U.S. Environmental Protection Agency
Hazard Characterization Document
September, 2009
SCREENING-LEVEL HAZARD CHARACTERIZATION
SPONSORED CHEMICALS
Phenolic Benzotriazoles Category
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
2-(2'-Hydroxy-5'-octylphenyl) benzotriazole (CASRN 3147-75-9)
2-(2'-Hydroxy-3',5,-di-t-amylphenyl) benzotriazole (CASRN 25973-55-1)
2-(2H-Benzotriazol-2-yl)-4,6-bis(l-methyl-l-phenylethyl) phenol
(CASRN 70321-86-7)
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
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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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
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
Registry Number
(CASRN)
CASRN 2440-22-4, CASRN 3147-75-9, CASRN 25973-55-1,
CASRN 70321-86-7
Chemical Abstract Index
Name
Phenol, 2-(2H-benzotriazol-2-yl)-4-methyl-,
Phenol, 2-(2H-benzotriazol-2-yl)-4-( 1,1,3,3-tetramethylbutyl)-
Phenol, 2-(2H-benzotriazol-2-yl)-4,6-bis(l,l-dimethylpropyl)-
Phenol, 2-(2H-benzotriazol-2-yl)-4,6-bis(l-methyl-l-
phenylethyl)-
Structural Formula
See Section 1.1
Summary
Phenolic benzotriazoles are solids with low water solubilities and low to negligible vapor
pressures. They are expected to have low mobility in soil. Volatilization of phenolic
benzotriazoles is considered low based on their Henry's Law constant. The rate of hydrolysis of
phenolic benzotriazoles cannot be measured due to a lack of water solubility; however the
chemical structure of these compounds suggests that hydrolysis is likely to be negligible under
environmental conditions. The rate of atmospheric photooxidation is considered rapid for
CASRN 2440-22-4 and CASRN 70321-86-7, and moderate for CASRN 3147-75-9 and CASRN
25973-55-1. CASRN 2440-22-4 is expected to have low bioaccumulation potential (Bl),
CASRN 3147-75-9 and CASRN 25973-55-1 are expected to have high bioaccumulation
potential (B3) and CASRN 70321-86-7 is expected to have moderate bioaccumulation potential
(B2). However, the relatively low solubility of these compounds may attenuate bioconcentration
and bioaccumulation. All four compounds contained in the phenolic benzotriazoles derivatives
category are expected to have high persistence (P3), although the phenolic portion of the
chemicals resembles many antioxidant phenols which may suggest that that portion of the
molecule could oxidize.
The acute toxicity of phenolic benzotriazoles is low in rats via the oral, route for all category
members. CASRN 2440-22-4 was not irritating to rodent skin and slightly irritating to rabbit
eyes. CASRN 2440-22-4 was extremely sensitizing when tested on guinea pigs; however, there
was no sensitization or irritation when tested on human volunteers. Following repeated oral
exposure of rats to CASRN 2440-22-4 for 90 days, there were liver and kidney effects at 500
mg/kg-day and above; the NOAEL for systemic toxicity was 100 mg/kg-day. No effects were
reported for rats administered CASRN 3147-75-9 in the diet for 30 days, with a NOAEL of 5658
mg/kg-day for systemic toxicity. There were blood, liver and kidney effects in rats administered
40 mg/kg-day of CASRN 25973-55-1 in the diet; the NOAEL for systemic toxicity was 20
mg/kg-day. There were liver effects in rats administered 15 mg/kg-day of CASRN 70321-86-7;
the NOAEL for systemic toxicity was 2.5 mg/kg-day. There are no specific reproductive toxicity
studies. No significant effects on reproductive organs were reported following repeated dietary
exposures of rats to two category members (CASRN 2440-22-4 and 70321-86-7). Mice and
dogs exposed to CASRN 2440-22-4 in dietary studies also showed no significant effects on	
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reproductive organs. However, effects on reproductive organs were seen following repeated
dietary exposures of dogs to CASRN 25973-55-1. A dominant lethal assay showed no male
reproductive toxicity in rats treated with CASRN 2440-22-4. In an oral prenatal developmental
toxicity study, CASRN 2440-22-4 showed no developmental toxicity in rats and mice; the
NOAEL was 1000 mg/kg-day. CASRN 70321-86-7 caused reduced pup weight and delays in
skeletal maturation at 1000 mg/kg-day; the NOAEL for developmental toxicity is 300 mg/kg-
day. The category members did not induce gene mutations in bacterial tests in vitro and did not
induce chromosomal aberration when tested in vivo. Long-term studies for CASRN 2440-22-4
showed no evidence of carcinogenicity in rats or mice.
The acute hazard of the phenolic benzotriazoles category to fish, aquatic invertebrates and plants
is considered to be > 0.17 mg/L.
No data gaps were identified under the HPV Challenge Program.	
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The sponsor, The Phenolic Benzotriazoles Association (Ciba Specialty Chemicals Corporation
and Cytec Industries, Inc.), submitted a Test Plan and Robust Summaries to EPA for the phenolic
benzotriazoles category on October 26, 2001. EPA posted the submission on the ChemRTK
HPV Challenge website on December 4, 2001
(http://www.epa.gov/chemrtk/pubs/summaries/phenbenz/cl3266tc.htm). EPA comments on the
original submission were posted to the website on June 19, 2002. Public comments were also
received and posted to the website.
The sponsor provided EPA with a response to comments on December 20, 2002 and submitted
revised documents February 18, 2004, which were posted to the ChemRTK website on August 7,
2003 and April 7, 2004, respectively. The phenolic benzotriazoles category consists of the
following four chemicals:
Sponsored Chemicals
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole	CASRN 2440-22-4
2-(2'-Hydroxy-5'-octylphenyl) benzotriazole	CASRN 3147-75-9
2-(2'-Hydroxy-3',5'-di-^-amylphenyl) benzotriazole	CASRN 25973-55-1
2-(2H-Benzotriazol-2-yl)-4,6-bis(l-methyl-1-phenylethyl) phenol	CASRN 70321-86-7
Category Justification
The four members of the phenolic benzotriazoles category have the identical molecular base
structure of a benzotriazole group. They also have in common a phenolic group attached to the
benzotriazole structure at the same location but the substituents (R1 and R2) on the phenolic
group vary.
HO r
I r n-% ;>
X
The submitter's primary justification for the category is twofold: (1) the similarity of the
structural backbone of all members (phenolic benzotriazoles), and (2) the similar or regular
pattern of the chemical, physical and toxicological properties of the members. The Agency
concluded that the submitter adequately supports the grouping of the category members with the
information provided the HPV Challenge Program.
Existing mammalian and ecotoxicity data for two of the members (CASRNs 2440-22-4 and
70321-86-7) are extrapolated to the other two members of the category. No specific
reproductive toxicity test data were available for any of the chemicals in the category. In
accordance with HPV Challenge Program guidance, EPA concluded that histological evaluation
of reproductive organs from the available 90-day and longer repeated-dose toxicity studies
address the reproductive toxicity endpoint.
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1 Chemical Identity
1.1 Identification and Purity
Table 1. Sponsored Chemicals
The sponsor did not discuss purity of the chemicals in this category in the Test Plan
1.2 Physical-Chemical Properties
The physical-chemical properties of phenolic benzotriazoles are summarized in Table 2.
Phenolic benzotriazoles are solids with low water solubilities and low to negligible vapor
pressures.
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Table 2. Physical-Chemical Properties of Phenolic Benzotriazoles1
Property
2-(2'-Hydroxy-5'-
methylphenyl)
benzotriazole
2-(2'-Hydroxy-5'-
octylphenyl)
benzotriazole
2-(2'-Hydroxy-3',5'-
di-f-amylphenyl)
benzotriazole
2-(2H-Benzotriazol-
2-yl)-4,6-bis(l-
methyl-1-
phenylethyl) phenol
CASRN
2440-22-4
3147-75-9
25973-55-1
70321-86-7
Molecular Weight
225.25
323.44
351.50
447.58
Physical State
Solid
Solid
Solid
Solid
Melting Point
131-133°C
(measured)
106-108°C
(measured)
80-83°C (measured)
139-143°C
(measured)
Boiling Point
358°C (measured)3
454.6°C (estimated)2
477.8°C (estimated)
599.8°C (estimated)
Vapor Pressure
1.9><10"6mmHg at
25°C (estimated)2
9.8><10"9mmHg
(estimated)2
4.3xlO"9mmHg
(estimated)2
4.18xl013mmHg
(estimated)2
Water Solubility
0.173 mg/L at 20°C
(measured)
<1 mg/L (measured);
0.274 mg/L
(estimated)2
0.042 mg/L at 25°C
(estimated)2
<0.04 mg/L at 20°C
(measured);
0.0031 mg/L
(estimated)2
Dissociation
Constant (pKa)
Not applicable
Not applicable
Not applicable
Not applicable
Henry's Law
6.2><10"14atm-
4.45xl013atm-
6.52xl013atm-
1.37xl0"15atm-
Constant
m3/mole (estimated)2
m3/mole (estimated)2
m3/mole (estimated)2
m3/mole (estimated)2
Log Kow
4.2 (measured)
6.2 (estimated)
7.3 (estimated)
>6.5 (measured);
7.7 2 (estimated)
1	Ciba Specialty Chemicals Corp and Cytec Industries, Inc. February 24, 2004. Revised Robust Summary for
Phenolic Benzotriazoles Category. http://www.epa.gov/HPV/pubs/summaries/phenbenz/cl3266tc.htm.
2U.S. EPA. 2008. Estimation Programs Interface Suite™ for Microsoft® Windows, v 3.20. United States
Environmental Protection Agency, Washington, DC, USA entering measured data where applicable.
http://www.epa.gov/opptintr/exposure/pubs/episuite.htm.
3Measured value is 225°C at 10 mm Hg which NOM05 (PC Nomograph program) converts to 358°C at 760 mm
Hg.
2	General Information on Exposure
2.1 Production Volume and Use Pattern
During calendar year 2005, the four chemicals in the phenolic benzotriazoles category had an
aggregated production and/or import volume in the United States of 3.5 million to 31 million
pounds (500 to 1 million pounds for CSRN 2440-22-4 and 1 to 10 million pounds for each of the
other chemicals in the category).
Information in the IUR indicated that the industrial processing and uses and some
commercial/consumer uses for these chemicals were claimed confidential. Non-confidential
information in the IUR indicated that the industrial processing and use of CASRN 3147-75-9
includes surface active agents in a variety of industries. Non-confidential information in the IUR
indicated that the commercial/consumer use categories containing the chemicals include paints
and coatings (CASRN 25973-55-1), rubber and plastic products (CASRN 3147-75-9), and
electrical and electronic products (CASRN 3147-75-9). The HPV submission for the phenolic
benzotriazoles category states that the chemicals are primarily used as industrial additives for a
variety of polymers and in light-stabilized coatings. All four phenolic benzotriazoles category
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chemicals have been cleared by the FDA for use in food contact polymers and adhesives or
antioxidants and stabilizers.
2.2 Environmental Exposure and Fate
No quantitative information is available on releases of these chemicals to the environment.
Phenolic benzotriazoles are expected to have low mobility in soil. The rate of biodegradation is
considered slow based on the results of ready biodegradation tests. The rate of volatilization of
phenolic benzotriazoles from water and moist soil is considered low based on their estimated
Henry's Law constants. The rate of hydrolysis is considered negligible under environmental
conditions. CASRN 2440-22-4 is expected to have low bioaccumulation potential (Bl), CASRN
3147-75-9 and CASRN 25973-55-1 are expected to have high bioaccumulation potential (B3)
and CASRN 70321-86-7 is expected to have moderate bioaccumulation potential (B2).
However, the relatively low solubility of these compounds may limit their potential for
bioconcentration and bioaccumulation. Phenolic benzotriazoles are expected to have high
potential for persistence (P3) as indicated by low percent degradation in ready biodegradation
tests. However, the phenolic portion of the chemicals resembles many antioxidant phenols
which may suggest that that portion of the molecule could oxidize. The environmental fate
characteristics of phenolic benzotriazoles are summarized in Table 3.
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Table 2
Environmental Fate Characteristics of Phenolic Benzotriazoles1
Property
2-(2'-Hydroxy-5'-
methylphenyl)
benzotriazole
2-(2'-Hydroxy-5'-
octylphenyl)
benzotriazole
2-(2'-Hydroxy-3',5'-
di-f-amylphenyl)
benzotriazole
2-(2H-Benzotriazol-2-
yl)-4,6-bis(l-methyl-l-
phenylethyl) phenol
Photodegradation
Half-life
1.39 hours (estimated)
4.02 hours (estimated)
8.1 hours (estimated)
1.06 hours (estimated)
Hydrolysis Half-life
Could not be
determined due to low
water solubility
Cannot be determined
due to low water
solubility
Cannot be determined
due to low water
solubility
Cannot be determined
due to low water
solubility
Biodegradation
0-2% after 28 days
(not readily
biodegradable)2
0-1% after 28 days
(not readily
biodegradable)2
2-8% after 28 days
(not readily
biodegradable)2
3-8% after 28 days
(not readily
biodegradable)2
Bioconcentration
BCF = 123-494 (carp;
1,000 ng/L);
BCF = 130-295 (carp;
100 ng/L);
BCF = 44-220 (carp;
10 |ig/L) (measured)5
BCF = 1.21xl04
(estimated)3
BCF = 1.04xl04
(estimated)3
BCF = 2,755
(estimated)3
Log Koc
5.0 (estimated)3
6.6 (estimated)3
7.1 (estimated)3
9.3 (estimated)3
Fugacity
(Level III Model)
Air (%)
Water (%)
Soil (%)
Sediment (%)
3.1
4.9
87.3
4.6
4.0xl0"5
3.5
44.6
51.9
2.3xl0"4
2.2
40.4
57.5
0.0
2.2
40.1
57.7
Persistence4
P3 (high)
P3 (high)
P3 (high)
P3 (high)
Bioaccumulation4
Bl (low)
B3 (high)
B3 (high)
B2 (moderate)
1 Ciba Specialty Chemicals Corp and Cytec Industries, Inc. February 24, 2004. Revised Robust Summary for
Phenolic Benzotriazoles Category. http://www.epa.gov/HPV/pubs/summaries/phenbenz/cl3266tc.htm.
2Ciba Specialty Chemicals Corp and Cytec Industries, Inc. October 29, 2001. Robust Summary for Phenolic
Benzotriazoles Category, http://www.epa.gov/chemrtk/pubs/summaries/phenbenz/cl3266tp.pdf
3U.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.
4Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal
Register 64, Number 213 (November 4, 1999) pp. 60194-60204.
5National Institute of Technology and Evaluation. 2002. Biodegradation and Bioconcentration of Existing
Chemical Substances under the Chemical Substances Control Law.
http://www.safe.nite.go.ip/english/kizon/KIZON start hazkizon.html.
Conclusion: Phenolic benzotriazoles are solids with low water solubilities and low to negligible
vapor pressures. They are expected to have low mobility in soil. Volatilization of phenolic
benzotriazoles is considered low based on their Henry's Law constant. The rate of hydrolysis of
phenolic benzotriazoles cannot be measured due to a lack of water solubility; however the
chemical structure of these compounds suggests that hydrolysis is likely to be negligible under
environmental conditions. The rate of atmospheric photooxidation is considered rapid for
CASRN 2440-22-4 and CASRN 70321-86-7, and moderate for CASRN 3147-75-9 and CASRN
25973-55-1. CASRN 2440-22-4 is expected to have low bioaccumulation potential (Bl),
CASRN 3147-75-9 and CASRN 25973-55-1 are expected to have high bioaccumulation
potential (B3) and CASRN 70321-86-7 is expected to have moderate bioaccumulation potential
(B2). However, the relatively low solubility of these compounds may attenuate bioconcentration
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and bioaccumulation. All four compounds contained in the phenolic benzotriazoles derivatives
category are expected to have high persistence (P3), although the phenolic portion of the
chemicals resembles many antioxidant phenols which may suggest that that portion of the
molecule could oxidize.
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
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
Tif Ralf (SPF) rats (5/sex/dose) were administered the test substance (suspended in PEG 400) via
gavage at 4640, 7750 and 10,000 mg/kg-bw and observed for 14 days. Two females in the
10,000 mg/kg-bw group died within the first 7 days. No treatment-related effects were observed
at necropsy.
LD50 > 10,000 mg/kg-bw
2-(2'-Hydroxy-5'octylphenyl) benzotriazole (CASRN3147-75-9)
Male Wistar rats (20/dose) were administered an aqueous suspension of test substance at 125,
250, 500 and 1000 mg/kg-bw via gavage at and observed for 14 days. No mortality was
observed.
LD50 > 1000 mg/kg-bw
2-(2'-Hydroxy-3,5-di-tert-amylphenyl) benzotriazole (CASRN25973-55-1)
Tif Ralf (SPF) rats (5/sex/dose) were administered the test substance (30% suspension in PEG
400) via gavage at 1392, 1800 and 2325 mg/kg-bw and observed for 14 days. No deaths
occurred during the 14-day test period. No treatment-related effects were observed at necropsy.
LD50 > 2325 mg/kg-bw
2-(2H-Benzotrialzol-2-yl)-4,6-bis(l-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
Tif Ralf (SPF) rats (5/sex/dose) were administered the test substance (suspension in PEG 400)
via gavage at 1000, 2150, 4640 and 7750 mg/kg-bw and observed for 14 days. No mortality
occurred. No treatment-related effects were observed at necropsy.
LD50 >7750 mg/kg-bw
Acute Inhalation Toxicity
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
Charles River rats (5/sex) were administered the test substance via air-dust mixture at 1420
mg/m3 (1.42 mg/L) for 4 hours and observed for 14 days following treatment. No deaths
occurred within 14 days. No test substance-related effects were noted.
LC50 > 1420 mg/m3 (1.42 mg/L)
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Acute Dermal Toxicity
2-(2H-Benzotrialzol-2-yl)-4,6-bis(l-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
Albino rats (5/sex/dose) were exposed to the test substance dermally under a semi-occlusive
dressing for 24 hours. Following removal of the dressing at 24 hoursand cleaning of the
application site, the rats were observed for 14 days. No mortalities occurred during this study.
Necropsy examination did not reveal any gross pathologic alterations.
LD50 > 2000 mg/kg-bw
Repeated-Dose Toxicity
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
(1)	Beagle dogs (6/sex/group) were administered the test substance in their diet at 1000, 3000 or
10,000 ppm for 13 weeks (corresponding to approximately 32, 96, and 320 mg/kg-bw/day for
males and 35, 105, and 350 mg/kg-bw/day for females). After exposure to the test material for 3
months, one animal per dose group was fed a control diet for a recovery period of 1 month. No
mortality and no local or systemic toxicity was reported. At 10,000 ppm, a decrease in body
weight gain and food consumption was reported (magnitude of change and significance not
reported). One female animal from the 10,000 ppm group was emaciated. Only enzyme level
changes are reported; alanine aminotransferase activity was increased in the 3000 and 10,000
ppm groups and gamma glutamyl transpeptidase activity was increased in the 10,000 ppm group.
Male and female reproductive organs were evaluated. No effects were seen on male
reproductive organs. Absolute ovary weights were decreased at all doses (significance not
stated); however, there were no histopathological changes related to treatment. The robust
summary concludes that there were no treatment-related gross or histopathological changes.
LOAEL -320 mg/kg-bw/day (based on decreased body weight)
NOAEL ~ 96 mg/kg-bw/day
(2)	Wistar rats (10/sex/dose) were administered the test substance via the diet at 0, 0.2, 1, or 5%
(approximately 0, 100, 500 or 2500 mg/kg-bw/day) for 90 days. There was no effect on
mortality. Body weight gain and food consumption were only decreased in the first 2 weeks of
the study in animals fed the 1 and 5% diet. No differences in body weight were observed in the
later part of the study. At the 5% level there was a decreased number of erythrocytes and
increased number of leukocytes in male rats (0.05 > P > 0.01). Relative liver weights were
significantly increased in both males and females fed both 1 and 5% diets (P < 0.01). Relative
kidney weights were increased significantly in both males and females fed the 5%diet. Relative
spleen weights were increased significantly in high-dose females (0.05 > P > 0.01) and testes
weights were decreased in 1 and 5% diet males (0.05 > P > 0.01). Distinct histopathological
changes were seen in the kidneys of both male and female rats and liver of 2 high dose males.
LOAEL ~ 500 mg/kg-bw/day (based on liver and kidney effects)
NOAEL ~ 100 mg/kg-bw/day
Source: TSCATS, Doc#:88-920002920
2-(2'-Hydroxy-5'-octylphenyl) benzotriazole (CASRN3147-75-9)
Wistar rats (5/sex/group) were administered the test substance via the diet at 0, 1.25, 2.5 and 5%
(corresponding to 0, 1286, 2594 and 5658 mg/kg-bw/day) for 30 days. There were no deaths and
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no effect on body weight or food consumption during the test period. Hydronephrosis was noted
in the high dose (four animals) and control (three animals) groups. The robust summary states
this effect is common in this strain of rats. No lesions were noted that were attributable to
ingestion of the test substance.
NOAEL = 5658 mg/kg-bw/day (highest dose tested)
2-(2'-Hydroxy-3',5'-di-t-amylphenyl) benzotriazole (CASRN25973-55-1)
(1)	Beagle dogs (3/sex/group) were administered the test substance via the diet at 0, 15, 30, 60,
120 or 240 mg/kg-bw/day daily for 3 months. Decreases in body weight and food consumption
were evident in the high-dose group animals. Males were more sensitive than females with
mortality of one male dog in the highest dose group. The liver was reported to be the primary
target organ for toxicity. Anemia was noted in animals from the 120 and 240 mg/kg dose groups
and "slight" changes in blood chemistry parameters included increased serum bilirubin levels
and gamma glutamyl transpeptidase (GTP), glutamyl oxalacetic transaminasae (GOT) and
alkaline phosphatase activity. In males, decreases in testes, prostrate and epididymal weights at
the two highest doses. In females, body weight and uterus weight was decreased in the three
highest dose groups. Increased liver weights associated with liver damage including icterus
(jaundice) were observed upon gross and histopathological examination in a few dogs in the 120
and 240 mg/kg-bw/day dose groups. Microscopically, fatty degeneration of hepatocytes,
presence of protein globules in the cytoplasm, Kupffer cell hyperplasia and centrilobular
choleostatis were seen. It was reported that the kidneys also exhibited toxicity, but no details
were provided. In higher dose groups, some animals showed atrophy of uterus, abnormal
spermiogenesis and atrophy of the prostate.
LOAEL = 60 mg/kg-bw/day (based on body weight, liver and kidney effects)
NOAEL = 30 mg/kg-bw/day
(2)	Rats (10/sex/group) were administered the test substance via the diet at 0, 100, 200, 400, 800
or 1600 ppm (approximately 5, 10, 20, 40 or 80 mg/kg/day) for 90 days. No mortality occurred.
Signs of anemia (decreased hemoglobin and packed cell volume) were seen in males at dietary
concentrations of 200 ppm and above (approximately 20 mg/kg-bw/day). In females, this effect
was less pronounced. An increase in glucose-6-phosphatase activity was noted at all dietary
concentrations. Liver, kidney, spleen and testes weights were increased in higher exposure
groups with "an indication" of increased thyroid weights (magnitude and significance of change
not reported). The liver was the primary target organ and had a greenish-drab discoloration in
males and females at higher exposure levels. Microscopic examination revealed foci of necrosis
and slight proliferation of bile duct epithelia. Paraenchymal cells were enlarged. In the kidney,
tubular necrosis was reported in some males from the higher dose groups. In females, a
treatment-related, yellowish-brown pigmentation in the cytoplasm of the proximal tubular cells
was noted.
LOAEL ~ 40 mg/kg-bw/day (based on blood, liver and kidney effects)
NOAEL ~ 20 mg/kg-bw/day
2-(2H-Benzotriazol-2-yl)-4,6-bis (1-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
Tif: RAIF (SPF) rats (10/sex/dose) were administered the test substance via the diet at 0, 50, 300,
2000 or 10,000 ppm (corresponding to approximately 0, 2.5, 15, 100 or 500 mg/kg-bw/day) for
92-94 days. No treatment-related clinical symptoms or signs of toxicity were observed. There
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was no effect on mortality; body weight; hematological, blood chemistry and urinalysis
parameters; nor macroscopic findings. A statistically significant increase in absolute and relative
(to body and brain weight) liver weight was seen in males and females at 2000 ppm and above
and in females at 300 ppm. A slight to moderate hypertrophy and/or cytoplasmic vacuolization
of hepatocytes were seen and in females from 300 ppm and above and in both males and females
at 2000 ppm and above.
LOAEL ~ 15 mg/kg-bw/day (based on liver effects)
NOAEL ~ 2.5 mg/kg-bw/day
Reproductive Toxicity
Reproductive toxicity tests were not submitted to address the reproductive toxicity endpoint for
this category. Evaluation of reproductive organs in repeated-dose toxicity and other studies were
used to address the reproductive endpoints for the purposes of the HPV Challenge Program.
Therefore, NOAEL/LOAELs for fertility and/or reproductive toxicity cannot be determined for
this endpoint.
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
(1)	In the 90-day dietary toxicity study in dogs described previously, reproductive organs were
weighed and examined macroscopically (ovaries or testes and uterus or prostate). No gross or
histopathological changes in reproductive organs were seen. The highest dose was
approximately 350 mg/kg-bw/day.
(2)	In a 2-year dietary toxicity study in rats (0, 100, 300, 1000 and 3000 ppm) and mice (0, 5, 50
and 500 ppm), organ weight analysis performed on the reproductive organs of male and female
rats sacrificed after 104 weeks of treatment revealed no differences between control and
treatment groups. General histopathology of the reproductive organs of rats and mice sacrificed
after 104 weeks of treatment showed no abnormalities. The highest doses tested were
approximately 62 mg/kg-bw/day for mice and 169 mg/kg bw/day for rats.
(3)	In a Dominant Lethal Assay, male NMRI derived albino mice (20/group) were treated with
the test chemical by gavage at a single dose of 0, 1000 or 3000 mg/kg-bw and were mated with
untreated females. The vehicle was aqueous carboxymethyl cellulose. Females were necropsied
on day 14 of pregnancy. There were no differences in mating ratio, number of implantations, or
embryonic deaths between control and treated groups.
2-(2'-Hydroxy-3',5'-di-t-amylphenyl) benzotriazole (CASRN25973-55-1)
(1) In the 90-day repeated-dose toxicity study conducted in Beagle dogs as described previously,
males showed greater signs of toxicity than females. In males, decreases in body weight and in
testes and epididymal weights at the two highest doses. In females, body weight and uterus
weight was decreased in the three highest dose groups. However, the significance of the body
and organ weight changes is not described. Microscopic changes included slight to moderate
atrophy of the uterus (60 mg/kg-bw/day and above), abnormal spermiogenesis (30 mg/kg-bw/day
and above) and atrophy of the prostate (30 mg/kg-bw/day and above).
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(2) In the 90-day repeated-dose dietary toxicity study conducted in rats described previously,
there was no treatment-related effect on female body weight or ovary weight (reported as ovary
weight per 100 g body weight). Body weights of male rats were significantly reduced at 800 and
1600 ppm (4% and 16%, respectively). Increases in testes weights (reported as testes weight per
100 g body weight) were statistically significant at 400 (p < 0.05), 800 and 1600 ppm (p < 0.01).
The robust summary judged this result to be caused by decreased body weight and not
toxicologically significant. Reproductive organs were not evaluated microscopically.
2-(2H-Benzotriazol-2-yl)-4,6-bis(l-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
In the 90-day repeated-dose dietary toxicity study conducted in rats described previously,
reproductive organs were weighed and evaluated microscopically. Reproductive organ weights
were not affected at the end of the treatment period. The summary states that there were no
histological effects on reproductive organs.
Developmental Toxicity
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
Groups of presumed pregnant female Sprague-Dawley rats and NMRI derived albino mice
(number unspecified) received the test substance (in 2% aqueous carboxymethyl cellulose) by
gavage at 150, 500 or 1000 mg/kg-bw on days 6-15 of gestation. The robust summary states that
no maternal toxicity was evident and the rates of implantation and embryotoxicity were not
affected by treatment. The robust summary states there were no teratogenic effects but it does
not specify what developmental endpoints were examined.
NOAEL (maternal/developmental toxicity) = 1000 mg/kg-bw/day (highest dose tested)
2-(2H-Benzotriazol-2-yl)-4,6-bis(l-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
Groups of presumed pregnant female Tif: RAIF (SPF) rats (number not specified) received the
test substance by gavage at 300, 1000 of 3000 mg/kg-bw on days 6 through 15 of gestation. No
maternal toxicity was evident at any dose. Fetal data indicated a significant reduction in body
weight for the 1000 mg/kg-bw dose group(magnitude and significance not specified). In
addition, an increased delay of skeletal maturation was noted for this group. However, there
were no similar effects in the high dose group so the robust summary categorized these effects as
"incidental". One fetus in the high dose group showed an omphalocele (failure of ventral closure
during last stages of embryonic development).
NOAEL (maternal toxicity = 3000 mg/kg-bw/day (highest dose tested)
LOAEL (developmental toxicity) = 1000 mg/kg-bw/day (based on body weight and delay
skeletal maturation)
NOAEL (developmental toxicity) = 300 mg/kg-bw/day
GeneticToxicity — Gene Mutation
In vitro
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
An Ames assay was conducted using Salmonella typhimurium strains TA 98, TA 100, TA 1535
and TA 1537 with and without metabolic activation at concentrations reported as 10, 30, 90, 270
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and 810 ju.g/0.1 mL. There is no discussion of positive or negative controls in the robust
summary.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole was not mutagenic in this assay.
2-(2'-Hydroxy-5'-octylphenyl) benzotriazole (CASRN3147-75-9)
A reverse mutation assay was conducted using S. typhimurium strains TA 98, TA100, TA 1535
and TA 1537 and E. coli WP2uvrA, with and without metabolic activation and at concentrations
of 20.5, 61.7, 185.2, 555.5, 1666.6 and 5000 |ig/plate. Appropriate positive and negative
controls were used. The results revealed no marked difference in mutagenic activity of the tested
concentrations when compared with negative controls; positive controls showed appropriate
response.
2-(2'-Hydroxy-5'-octylphenyl) benzotriazole was not mutagenic in this assay.
2-(2'-Hydroxy-3',5'-di-t-amylphenyl) benzotriazole (CASRN25973-55-1)
An Ames assay was conducted using S. typhimurium strains TA 98, TA 100, TA 1535 and TA
1535 with and without metabolic activation at 25, 75, 225, 675 and 2025 |ig/0.1 mL. The
comparison of results between the negative control and test chemical revealed no marked
differences. No other description of controls is provided. No evidence of point mutation was
detected.
2-(2'-Hydroxy-3',5'-di-t-amylphenyl) benzotriazole was not mutagenic in this assay.
2-(2H-Benzotriazol-2-yl)-4,6-bis (1-methyl-l-phenylethyl) phenol (CASRN 70321-86-7)
In a reverse mutation assay, S.typhimurium strains TA 98, TA 100, TA 1535, and TA 1537 were
exposed to the test chemical at 25, 75, 225, 675 and 2025 ju.g/0.1 mL with and without metabolic
activation. Appropriate positive and negative controls were used. The results revealed no
marked difference in mutagenic activity of the tested concentrations when compared with
negative controls; positive controls showed appropriate response.
2-(2H-Benzotriazol-2-yl)-4,6-bis (1-methyl-l-phenylethyl) phenol was not mutagenic in this
assay.
Genetic Toxicity — Chromosomal Aberrations
In vivo
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
Chinese hamsters (6 females and 4 males/dose)were administered the test chemical by gavage
for 2 consecutive days at doses of 500, 1000 and 2000 mg/kg-bw; injected intra peritoneally with
colcemide 2 hours after administration of the second dose and sacrificed 4 hours later. Bone
marrow was harvested and analyzed for chromosomal aberrations. Chromosomes from animals
treated with the test chemical showed no aberrations; two metaphase figures were observed in
the negative control and there was a significant increase in aberrations in the positive controls.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole did not induce chromosomal aberrations in
this assay.
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Additional Information
Skin Irritation
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
5 rats and 5 mice (sex and strain not specified) were administered 0.1 cm3 per mouse or 0.4 cm3
per rat of a 5 % suspension of the chemical in gum arabic on a clipped spot on the back for 5
consecutive days. The report concludes there was no local irritation and no systemic toxicity.
No other study details were provided.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4) was not irritating to
rodent skin.
Eye Irritation
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
100 mg was instilled in the eyes of six rabbits (sex and strain not provided). Irritation was noted
in 2 of the 6 rabbits. The report concludes that the chemical is "minimally" irritating to rabbit
eye mucosa.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4) was slightly irritating
to rabbit eyes.
Skin Sensitization
(1)	On day 1 of a guinea pig maximization test, 0.1 mL of three pairs of intradermal injections
were made into the shaved neck adjuvant/saline mixture, test article in Oleum arachidis, and test
article in adjuvant saline mixture). On day 8, approximately 0.4g of a paste containing 1, 5, 10
or 30% (w/w) chemical in Vaseline, was cutaneously applied to the neck for 48 hours using an
occlusive dressing. After 2 additional weeks (week 3 and 4) without treatment, a challenge
cutaneous application of the chemical in vaseline was applied for 24 hours using an occlusive
dressing on the animals' flanks. Under these experimental conditions, 80-90% of the animals
tested showed skin reactions 24 and 48 hours after removing the dressing. The chemical was
classified as an "extreme" sensitizer in albino guinea pigs.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4) caused skin
sensitization in guinea pigs.
Source: TSCATS, Doc#:88-920001579
(2)	Patch testing of 59 volunteers with 0.5 ml of 5% test material in dimethyl phthalate produced
no irritation following initial application. The patch test was repeated three times weekly for
three weeks followed by a similar challenge exposure in the sixth week. Two of the original 66
subjects displayed positive reactions during subsequent exposures during the induction phase,
but one was reacting to dimethyl phthalate and the other reacted to a different test chemical and
still had "congestion" on their skin at the time of challenge so was excluded. Five subjects
dropped out. The 59 subjects (12 men, 47 women) completing the test showed no irritation or
sensitization.
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4) caused no skin
sensitization in humans.
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Carcinogenicity
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
(1)	In a lifetime carcinogenicity study, 50 strain Tif: MAGf(SPF)mice/sex/group were given the
test substance in the diet for 24 months at concentrations of 5, 50 or 500 ppm (corresponding to
0.8, 6.5 and 64 and 0.8, 6.7 and 62 mg/kg bw/day for males and females, respectively). There
was no effect on mortality, bodyweight, food consumption, and clinical signs of toxicity. No
systemic toxicity was observed. The robust summary concludes that it can be inferred that the
test substance did not produce inflammatory, degenerative, proliferative or neoplastic lesions.
NOAEL (systemic toxicity) ~ 62 mg/kg-bw/day (no effect at highest dose tested)
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole was not carcinogenic in this assay.
(2)	In a long-term feeding study, 50 CFY strain rats/sex/group were administered the test
substance for 104 weeks at concentrations of 0, 100, 300, 1000 or 3000 ppm (corresponding to 0,
4, 14, 47 and 142 mg/kg-bw/day in males and 6, 17, 58,and 169 mg/kg bw/day in females).
Although not statistically significant, marginally lower survival rate was noted in males in the
highest dose group. A statistically significant (P<0.05) decreased bodyweight gain (magnitude
of change not reported) in males in this group over the last 52 weeks of treatment was reported.
The robust summary concludes that administration of the test substance did not have an effect on
the spontaneous tumors.
LOAEL (systemic toxicity) = 142 mg/kg-bw/day (reduced body weight gain in males)
NOAEL(systemic toxicity) = 47 mg/kg-bw/day
2-(2'-Hydroxy-5'-methylphenyl) benzotriazole was not carcinogenic in this assay.
Conclusion: The acute toxicity of phenolic benzotriazoles is low in rats via the oral, route for all
category members. CASRN 2440-22-4 was not irritating to rodent skin and slightly irritating to
rabbit eyes. CASRN 2440-22-4 was extremely sensitizing when tested on guinea pigs; however,
there was no sensitization or irritation when tested on human volunteers. Following repeated
oral exposure of rats to CASRN 2440-22-4 for 90 days, there were liver and kidney effects at
500 mg/kg-day and above; the NOAEL for systemic toxicity was 100 mg/kg-day. No effects
were reported for rats administered CASRN 3147-75-9 in the diet for 30 days, with a NOAEL of
5658 mg/kg-day for systemic toxicity.. There were blood, liver and kidney effects in rats
administered 40 mg/kg-day of CASRN 25973-55-1 in the diet; the NOAEL for systemic toxicity
was 20 mg/kg-day. There were liver effects in rats administered 15 mg/kg-day of CASRN
70321-86-7; the NOAEL for systemic toxicity was 2.5 mg/kg-day. There are no specific
reproductive toxicity studies. No significant effects on reproductive organs were reported
following repeated dietary exposures of rats to two category members (CASRN 2440-22-4 and
70321-86-7). Mice and dogs exposed to CASRN 2440-22-4 in dietary studies also showed no
significant effects on reproductive organs. However, effects on reproductive organs were seen
following repeated dietary exposures of dogs to CASRN 25973-55-1. A dominant lethal assay
showed no male reproductive toxicity in rats treated with CASRN 2440-22-4. In an oral prenatal
developmental toxicity study, CASRN 2440-22-4 showed no developmental toxicity in rats and
mice; the NOAEL was 1000 mg/kg-day. CASRN 70321-86-7 caused reduced pup weight and
delays in skeletal maturation at 1000 mg/kg-day; the NOAEL for developmental toxicity is 300
mg/kg-day. The category members did not induce gene mutations in bacterial tests in vitro and
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did not induce chromosomal aberration when tested in vivo. Long-term studies for CASRN
2440-22-4 showed no evidence of carcinogenicity in rats or mice.
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Table 4. Summary of Human Health Data
Endpoints
2-(2'-Hvdroxy-5-
methylphenvl)benzo-
triazolc
(2440-22-4)
2-(2'-Hvdroxy-5'-
octvlphenvl)
bcnzotriazolc
(3147-75-9)
2-(2'-Hydroxy-3,5-di-
tert-
amylphenvl)benzo-
triazolc
(25973-55-1)
2-(2H-benzotrialzol-2-
yl)-4,6-bis(l-methvl-l-
phenylethvl)phenol
(70321-86-7)
Acute Oral Toxicity
LDS0 (mg/kg-bw)
> 10,000
> 10,000
>2325
>7750
Repeated-Dose Toxicity
NOAEL/LOAEL (mg/kg-bw/day)
NOAEL ~ 100
LOAEL ~ 500
(30 days)
NOAEL = 5,658
NOAEL-20
LOAEL ~ 40
NOAEL -2.5
LOAEL ~ 15
Reproductive Toxicity
No effects on
reproductive organs in
the repeated-dose study
No Data
No effects on
reproductive organs in
the rat repeated-dose
study
No effects on
reproductive organs in
the repeated-dose study
Developmental Toxicity
NOAEL/LOAEL
(mg/kg-bw/day)
Maternal Toxicity
NOAEL =1000
No Data
NOAEL = 1000
(RA)
No Data
NOAEL = 3000
(RA)
NOAEL = 3000
Developmental Toxicity
NOAEL =1000
NOAEL = 1000
(RA)
LOAEL = 1000
NOAEL = 300
(RA)
LOAEL = 1000
NOAEL = 300
Genetic Toxicity -
Gene Mutation
In vitro
Negative
Negative
Negative
Negative
Genetic Toxicity -
Chromosomal Aberrations
In vivo
Negative
No Data
Negative
(RA)
No Data
Negative
(RA)
No Data
Negative
(RA)
Additional Information -
Carcinogenicity
No evidence of
carcinogenicity in
mice or rats
No systemic toxicity in
mice, low in rats



Bold = measured data; (RA) = Read Across
4 Hazards to the Environment
Based on EPA's comments on the original submission, a study to evaluate the acute toxicity to
fish was conducted on the least hydrophobic category member for which measured solubility
data were available (i.e., CASRN 2440-22-4). EPA indicated that if no effects were seen in this
test at the limit of solubility, no further aquatic toxicity testing would be needed.
Acute Toxicity to Fish
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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.
2-(2 '-Hydroxy-5'-methylphenyl) benzotriazole (CASRN 2440-22-4)
Rainbow trout (Oncorhynchus mykiss) were exposed to 2-(2'-hydroxy-5'-methylphenyl)
benzotriazole at nominal concentrations of 0.022, 0.037, 0.061, 0.10 and 0.17 mg/L for 96 hours
under static conditions. The highest concentration tested approximated the water solubility limit
of the compound. The concentrations were measured in the exposure solutions. At test
termination, no mortality or adverse effects were observed in the test.
96-h LC50 > 0.17 mg/L
Conclusion: The acute hazard of the phenolic benzotriazoles category to fish, aquatic
invertebrates and plants is considered to be > 0.17 mg/L.
Table 5. Summary of Environmental Effects - Aquatic Toxicity Data
Endpoints
2-(2'-Hvdroxy-5'-
mcthylphcnyl)
benzotriazole
(2440-22-4)
2-(2'-Hvtl roxy-5'-
octylphcnvl)
benzotriazole
(3147-75-9)
2-(2'-Hvdroxy-3\5'-
di-?-amylphcnyl)
benzotriazole
(25973-55-1)
2-(2H-Bcnzotriazo!-2-
yl)-4,6-bis(l-mcthyl-l-
phcnylcthyl) phenol
(70321-86-7)
Fish
96-h LCS0 (mg/L)
> 0.17 (m)
No Data
> 0.17 (m)
(RA)
No Data
> 0.17 (m)
(RA)
No Data
>0.17 (m)
(RA)
Aquatic
Invertebrates
48-h ECS0 (mg/L)
No Data1
No Data1
No Data1
No Data1
Aquatic Plants
72-h ECS0 (mg/L)
No Data1
No Data1
No Data1
No Data1
(m) = measured data (i.e., derived from testing); 1 In test plan comments EPA indicated that if no effects were seen in the fish
test with 2-(2'-hydroxy-5-methylphenyl)benzo-triazole (2440-22-4) at the limit of solubility, no further aquatic toxicity testing
would be needed.
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