U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2012
SCREENING-LEVEL HAZARD CHARACTERIZATION
SPONSORED CHEMICAL
ar-Methylbenzenesulfonamide
(CASRN 1333-07-9)
SUPPORTING CHEMICALS
2-Methylbenzenesulfonamide (o-TSA)
(CASRN 88-19-7)
4-Methylbenzenesulfonamide (p-TSA)
(CASRN 70-55-3)
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 Setl1'2) 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
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.
4 European Chemicals Agency, http://echa.europa.eu.
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Medline/PubMed, Toxline, HSDB, IRIS, NTP, ATSDR, IARC, EXTOXNET, EPA SRS, etc.),
STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS,
Merck, etc.), Science Direct and ECHA4. 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
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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Chemical Abstract Service
Registry Number
(CASRN)
Sponsored Chemical
1333-07-9
Supporting Chemicals
88-19-7
70-55-3
Chemical Abstract Index
Name
Sponsored Chemical
Benzenesulfonamide, ar-methyl
Supporting Chemicals
Benzenesulfonamide, 2-methyl-
Benzenesulfonamide, 4-methyl-
Structural Formula
See Appendix I.
Summary
Benzenesulfonamide, ar-methyl- is a mixture of benzenesulfonamide, 2-methyl- (CASRN 88-19-
7) and benzenesulfonamide, 4-methyl- (CASRN 70-55-3), with current commercially available
forms having ortho/para ratios of 20/80 and 40/60. This mixture is a solid with low vapor
pressure and high water solubility. It is expected to have high mobility in soil. Neither isomer
was readily biodegradable using a standard OECD screening test, but a commercial mixture
containing approximately a 30/70 ortho/para ratio was inherently biodegradable after a short
acclimation period. Volatilization of benzenesulfonamide, ar-methyl- is low based on its
Henry's Law constant. The rate of hydrolysis is expected to be negligible. Measured
bioconcentration factors for one of the isomers suggest that bioconcentration in aquatic
organisms is low. The rate of atmospheric photooxidation is slow. Benzenesulfonamide, ar-
methyl- is expected to have low persistence (PI) and low bioaccumulation potential (B1).
The acute oral toxicity of the sponsored chemical, CASRN 1333-07-9, is low in rats. The
repeated dose toxicity of rats in an oral combined repeated-dose/reproductive toxicity study with
the supporting chemical, CASRN 88-19-7, resulted in clinical signs and effects on several
organs. The NOAEL is not established for repeated dose toxicity. In this same study,
reproductive findings of decreases in lactation and birth index were observed at the study's
highest dose. The NOAEL is not established for systemic toxicity and is 100 mg/kg-bw/day for
reproductive toxicity. A developmental toxicity study with the supporting chemical, CASRN 88-
19-7, resulted in decreases of birth index, number of pups alive on day 0 of lactation, and pup
weight, as well as maternal clinical signs and decreases in body weight parameters. The
NOAEL is 100 mg/kg-bw/day for developmental toxicity and 20 mg/kg-bw-day for maternal
toxicity. The sponsored chemical, CASRN 1333-07-9, is not mutagenic in vitro and the
supporting chemicals, CASRN 88-19-7 and CASRN 70-55-3, do not cause chromosomal
aberrations in vitro. The sponsored chemical, CASRN 133-07-9, is both a skin and eye irritant in
rabbit.
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The 96 hour LC50 of o, p-TSA for fish is 120 mg/L. The48 hour EC50 of o, p-TSA for aquatic
invertebrates is 1,000 mg/L. There were no adequate data provided to assess toxicity to aquatic
plants.
The toxicity to aquatic plants endpoint was identified as a data gap under the HPV Challenge
Program.
There are no health endpoint data gaps under the HPV Challenge Program.
On behalf of the sponsor, Day-Glo-Corporation, Akzo Nobel Services Inc. submitted a Test
Plan and Robust Summaries to EPA for ar-methylbenezenesulfonamide (o,p-
toluenesulfonamide; <\p-TSA) (CASRN 1333-07-9) on September 19,2008. EPA posted the
submission on the ChemRTK HPV Challenge website on October 20, 2008
rhttp://www.epa.gov/oppt/chemrtk/pubs/summaries/benzptsa/cl6748tc.htm'l. EPA comments on
the original submission were posted to the website on September 3, 2009. Public comments
were also received and posted to the website.
Justification for Supporting Chemicals
The sponsored chemical is a mixture of ortho- and para- isomers. Current commercially
available forms of the sponsored chemical have ortho-lpara- ratios of 20/80 and 40/60.
However, some data provided in this submission are for older commercial products that have
different ortho-lpara- ratios, such as Ketjenflex® 9 (ortho-lmeta-lpara- ratio 40/10/50) and
Santicizer® 9 (ortho-lpara- ratio 30/70). The slight difference in the ratios of isomers between
former and current commercial products is not expected to affect the toxicity based on the data
for the mixed and individual isomers presented. Additionally, the sponsor provided data for the
ortho- isomer, 2-methylbenzensulfonamide (CASRN 88-19-7) and the para- isomer, 4-
methylbenzenesulfonamide (CASRN 70-55-3) as supporting chemicals for the sponsored
mixture, o,p-TSA. Data from these isomers were used in conjunction with the original data for
the sponsored chemical for several human health endpoints. EPA considers that the use of data
on these substances is reasonable since the sponsored substance is a mixture of these two
chemicals. For the purpose of this hazard characterization, the ortho- and para- isomer mixtures
and the ortho-, meta- and para- isomer mixture represent the sponsored chemical, and the
supporting chemicals are the individual ortho- and para- isomers.
1. Chemical Identity
1.1 Identification and Purity
Purity of CASRN 1333-07-9, CASRN 70-55-3 or CASRN 88-19-7, if mentioned in the robust
summary and supporting documents, was noted to be > 99%.
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1.2 Physical-Chemical Properties
The physical-chemical properties of benzenesulfonamide, ar-methyl- are summarized in Table 1.
Benzenesulfonamide, ar-methyl- (CASRN 70-55-3) is a solid with low vapor pressure and high
water solubility. This substance is a mixture of ortho- and para-isomers (benzenesulfonamide, 2-
methyl- and benzenesulfonamide, 4-methyl-), with current commercially available forms having
ortho/para ratios of 20/80 and 40/60.
Table 1. Physical-Chemical Properties of Benzenesulfonamide, ar-methyl-1
Property
Value
CASRN
1333-07-9
Molecular Weight
171.22
Physical State
Solid
Melting Point
106°C (measured)2
Boiling Point
215°C at 10 mm Hg (measured)
>300°C (estimated)^
Vapor Pressure
<3x10"7 mm Hg at 22°C (measured)4
Dissociation Constant
(PKa)
10.17 (measured)5'6
Henry's Law Constant
4.7* 10"7 atm-m3/mole (estimated)7'8
Water Solubility
5xl03mg/L at25°C (measured)4
Log Kow
0.82-0.84 (measured)5'7
i Field Code Changed
'Day-Glo Color Corporation. 2008. Test Plan and Robust Summary for Benzenesulfonamide,
ar-methyl (o,p-TSA). Available online at
http://www.epa.gov/chemrtk/pubs/summaries/benzptsa/cl6748tc.htm as of July 9, 2012.
2This value represents the lowest melting point achieved for the mixture with an ortho/para ratio of 40/60.
^OMOS. 1987. Programs to Enhance PC-Gems Estimates of Physical Properties for Organic
Compounds. The
Mitre Corp.
^Measured for a commercial mixture Santicizer®9 (ortho/para ratio 30/70).
5SRC. 2012. The Physical Properties Database (PHYSPROP). Syracuse, NY: Syracuse
Research Corporation. Available online at http://www.svrres.com/esc/phvsprop.htm as of July
9,2012
6This value is a measured value for the para-isomer (CASRN 70-55-3) of the sponsored
chemical. This pKa indicates that this substance will exist as the neutral species in the
environment.
7Data and data ranges are based on the ortho- and para-isomers that comprise the mixture; see Appendix for
detailed information on the representative structures.
8U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10.
U.S. Environmental Protection Agency, Washington, DC, USA. Available online at
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of July 9, 2012.
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2. General Information on Exposure
2.1 Production Volume and Use Pattern
CASRN 1333-07-9 had an aggregated production and/or import volume in the United States
between 1 to 10 million pounds during calendar year 2005.
Industrial processing and uses for the chemical were claimed confidential. Intermediate for
pesticides and drugs; used in the production of resins & fluorescent pigments. Used in the
anodizing of aluminum products.
2.2 Environmental Exposure and Fate
The environmental fate properties of benzenesulfonamide, ar-methyl- are summarized in Table
2.
Benzenesulfonamide, ar-methyl- is expected to have high mobility in soil4 A commercial i Field Code changed
preparation of benzenesulfonamide, ar-methyl- (Santicizer®9 ortho/para ratio 30/70) achieved
13% degradation over the course of a 35-day incubation period using an acclimated, activated
sludge inoculum and a shake flask C02 evolution test (similar to OECD 30 IB) and is considered
not readily biodegradable. Neither isomer of this mixture was readily biodegradable when tested
using a standard OECD 301C screening test. The para isomer, benzenesulfonamide, 4-methyl-
(CASRN 70-55-3) achieved 3% of its theoretical biochemical oxygen demand after 28 days, and
the ortho isomer, benzenesulfonamide, 2-methyl- (CASRN 88-19-7) achieved 0% of its
theoretical BOD after 14 days using an activated sludge inoculum and the MITI (OECD 301C)
test. Using a semi-continuous activated sludge (SCAS) biodegradation test, a commercial
preparation of benzenesulfonamide, ar-methyl- degraded 92.9% as measured by dissolved
organic carbon (DOC) removal after 21 days using an activated sludge inoculum and is
considered inherently biodegradable. Volatilization of benzenesulfonamide, ar-methyl- is low
based on the Henry's Law constants of the two individual isomers. The rate of hydrolysis is
expected to be negligible. Bioconcentration factors (BCF) of 0.4-0.9 and 0.8-2.6 were measured
for carp exposed to benzenesulfonamide, 2-methyl- (CASRN 88-19-7) for 6 weeks at 3 and 0.3
mg/L, respectively. The rate of atmospheric photooxidation is slow. Benzenesulfonamide, ar-
methyl- is expected to have low persistence (PI) and low bioaccumulation potential (B1).
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Table 2. Environmental Fate Characteristics of Benzenesulfonamide, ar-methyl-1
Property
Value
CASRN
1333-07-9
Photodegradation Half-life
8.7 days (estimated)2'3
Hydrolysis Half-life
Stable
Biodegradation
13% after 35 days (not readily biodegradable; C02 evolution
similar to OECD 301B);
92.9% after 21 days (inherently biodegradable; SCAS OECD
302A);
3% after 28 days (not readily biodegradable, OECD301C)4'5;
0%) after 14 days (not readily biodegradable, OECD301C)5'6
Bioaccumulation Factor
BCF = 0.4-0.9 (measured in carp at 3 mg/L)5'6;
BCF = 0.8-2.6 (measured in carp at 0.3 mg/L)5'6
BAF =1.5 (estimated)2'3
Log Koc
1.9 (estimated)2'3
Fugacity
(Level III Model)2'3
Air (%)
Water (%)
Soil (%)
Sediment (%)
1.6-1.7
22.7-22.9
75.4-77.5
0.1-0.1
Persistence7
PI (low)
Bioaccumulation7
B1 (low)
'Day-Glo Color Corporation. 2008. Test Plan and Robust Summary for Benzenesulfonamide,
ar-methyl (o,p-TSA). Available online at
http://www.epa.gov/chemrtk/pubs/summaries/benzptsa/cl6748tc.htm as of July 9, 2012.
2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10.
U.S. Environmental Protection Agency, Washington, DC, USA. Available online at
http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of July 9, 2012.
3Data and data ranges are based on the ortho- and para-isomers that comprise the mixture; see Appendix for
detailed information on the representative structures.
4Data for the para isomer (CASRN 70-55-3).
5National Institute of Technology and Evaluation. 2002. Chemical Risk Information Platform (CHIRP). Available
online at http://www.safe.nite.go.jp/english/db.html as of July 6, 2012.
6Data for the ortho isomer (CASRN 88-19-7).
^Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical
Substances. Federal Register 64, Number 213 (November4,1999)pp. 60194-60204.
Conclusion: Benzenesulfonamide, ar-methyl- is a mixture of benzenesulfonamide, 2-methyl-
(CASRN 88-19-7) and benzenesulfonamide, 4-methyl- (CASRN 70-55-3), with current
commercially available forms having ortho/para ratios of 20/80 and 40/60. This mixture is a
solid with low vapor pressure and high water solubility. It is expected to have high mobility in
soil. Neither isomer was readily biodegradable using a standard OECD screening test, but a
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commercial mixture containing approximately a 30/70 ortho/para ratio was inherently
biodegradable after a short acclimation period. Volatilization of benzenesulfonamide, ar-methyl-
is low based on its Henry's Law constant. The rate of hydrolysis is expected to be negligible.
Measured bioconcentration factors for one of the isomers suggest that bio concentration in
aquatic organisms is low. The rate of atmospheric photooxidation is slow. Benzenesulfonamide,
ar-methyl- is expected to have low persistence (PI) and low bioaccumulation potential (Bl).
3. Human Health Hazard
A summary of health effects data submitted for SIDS endpoints is provided in Table 3.
Acute Oral Toxicity
o,p-TSA (CASRN1333-07-9), Sponsored Chemical
Sprague Dawley albino rats (5-6 animals/dose; variable number of each sex) were administered
<\p-TSA (as "Santicizer® 9") in a 25% corn oil suspension via gavage in four dose groups
(3000, 3500,4000 and 4500 mg/kg-bw). One out of five animals died in the two lowest dose
groups, four out of six animals died at 4000 mg/kg-bw, and all animals died in the high-dose
group. All deaths occurred within 48 hours of dosing. Additional details are from TSCATS
(OTS0545835).
LD5o = 3800 mg/kg-bw
o,m,p-TSA (CASRN 1333-07-9), Sponsored Chemical
Wistar rats (5/sex/dose) were administered o,m,p-TSA ( as "Ketjenflex® 9", 41:8:51 ortho-
/meta-/para- ratio) in corn oil via gavage at 1800, 2100 or 2400 mg/kg-bw and observed for 14
days following dosing. Five out of 10 animals in the high-dose group died within 3 days of
dosing.
LD50 = 2400 mg/kg-bw
Repeated-Dose Toxicity
p-TSA (CASRN 70-55-3), Supporting Chemical
In a combined repeated-dose/reproductive/developmental toxicity screening test, Crj:CD(SD)
rats (13/sex/dose) were administered/>-TSA in 5% gum Arabic solution via oral gavage at doses
of 0, 120, 300 or 750 mg/kg-bw/day for 42 days (males) or from 14 days before mating to day 3
of lactation (females). For more information on this study, see OECD SIDS report at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL = 120 mg/kg-bw/day (based upon the thickened urinary bladder epithelium at the
lowest dose tested)
NOAEL = Not established
o-TSA (CASRN 88-19-7), Supporting Chemical
In a combined repeated-dose/reproductive/developmental toxicity screening test, Crj:CD(IGS)
rats (13/sex/dose) were administered o-TSA in 5% sodium carboxylmethyl cellulose (CMC Na)
via oral gavage at 0, 20,100 or 500 mg/kg-bw/day for 42 days (males) and for 14 days prior to
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mating to day 3 of lactation (females). For more information on this study, see OECD SIDS
report at: http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL = 20 mg/kg-bw/day (based upon clinical signs, and effects on liver, kidneys, heart,
spleen, and thymus)
NOAEL = Not established
Reproductive Toxicity
p-TSA (CASRN 70-55-3), Supporting Chemical
Findings on reproductive effects observed in the rat combined repeated-
dose/reproductive/developmental toxicity screening test described previously, at doses of 0, 120,
300 or 750 mg/kg-bw/day are described in OECD SIDS report at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL (reproductive toxicity) = 750 mg/kg-bw/day (based upon difficult labor and
decreased lactation index)
NOAEL (reproductive toxicity) = 300 mg/kg-bw/day
LOAEL (systemic toxicity) = 120 mg/kg-bw/day (based upon thickened urinary bladder
epithelium)
NOAEL (systemic toxicity) = Not established
o-TSA (CASRN 88-19-7), Supporting Chemical
In the rat combined repeated-dose/reproductive/developmental toxicity screening test described
previously, there were no effects on copulation, ovulation and fertility, or delivery at doses of 0,
20, 100, and 500 mg/kg-bw/day. For more information on this study, see OECD SIDS report at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL (reproductive toxicity) = 500 mg/kg-bw/day (based on slight decreases in lactation
and birth index)
NOAEL (reproductive toxicity) = 100 mg/kg-bw/day
LOAEL (systemic toxicity) = 20 mg/kg-bw/day (based upon clinical signs, and effects on liver,
kidneys, heart, spleen, and thymus)
NOAEL (systemic toxicity) = Not established
Developmental Toxicity
p-TSA (CASRN 70-55-3), Supporting Chemical
Developmental findings on the rat combined repeated-dose/reproductive/developmental toxicity
screening test described previously, in which animals were dosed with 0,120, 300 or 750 mg/kg-
bw/day are described in OECD SIDS report at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL (developmental toxicity) = 750mg/kg-bw/day (based upon decreased lactation index,
viability rate and bodyweights)
NOAEL (developmental toxicity) = 300mg/kg-bw/day
LOAEL (maternal toxicity) = 120 mg/kg-bw/day (based upon the thickened urinary bladder
epithelium)
NOAEL (maternal toxicity) = Not established
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o-TSA (CASRN 88-19-7), Supporting Chemical
Findings on the rat combined repeated-dose/reproductive/developmental toxicity screening test
described previously in which animals were dosed by oral gavage to the supporting chemical
with 0,20,100 and 500 mg/kg-bw/day are described in OECD SIDS report at:
http://www.chem.unep.ch/irptc/sids/OECDSIDS/sidspub.html.
LOAEL (developmental toxicity) = 500 mg/kg-bw/day (based on decreased birth index,
number of pups alive on day 0 of lactation, and pup weight)
NOAEL (developmental toxicity) = 100 mg/kg-bw/day
LOAEL (maternal toxicity) = 100 mg/kg-bw/day (based upon clinical signs and body weights)
NOAEL (maternal toxicity) = 20 mg/kg-bw/day
Genetic Toxicity - Gene Mutation
In vitro
o,m,p-TSA (CASRN 1333-07-9), Sponsored Chemical
Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, TA100 and Saccharomyces
D4 strain were exposed to o,m,p-TSA ("Ketjenflex® 9R", 40:10:50 ortho-/meta-/para- ratio) in
DMSO at concentrations of 0 (solvent control), 1, 10, 100, 500 or 1000 (ig/plate with or without
metabolic activation. There were no increases in the number of revertants with or without
metabolic activation. Positive controls were tested concurrently and responded appropriately.
Cytotoxic concentrations were not specified.
o,m,p-TSA was not mutagenic in this assay.
o,p-TSA (CASRN 1333-07-9), Sponsored Chemical
Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, TA100 and Saccharomyces
D4 strain were exposed to o,/>-TSA ('Santicizer® 9E',~ 30:70 ortho-/para- ratio) in DMSO at
concentrations of 0 (solvent control), 0.5, 5, 50 or 250 (ig/plate. There were no increases in the
number of revertants with or without metabolic activation. Positive controls were tested
concurrently and responded appropriately. Cytotoxic concentrations were not specified.
0,/>-TSA was not mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberrations
In vitro
p-TSA (CASRN 70-55-3), Supporting Chemical
Chinese hamster lung Cells (CHL) were exposed to />-TSA in DMSO at concentrations 0
(solvent control), 0.33, 0.65 or 1.3 mg/mL without activation (continuous treatment for 24 and
48 hours), or 0 (solvent control), 0.43, 0.85 or 1.7 mg/mL with and without activation (6-hour
treatment and 18 hours of culturing). Positive controls were tested concurrently and responded
appropriately. Cytotoxicity was observed at concentrations >1.7 mg/mL with activation and >
1.3 mg/mL without activation.
p-TSA did not induce chromosomal aberrations in this assay.
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o-TSA (CASRN 88-19-7), Supporting Chemical
CHL cells were exposed to o-TSA in DMSO at concentrations 0 (solvent control), 375, 750,
1500,2250 or 3000 ng/mL without activation (continuous treatment for 24 and 48 hours) and 0
(solvent control), 375, 750,1500 or 3000 ng/mL with and without activation (6-hour treatment
and 18 hours of culturing). Positive controls were tested concurrently and responded
appropriately. Cytotoxicity was observed at 2250 ng/mL with continuous treatment and no
cytotoxicity was observed with the short-term treatments with or without activation.
o-TSA did not induce chromosomal aberrations in this assay.
Additional Information
Skin Irritation
o,m,p-TSA (CASRN 1333-07-9), Sponsored Chemical
o,m,p-TSA ("Ketjenflex® 9R"), 40:10:50 ortho-/meta-/para- ratio, 0.5 el was applied to the
skin, intact and abraded, of New Zealand White albino rabbits (6/sex/dose). Patches remained
in place for 24 hours and the application site was observed 72 hours following patch removal.
Slight erythema was noted at both intact and abraded application sites.
o,m,p-TSA was irritating to rabbit skin in this assay.
Eye Irritation
o,m,p-TSA (CASRN 1333-07-9), Sponsored Chemical
o,m,p-TSA ("Ketjenflex® 9R", 40:10:50 ortho-/meta-/para- ratio; 100 mg) was instilled into the
everted lower lid of one eye of each of six New Zealand White rabbits (sex not specified) and
washed 24 hours after instillation. Animals were observed up to 7 days following instillation.
The test article caused slight corneal and iridal effects and redness and chemosis.
o,m,p-TSA was irritating rabbit eyes in this study.
Conclusion: The acute oral toxicity of the sponsored chemical, CASRN 1333-07-9, is low in
rats. The repeated dose toxicity of rats in an oral combined repeated-dose/reproductive toxicity
study with the supporting chemical, CASRN 88-19-7, resulted in clinical signs and effects on
several organs. The NOAEL is not established for repeated dose toxicity. In this same study,
reproductive findings of decreases in lactation and birth index were observed at the study's
highest dose. The NOAEL is not established for systemic toxicity and is 100 mg/kg-bw/day for
reproductive toxicity. A developmental toxicity study with the supporting chemical, CASRN 88-
19-7, resulted in decreases of birth index, number of pups alive on day 0 of lactation, and pup
weight, as well as maternal clinical signs and decreases in body weight parameters. The
NOAEL is 100 mg/kg-bw/day for developmental toxicity and 20 mg/kg-bw-day for maternal
toxicity. The sponsored chemical, CASRN 1333-07-9, is not mutagenic in vitro and the
supporting chemicals, CASRN 88-19-7 and CASRN 70-55-3, do not cause chromosomal
aberrations in vitro. The sponsored chemical, CASRN 133-07-9, is both a skin and eye irritant in
rabbit.
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Table 3. Summary of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program - Human Health Data
Endpoints
SPONSORED
CHEMICAL
«,/;-TSA;
o,m,p-TSA
(CASRN 1333-07-9)
SUPPORTING
CHEMICAL
«-TSA
(CASRN 88-19-7)
SUPPORTING
CHEMICAL
p-JSA
(CASRN 70-55-3)
Acute Oral Toxicity
LD50 (mg/kg-bw)
2400
-
-
Repeated-Dose
Toxicity
NOAEL/LOAEL
Oral (mg/kg-
bw/day)
No Data
NOAEL = not
established
LOAEL = 20
(RA)
NOAEL = not
established
LOAEL = 20
NOAEL = not
established
LOAEL = 120
Reproductive
Toxicity
NOAEL/LOAEL
Oral (mg/kg-
bw/day)
Systemic Toxicity
No Data
NOAEL = not
established
LOAEL = 20
NOAEL = not
established
LOAEL = 20
NOAEL = not
established
LOAEL = 120
Reproductive
Toxicity
NOAEL = 100
LOAEL = 500
(RA)
NOAEL = 100
LOAEL = 500
NOAEL = 300
LOAEL = 750
12
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U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2012
Table 3. Summary of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program - Human Health Data
Endpoints
SPONSORED
CHEMICAL
<>,/;-TSA;
o,m,p-TSA
(CASRN 1333-07-9)
SUPPORTING
CHEMICAL
o-TSA
(CASRN 88-19-7)
SUPPORTING
CHEMICAL
p-TSA
(CASRN 70-55-3)
Developmental
Toxicity
Oral Diet (mg/kg-
bw/day)
No Data
Maternal Toxicity
NOAEL = 20
LOAEL = 100
NOAEL = 20
LOAEL = 100
NOAEL = not
established
LOAEL = 120
Developmental
Toxicity
NOAEL = 100
LOAEL 500
(RA)
NOAEL = 100
LOAEL 500
NOAEL = 300
LOAEL = 750
Genetic Toxicity -
Gene Mutations in
vitro
Negative
-
-
Genetic Toxicity -
Chromosomal
Aberrations
in vitro
No Data
Negative
(RA)
Negative
Negative
Additional
Information:
Skin Irritation
Irritating
-
-
Eye Irritation
Irritating
-
-
13
-------
U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2012
4. Hazard to the Environment
A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4.
Acute Toxicity to Fish
o,p-TSA (CASRN1333-07-9)
(1) Rainbow trout (Salmo gairdneri) were exposed to <\p-TSA (Santicizer® 9, -30:70 ortho-
Ipara- ratio; > 95% purity) at nominal concentrations of 56, 100, 180, 320 and 560 mg/L under
static conditions for 96 hours. Analytical monitoring was not conducted. A positive control
(Antimycin A) was tested concurrently. Percent mortality at 96 hours was 0, 0,20, 100, 100 and
100 for the control, 56, 100, 180, 320 and 560 mg/L groups, respectively.
96-h LCso = 120 mg/L
(2) Bluegill Sunfish (Lepomis macrochirus) were exposed to <\p-TSA (Santicizer® 9, ~ 30:70
ortho-lpara- ratio; > 95% purity) atnominal concentrations of 56,100,180, 320 and 560 mg/L
under static conditions for 96 hours. Analytical monitoring was not conducted. A positive
control (Antimycin A) was tested concurrently. Percent mortality at 96 hours was 0, 0, 0, 0, 90
and 100 for the control, 56,100,180, 320 and 560 mg/L groups, respectively. The no-effect
concentration was 56 mg/L. An oily film was noted in the two highest concentrations.
96-h LCso = 260 mg/L
Acute Toxicity to Aquatic Invertebrates
o,p-TSA (CASRN 1333-07-9)
Daphnia magna were exposed to <\p-TSA (Santicizer® 9, ~ 30:70 ortho-lpara- ratio; purity not
provided) in dimethylformamide (DMF) at nominal concentrations of 1000 mg/L under static
conditions for 48 hours. Analytical monitoring was not conducted. A negative control (dilution
water and 1 mL/L of DMF) was tested concurrently. 48-h EC50 > 1,000 mg/L
Toxicity to Aquatic Plants
No adequate data were provided.
Conclusion:
The 96 hour LC50 of o, p-TSA for fish is 120 mg/L. The48 hour EC50 of o, p-TSA for aquatic
invertebrates is 1,000 mg/L. There were no adequate data provided to assess toxicity to aquatic
plants.
The toxicity to aquatic plants endpoint was identified as a data gap under the HPV Challenge
Program.
14
-------
U.S. Environmental Protection Agency
Hazard Characterization Document
December, 2012
Table 4. Summar\ Table of llic Scrivniii" 1 nl'<>rm;ilion l);il;i Sii
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED
SUPPORTING
SUPPORTING
CHEMICAL
CHEMICAL
CHEMICAL
«,/>-TSA; o,m,p-TSA
o-TSA
p-TSA
(1333-07-9)
(88-19-7)
(70-55-3)
Summary of Environmental Effects - Aquatic Toxicity Data
Fish
-
-
96-h LCS„ (mg/L)
120
Aquatic Invertebrates
-
-
48-h ECS„ (mg/L)
>1000
Aquatic Plants
No data
-
-
72-h ECS„ (mg/L)
Bold = indicates experimental data were provided.
APPENDIX
Sponsored Chemical
Chemical Name
CASRN
Representative Structure1
Benzenesulfonamide,
1333-07-9
ar-methyl-
/ \ O
f>f=0
NH2
ch3
SMILES: 0=S(=0)(N)c(c(cccl )C)cl
/ v o
/^\ "
H,C—(' N>—S=0
nh2
SMILES: 0=S(=0)(N)c(ccc(cl )C)cl
Benzenesulfonamide, ar-methyl- is a mixture of ortho- and para-isomers, with current
commercially available forms having ortho/para ratios of 20/80 and 40/60.
15
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