way resistance) in the challenge test.
Data from the RAST and skin prick tests showed that both methods could be used to evaluate the
workplace-related sensitization to HHPA and MTHPA.
HHPA and MTHPA were respiratory sensitizers in humans.
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7)
A total of 81 workers exposed to HHPA while preparing an epoxy resin product were studied
(Grammer et al., 1995). The age and gender of the workers was not specified. All subjects
identified by the chemical plant management as HHPA-exposed workers agreed to participate in
the study and informed consent was obtained. The investigators evaluated the history of
occupational immunologic lung disease by questionnaire, spirometry and chest film. Blood
samples were collected to measure specific IgE and IgG antibodies against HHP-HSA by
ELISA. Those workers that had a positive ELISA and/or the presence of HHPA-related
respiratory symptoms were interviewed, examined and skin tested with HHP-HAS.
4 The submitter provided data from the published literature indicating that cyclic anhydrides as a class are
respiratory sensitizers. Some of the information is based on chemicals not part of this category, but which are close
analogs, including CASRN 26590-20-5, CA Index Name 1,3-Isobenzofurandione, 3a,4,7,7a-tetrahydromethyl-.
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Antibodies against HHP-HSA were detected in 14 workers reporting IgE- and/or IgG-mediated
disease; the remaining 67 workers had no disease and no detectable response against the HHP-
HSA conjugate. The authors used the Univariable Optimal Discriminant Analysis (ODA) model
to study whether the antibody levels could be used to predict an immunologically-mediated
respiratory disease. Based on the results of the model, the authors concluded that HHPA
workers with high antibody titers (IgE or IgG) would have a significant likelihood of exhibiting
an immunologically-mediated respiratory condition.
HHPA was a respiratory sensitizer in humans.
Hexahydrophthalic anhydride (HHPA) (CASRN 85-42-7)
A total of 33 subjects (20-58 years old; gender not specified) employed in a plant manufacturing
components for the electronic industry were studied (Nielsen et al., 1994). Additional details on
the recruitment process were not provided in the report. No reference is made regarding
informed consent.
Thirteen workers tested positive for sensitization against HHPA; the remaining 20 subjects tested
negative for sensitization, although 9 workers showed symptoms associated with an acid
anhydride allergy. The investigators evaluated the medical and occupational history of the
workers by questionnaire and skin prick tests. Prior to the challenge test, the investigators
recorded the exposure to HHPA, smoking habits and current clinical symptoms as well as
conducted a physical examination and a skin prick test against HHPA-HAS. Blood samples
were collected to measure specific IgE and IgG antibodies by RAST and ELISA. For the nasal
challenge test, a mist of HHPA-HSA solution was sprayed into each worker's nostrils. Nasal
symptoms, nasal inspiratory peak flow and nasal lavage were recorded before and after the
challenge test. Nasal lavage fluid was used for tests measuring tryptase, eosinophil cationic
protein, myeloperoxidase and albumin.
Eleven workers who were IgE-sensitized against HHPA and reported clinical symptoms
demonstrated a decrease in nasal inspiratory peak flow and an increase in nasal symptoms after
the challenges. Although not explicitly stated, the report suggested that the nasal symptoms were
reversible. Workers who were IgE-sensitized against HHPA showed a significant elevation of
eosinophil and neutrophil counts as well as an increase in the levels of tryptase and albumin. No
significant changes were reported for eosinophil cationic protein. The non-sensitized workers
did not exhibit significant changes in the parameters measured in the study. These observations
suggested a possible role of IgE in the HHPA-mediated sensitization in humans. The study did
not show a role of IgG antibodies in the pathomechanism of the HHPA sensitization.
HHPA was a respiratory sensitizer in humans.
Conclusion: The acute toxicity of the category members was low for the oral, dermal and
inhalation routes. A combined repeated-dose/reproductive/developmental toxicity study by the
oral routes in rats with CASRN 11070-44-3 showed histological changes in the forestomach at
300 mg/kg-bw/day; the NOAEL for systemic and maternal toxicity was 100 mg/kg-bw/day.
There was no evidence of reproductive or developmental toxicity and the NOAEL was 300
mg/kg-bw/day. CASRN 34090-76-1 did not induce gene mutations or structural chromosomal
aberrations when tested in vitro. CASRNs 84-42-7, 85-43-8, 34090-76-1, and 25134-21-8 were
slightly irritating to rabbit skin and severely irritating or corrosive to rabbit eyes. CASRN 85-43-
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U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
8 was a skin sensitizer in guinea pigs. CASRNs 85-42-7 and 26590-20-5 were respiratory
sensitizers in humans.
Table 4. Summary Table of the Screening Information Data Set as Submitted under the

U.S. HPV Challenge Prgram: Human Health Data


Hexahydro-
Methylhexa-
Tetra-
Methyltetra-
Nadic methyl

phthalic
hydrophthalic
hydro-
hydrophthalic
anhydride

anhydride
anhydride
phthalic
anhydride
(NMA)
Endpoints
(HHPA)
(MHHPA)
anhydride
(MTHPA)




(THPA)
(34090-76-1/


(85-42-7)
(25550-51-0)

11070-44-3)1
(25134-21-8)



(85-43-8)


Acute Oral

No Data
No Data


Toxicity
3307
>2000
>2000
>2000
958
LD5o (mg/kg-bw)

(RA)
(RA)


Acute Dermal

No Data
No Data
No Data

Toxicity
>2000
>2000
>2000
>2000
> 2000 - 4920
LD50 (mg/kg-bw)

(RA)
(RA)
(RA)

Acute Inhalation

No Data
No Data
No Data
No Data
Toxicity
> 1.1
> 1.1
> 1.1
> 1.1
> 1.1
LC5o (mg/L)

(RA)
(RA)
(RA)
(RA)
Repeated-Dose





Toxicity
No Data
No Data
No Data

No Data
NOAEL/LOAEL
NOAEL =
NOAEL = 100
NOAEL=
NOAEL = 100
NOAEL=
(mg/kg-bw/day)
100
LOAEL = 300
100
LOAEL = 300
100

LOAEL =
(RA)
LOAEL=

LOAEL=

300

300

300

(RA)

(RA)

(RA)
Reproductive





Toxicity
No Data
No Data
No Data

No Data
NOAEL/LOAEL
NOAEL=
NOAEL = 300
NOAEL=
NOAEL = 300
NOAEL=
(mg/kg-bw/day)
300
(RA)
300
(hdt)
300

(RA)



(RA)



(RA)


Developmental





Toxicity
No Data
No Data
No Data

No Data
NOAEL/LOAEL





(mg/kg-bw/day)
NOAEL=
NOAEL = 100
NOAEL=
NOAEL = 100
NOAEL=
Maternal toxicity
100 LOAEL
LOAEL = 300
100
LOAEL = 300
100 LOAEL

= 300

LOAEL=

= 300


NOAEL = 300
300
NOAEL = 300

Developmental
NOAEL=


(hdt)
NOAEL=
Toxicity
300
(RA)
NOAEL=

300

(RA)

300

(RA)



(RA)


17

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U.S. Environmental Protection Agency	September, 2009
Hazard Characterization Document
Table 4. Summary Table of the Screening Information Data Set as Submitted under the
U.S. HPV Challenge Prgram: Human Health Data
Endpoints
Hexahydro-
phthalic
anhydride
(HHPA)
(85-42-7)
Methylhexa-
hydrophthalic
anhydride
(MHHPA)
(25550-51-0)
Tetra-
hydro-
phthalic
anhydride
(THPA)
(85-43-8)
Methyltetra-
hydrophthalic
anhydride
(MTHPA)
(34090-76-1/
11070-44-3)1
Nadic methyl
anhydride
(NMA)
(25134-21-8)
Genetic Toxicity -
Gene Mutations
In vitro
No Data
Negative
(RA)
No Data
Negative
(RA)
No Data
Negative
(RA)
Negative
No Data
Negative
(RA)
Genetic Toxicity -
Chromosomal
Aberrations
In vitro
No Data
Negative
(RA)
No Data
Negative
(RA)
No Data
Negative
(RA)
Negative
No Data
Negative
(RA)
Additional
Information
Skin Irritation
Eye Irritation
Slightly
irritating
Highly
irritating to
corrosive
-
Not
irritating
Corrosive
Slightly
irritating
Irritating
Slightly to
moderately
irritating
Irritating to
highly
corrosive
Skin Sensitization
Positive
Positive
Positive
-

Respiratory
Sensitization
Positive
-
—
Positive

Measured data in bold text; (RA) = Read Across; (hdt) = highest dose tested
1 Data from OECD HPV Chemicals Program (http://www.chem. unep.ch/irptc/sids/OECDSIDS/11070443.pdf) were used
because the documents are more recent than the November 2001 test plan.
4 Hazards to the Environment
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 5. The
table also indicates where data for tested category members are read-across (RA) to untested
members of the category.
Acute Toxicity to Fish
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN11070-44-3)
(1) Japanese medaka (Oryzias latipes) were exposed to methyltetrahydrophthalic anhydride at
nominal concentrations of 0 or 100 mg/L under flow-through conditions for 96 hours. The
measured concentrations were within 20% of the nominal concentration; however, the LC50 was
expressed based on the nominal concentration. The pH at 100 mg/L was 6.3-6.4, possibly due to
the hydrolysis.
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September, 2009
96-h LC50 > 100 mg/L
(2) Japanese medaka (Oryzias latipes) were exposed to methyltetrahydrophthalic anhydride at
nominal concentrations of 0 or 100 mg/L under flow-through conditions for 14 days. The pH at
100 mg/L varied from 6.3 to 6.6, possibly due to the hydrolysis.
96-h LC50 > 86 mg/L
Acute Toxicity to Aquatic Invertebrates
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN11070-44-3)
Water fleas {Daphnia magna) were exposed to methyltetrahydrophthalic anhydride at nominal
concentrations of 0, 32, 56, 100, 180, and 320 mg/L under static conditions for 48 hours. The
mean measured concentrations were 0, 31, 49, 87, 140, and 270 mg/L. The pH for test substance
concentrations up to 140 mg/L ranged from 5.6 to 7.8, possibly due to hydrolysis. At 270 mg/L,
the pH was 4.3 at the beginning of the test and was not measured at the end of the test; all
Daphnids at this concentration died by the end of the test.
48-h EC50 = 130 mg/L
Toxicity to Aquatic Plants
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 11070-44-3)
Green algae (Pseudokirchneriella subcapitata) were exposed to methyltetrahydrophthalic
anhydride at nominal concentrations of 0, 10, 18, 32, 56, and 100 mg/L under static conditions
for 72 hours. The mean measured concentrations were 0, 9, 15, 28, 49, and 86 mg/L. The pH
for the test substance concentrations up to 56 mg/L ranged from 5.2 to 7.8, and was lower at 100
mg/L, possibly due to hydrolysis.
72-h EC50 (growth rate) = 68 mg/L
72-h EC50 (biomass) = 64 mg/L
Chronic Toxicity to Aquatic Invertebrates
Methyltetrahydrophthalic anhydride (MTHPA) (CASRN 11070-44-3)
Water fleas (Daphnia magna) were exposed to methyltetrahydrophthalic anhydride at nominal
concentrations of 0, 1.3, 4.1, 13, 41 and 130 mg/L for 21 days in a reproduction toxicity test.
Concentrations were measured at preparation and before renewal on both day 9 and day 16.
Time-weighted mean measured concentrations were < 0.2, 0.94, 3.5, 11,35, and 110 mg/L. The
pH varied from 6.1 to 8.2.
EC50 (21-day, reproduction) = 9.2 mg/L
NOEC (21-day, reproduction rate) = 0.94 mg/L
LOEC (21-day, reproduction rate) = 3.5 mg/L
Conclusion: The 96-hour LC50 of the cyclic anhydride category members to fish is >86 mg/L,
the 48-hour EC50 to aquatic invertebrates is 130 mg/L, and the 72-hour EC50 to aquatic plants is
64 mg/L (biomass) and 68 mg/L (growth rate). The 21-day chronic reproduction EC50 daphnia is
9.2 mg/L, and the NOEC and LOEC are 0.94 and 3.5 mg/L, respectively.
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Table 5. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV
Challenge Program: Aquatic Toxicity Data
Endpoints
Hexahydro-
phthalic
anhydride
(HHP A)
(85-42-7)1
Methylhexa-
hydro-
phthalic
anhydride
(MHHPA)
(25550-51-0)
i
Tetrahydro-
phthalic
anhydride
(THPA)
(85-43-8)1
Methyltetra-
hydro-
phthalic
anhydride
(MTHPA)
(34090-76-1)
Methyltetra-
hydro-
phthalic
anhydride
(MTHPA)
(11070-44-3)
2
Nadic
methyl
anhydride
(NMA)
(25134-21-8)
3
Fish
96-h LCso
(mg/L)
No Data
> 86
(RA)
No Data
>86
(RA)
No Data
> 86
(RA)
No Data
>86
(RA)
>86
No Data
> 86
(RA)
Aquatic
Invertebrates
48-h ECso
(mg/L)
No Data
130
(RA)
No Data
130
(RA)
No Data
130
(RA)
No Data
130
(RA)
130
No Data
130
(RA)
Aquatic Plants
72-h ECso
(mg/L)
(growth rate)
(biomass)
No Data
68
64
(RA)
No Data
68
64
(RA)
No Data
68
64
(RA)
No Data
68
64
(RA)
68
64
No Data
68
64
(RA)
Chronic Toxicity
to Aquatic
Invertebrates
21-day ECS0/
LOEC/NOEC
(mg/L)
No Data
9.2
3.5/0.94
(RA)
No Data
9.2
3.5/0.94
(RA)
No Data
9.2
3.5/0.94
(RA)
No Data
9.2
3.5/0.94
(RA)
9.2
3.5/0.94
No Data
9.2
3.5/0.94
(RA)
bold = measured data (i.e., derived from testing); 'Sponsor withdrew the ecotoxicity data in their revised test plan based on
earlier EPA comments about the inadequacy of the information; 2Data from published SIDS documents
http://www.chem.unep.ch/irptc/sids/OECDSIDS/11070443.pdf): toxicity should reflect hydrolysis products because the parent was stirred for > 1
hr; 3The sponsor proposed testing for this compound.
5_ References
Drexler, H., A. Weber, S. Letzel, G. Kraus, K. H. Schaller, and G. Lenhert. 1994. Detection and
clinical relevance of a type I allergy with occupational exposure to hexahydrophthalic anhydride
and methyltetrahydrophthalic anhydride. Int Arch Occup Environ Health 65 (5):279-83.
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September, 2009
Grammer, L. C., M. A. Shaughnessy, M. B. Hogan, S. M. Berggruen, D. M. Watkins, and P. R.
Yarnold. 1995. Value of antibody level in diagnosing anhydride-induced immunologic
respiratory disease. J Lab Clin Med 125 (5):650-3.
Nielsen, J., H. Welinder, H. Ottosson, I. Bensryd, P. Venge, and S. Skerfving. 1994. Nasal
challenge shows pathogenetic relevance of specific IgE serum antibodies for nasal symptoms
caused by hexahydrophthalic anhydride. Clin Exp Allergy 24 (5):440-9.
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