SRC TR

- 1 2

- 031

HPV2 TEST RULE DATA ADEQUACY REVIEW (REVISED)

Methanone, diphenyl

- , CASRN 119

- 61

- 9

Prepared by:

Teresa Manyin

, Justine Von Runnen, and William L. Richards

Chemical, Biological and Environmental Center
SRC, Inc.

7502 Round Pond Road North Syracuse, NY 13212

Contract No. EP

- W

- 09

- 027

Task FG007. 2 .009.001

Submitted to:

OCSPP/ OPPT/RAD (7403M) U.S. Environmental Protection Agency 1200 Pennsylvania Avenue

Washington, D.C. 20460

Debra Milligan, Project Officer Meena Sonawane, Work Assignment Manager David Brooks, Alternate Work Assignment Manager

March 1 6 , 201 2Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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i TABLE OF CONTENTS

A. INTRODUCTION

................................ ................................ ................................ .................... 1

B. SUMMARY OF DATA ADEQUACY FOR TESTING REQUIRED BY TEST RULE

........ 1

C. DATA FOR SIDS ENDPOINTS

................................ ................................ .............................. 2

C

- 1. Acute Toxicity to Fish

................................ ................................ ................................ ........ 2

C

- 2. Acute Toxicity to Daphnia : Test Requirement C2 Under Final Test Rule Dated January

7, 2011

................................ ................................ ................................ ................................ ......... 4

C

- 3. Toxicity to Plants (Algae): Test R equirement C2 Under Final Test Rule Dated January

7, 2011

................................ ................................ ................................ ................................ ....... 13

C

- 4. Acute Toxicity

................................ ................................ ................................ .................. 16

C

- 5. Repeated

- Dose Toxicity

................................ ................................ ................................ ... 18

C

- 6. Genetic Toxicity

– Bacterial Reverse Mutation

................................ ............................... 20

C

- 7. Genetic Toxicity

– Chromosomal Aberrations

................................ ................................ 23

C

- 8. Reproductive Toxicity

................................ ................................ ................................ ...... 26

C

- 9. Developmental Toxicity

................................ ................................ ................................ ... 33

D. SUPPLEMENTAL DATA (NON

- SIDS E NDPOINTS)

................................ ........................ 36

D

- 1. Skin Irritation

................................ ................................ ................................ ................... 36

D

- 2. Eye Irritation

................................ ................................ ................................ .................... 41

D

- 3. Skin Sensitization

................................ ................................ ................................ ............. 43

D

- 4. Carcinogenicity

................................ ................................ ................................ ................ 48

D

- 5. Genetic Toxicity

– Other

................................ ................................ ................................ .. 52

E. DATA ADEQACY SUMMARY TABLE

................................ ................................ .............. 57Final HPV2 Chemical Data and Protocol Adequacy Rev iew CASRN 119

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1 A. INTRODUCTION

This document evaluates a submission by the Benzophenone HPV Consortium of the American Chemistry Council received by EPA 1 in response to the final t est rule, “Testing of Certain High Production Volume Chemicals; Second Group of Chemicals” (76 FR 1067, January 7, 2011 ; referred to here as HPV2 ) for m ethanone, diphenyl

- (CASRN 119

- 61

- 9 )

. In this submission, the Benzophenone HPV Consortium supplied data for required aquatic toxicity test s

. Data were also submitted previously by Cytec Industries ( a member of the Benzophenone HPV Consortium ). 2

Data available for the SIDS toxicity endpoints are evaluated for adequacy in Section C

. Using standard testing guidelines and professional judgment as guides, each study was assigned a

Klimisch reliability code. Additional data for non

- SIDS toxicity endpoints (“supplemental” data) are reviewed in Section D

. Sections C and D incorporate information from a data ad equacy assessment that was conducted previously in the following report: “ Oak Ridge National Laboratory, Toxicology and Hazard Assessment Group. 2005. Data Adequacy Report for Orphan HPV Chemicals: Methanone, diphenyl

- (Benzophenone) CAS No. 119

- 61

- 9. May

2005. ” Additional i nformation was obtained from the High Production Volume Information System ( HPVIS ) and European Chemicals Agency ( ECHA ) website ( http://echa.europa.eu/ ).

B

. SUMMARY OF DATA ADEQUACY FOR TESTI NG REQUIRED BY TEST RULE

The HPV2 final test rule requires C2 aquatic toxicity testing for methanone, diphenyl

- . Given that a log K

ow of 3.18 has been measured by Hansch et al. (1995), 3 the use of Test Group 1, which applies to chemicals with log K

ow < 4 .2 is required. Test Group 1 for C2 consists of the following tests: (1) Acute Toxicity to Daphnia (ASTM E 729

- 96) and (2) Toxicity to Plants (Algae; ASTM E 1218

- 04).

Aquatic toxicity data supplied by the Benzophenone HPV Consortium were inadequate to fulfill the Acute Toxicity to Daphnia and Toxicity to Plants (Algae) endpoints that were C2 test requirements under the final test rule. However, EPA located an Acute Toxicity to Daphnia study on the ECHA website that is adequate to fulfill the test requi rement ; the Benzophenone HPV Consortium does not need to conduct an additional study for this endpoint

. The Toxicity to

Plants (Algae) endpoint remains a data gap ; the Benzophenone HPV Consortium needs to conduct a study following ASTM E 1218

- 04 to addres s this data gap

.

A summary of the adequacy assessment for each SIDS endpoint is provided on the last page of

this document (Section E )

.

1 Submission dated January 17, 2012

2 Submission dated March 8, 2011

3 Hansch, C., Leo, A., and Hoekman, D. 1995. Exploring QSAR: Hydrophic, Electronic, and Steric Constants. American Chemistry Society , Washington, DC

.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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2 C . DATA FOR SIDS ENDPOINTS

C

- 1. Acute Toxicity to Fish

Summary of endpoint: Adequate

Study 1: Acute toxicit y study in fathead minnow (Marchini et al., 1992)

Title: Lethal and sublethal toxicity of benzene derivatives to the fathead minnow, using a short

term test

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: > 99% pure

METHOD

Method/guideline followed: Not available

Test type: Short

- term toxicity to fish (flow

- through)

GLP compliant?: Not specified

Year study was performed: 1992

Test species: Fathead minnow ( Pimephales promelas )

Analytical monitoring: Yes

Exposure duration: 4

- 7 days

Concentrations tested: Not available

Test method/conditions remarks: The dilution water utilized for this test was a filtered, aerated, and heated Lake Superior water (freshwater)

. This 7

- day test followed current EPA

short

- term chronic methods. The test lasted 7 days with su rvival and growth as the end points.

There was a control and five other test concentrations. The minidiluter distributed the test

concentrations and the control. Six tanks represented the test concentrations ; they were partitioned to allow for two replicates. Forty fathead minnow larvae (< 24 hours old) were exposed to each test concentration. Fish were fed live < 24 h

- old brine shrimp nauplii ( Artemia

salina ), three times a day. However, on day 7 they were only fed once. All of the toxic endpoint

values are based on measured concentrations.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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3 The toxicant concentration in the stock solution and in each exposure tank was analyze d before starting the tests and two or three times during the test.

Alkalinity was 39 mg CaCO 3 /L, water hardness was 44.5 to 46.5 mg CaCO 3 /L, dissolved oxygen was 7.2 to 7.4 mg/L, pH was 7.15 to 8.25, and temperature was 24 to 26 °C. The photoperiod

was 16 hours light and 8 hours dark.

The trimmed Spearman

- Karber method was used to calculate the LC 50 s at 96 hours and at 7 days.

RESULTS

Endpoint value(s): 96

- hour LC 50 = 10.89 mg/L; 7

- day LOEC (survival) = 9.24 mg/L; 7

- day NOEC (survival) = 5.86 mg/L

Results remarks: The confidence interval for the 96

- hour LC 50 was 9.64 to 12.31 mg/L.

CONCLUSIONS

The 96

- hour LC 50 for fathead minnow was 10.89 mg/L.

STUDY RELIABILITY

[1] Reliable without restrictions. Data appeared in a peer

- reviewed journal arti cle. The test method is well described, and the test solutions were measured.

REFERENCE

Marchini, S., Tosato, M.L., Norberg

- King, T.J., Hammermeister, D.E., and Hoglund, M.D

. 1992. Lethal and sublethal toxicity of benzene derivatives to the fathead min now, using a short

term test. Environmental Toxicology and Chemistry 1 1: 187

- 195. As summarized in HPVIS.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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4 C

- 2

. Acute Toxicity to Daphnia : Test Requirement C2 Under Final Test Rule Dated January 7, 2011

Sum mary of endpoint: A dequate

NOTE: Acute toxi city to Daphnia data supplied by the Benzophenone HPV Consortium ( Studies 2

- 4 , below) were inadequate to fulfill this endpoint. However, EPA located an Acute Toxicity to Daphnia study on the ECHA website ( Study 1 , below) that is adequate to fulfill the

te st requirement; the Benzophenone HPV Consortium does not need to conduct an additional study for the Acute Toxicity to Daphnia endpoint.

Study 1 : Acute toxicity study in Daphnia magna (From ECHA website, Exp Key Short

- term toxicity to aquatic invertebrat es.001)

Title: Not provided

This study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: Purity not provided

METHOD

Method/guideline followed: OECD TG 202

Test type: Daphnia sp., Acute Immobilization Test ( Semi

- s tatic)

GLP compliant?: Yes

Year study was performed: 2011

Test species: Water flea ( Daphnia magna ), 4

- 24 hours old, bred at test facility

Analytical monitoring: Yes

Exposure duration: 48 hours

Concentrations tested: Nominal concentrations: 2.1, 4.7, 10.3, 22.7, and 50.1mg/L ; Maesured concentrations: 2.1, 4.47, 8.78,17.9, and 37.4 mg/L.

Test method/conditions remarks: The test item was distributed to the replicate beakers using

an aqu eous stock solution. The stock solution (50.1 mg test item/L) was prepared in dilutionFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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5 water and stirred for 24 hours. The individual test solutions were prepared by dilution of the

stock solution with dilution water and distributed to the test beakers.

Four replicates per treatment with 5 specimens per replicate were conducted.

The total hardness of the dilution water was 1.3 mmol/L ( equivalent to 107 mg CaCO 3 /L

. The water temperature ranged between 20.3°C and 20.7°C. The pH values throughout the tes t were within a range of pH 7.6

– 8.6 at all treatment levels. The oxygen saturation was between 7.8 mg/L and 8.7 mg/L. Conductivity was 314.0 μS/cm

.

The concentration of the test item in the aqueous phase of the test was assessed by chemical analysis. Test samples were analysed from fresh media at test start and at 24 h ours

. Samples of aged test media were analy z ed after 24 h ours and at the end of the test. All test concentrations and the control were analy z ed.

Due to recovery rates outside the rang e of 80

– 120 % of nominal for the highest treatment

, mean measured concentrations were applied for effect assessment.

K 2 Cr 2 O 7 was used as a reference substance (positive control).

RESULTS

Endpoint value(s): 48

- hour EC 50 = 6.784 mg/L ( based on mean mea sured concentrations) ; 48

- hour NOEC = 4.47 mg/L

Results remarks: The means of initial and aged measured concentrations were 2.1, 4.47, 8.78, 17.9, and 37.4 mg/L at nominal concentrations of 2.1, 4.7, 10.3, 22.7, and 50.1mg/L

, respectively, correspondin g with 100, 95, 85, 79, and 75 % of the nominal loading.

Confidence limits of the 48

- hour EC 50 were 5.514

- 8.327 mg/L. Immobilization rates after 24 hours were 0, 0, 5, 45, 100, and 100% at 0, 2.1, 4.47, 8.78, 17.9, and 37.4 mg/L, respectively.

Immobiliz ation rates after 48 hours were 0, 5, 10, 70, 100, and 100% at 0, 2.1, 4.47, 8.78, 17.9, and 37.4 mg/L, respectively.

CONCLUSIONS

The 48

- hour EC 50 for Daphnia magna was 6.784 mg/L.

STUDY RELIABILITY

[2] Reliable with restrictions. The summary does n ot provide a full citation for the study report. Data, including immobilization rates and water quality values, for each replicate are not provided in the summary.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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6 REFERENCE

Study available from ECHA website, http:// echa.europa.eu

, fourth row of the “Search results”

table resulting from a “Chemical Substance Search” for CASRN 119

- 61

- 9. Study indicated as Exp Key Short

- term toxicity to aquatic invertebrates.001 . The data source is referred to as a “study report”, wi th a report date of 2011

- 11

- 10. No other reference information is provided.

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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7 Study 2 : Acute toxicity study in Daphnia magna ( Tosato et al., 1991 )

Title : A new strategy for ranking chemical hazards. Framework and a pplication.

This study is: Adequate Not Adequate

This study is not adequate because t he duration of exposure is 24 hours (per OECD TG 202),

which is shor ter than the 48

- hour duration specified by the test rule guideline, ASTM E 729

- 96. In addition, study details are limited; missing information includes concentrations tested, measurements of dissolved oxygen and pH during the test, and immobilization coun ts at each

test concentration.

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9 (referred to as benzophenone in study description )

Remarks : 99% pur e

METHOD

Method/guideline followed: OECD TG 202

Test type: Daphnia sp., Acute Immob ilization Test and Reproduction Test: Part I

– 24h EC 50 Acute Immobilization Test (Static)

GLP compliant?: Not specified

Year study was performed: 1991

Test species: Water flea ( Daphnia magna )

, < 24 hours old

Analytical monitoring: Yes

Exposure d uration: 24 hours

Concentrations tested: Not specified

Test method/conditions remarks: Dil ution water was prepared by mixing Milli

- Q and tap water in approximately a 1:1 ratio, adjusted to attain a hardness of 130

- 150 mg CaCO 3 /L , with a pH of 8.2 ± 0.5 and conductivity of 400 ± 25 μS/cm. Stock solutions were prepared by adding the chemicals to the dilution water with mechanical stirring. Test solutions were obtained by diluting the stock solutions. The concentrations of the test solutions were det ermined at the beginning and end of the experiment. Quantitative analyses were carried out on Varian 5000 HPLC equipment under the following conditions: C

- 18 reverse

- phase column (Micro Pack

MCH

- 5, length 15 cm); eluting mixture methanol

- water (3:1); flow rate 1 mL/min; volumeFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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8 injected, as adequate (mainly 10 μL). Chromatographic peaks were recorded on a Varian 4270 integrator and quantified by the external standard method.

Daphnids ( Daphnia magna ) < 24 hours old were obtained from an in

- house laboratory culture maintained in the same water as the dilution water and fed yeast and Selenastrum capricornutum

. Ten animals, subdivided in two replicates, were used for each of the concentrations tested (a minimum of five) and the control.

The tests were perfor med in closed bottles (150 mL) filled to the top in order to avoid loss of chemical due to volatilization. The temperature was 20 ± 1 °C and the photoperiod was 16 hours light: 8 hours dark. The 24

- hour EC 50 was estimated by the Litchfield and Wilcoxon m ethod.

RESULTS

Endpoint value(s): 24

- hour EC 50 = 0.28 mg/L (use of nominal or measured concentrations not specified)

Results remarks: Confidence limits of the 24

- hour EC 50 were 0.21

- 0.37 mg/L.

CONCLUSIONS

The 24

- hour EC 50 for Daphnia magna was 0.2 8 mg/L

.

STUDY RELIABILITY

[ 3 ] Not r eliable. The duration of exposure is 24 hours (per OECD TG 202) , which is shorter than

the 48

- hour duration specified by the test rule guideline, ASTM E 729

- 96. In addition, study details are limited; missing informat ion includes concentrations tested, measurements of dissolved oxygen and pH during the test , and immobilization counts at each test concentration

.

REFERENCE

Tosato, M.L., Vigano, L., Skagerberg, B., and Clementi, S. 1991. A new strategy for ranking

che mical hazards. Framework and a pplication. Environmental Science & Technology 25: 695

- 702. ( In a submission dated March 8, 2011, Cytec Industries [a member of the Benzophenone HPV Consortium] presented the results of this study. In a submission dated Ja nuary 17, 2012,

t he Benzophenone HPV Consortium provided a link to a summary of this study at http://apps.echa.europa.eu/registered/data/dossiers/DISS

- 9c7935fb

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. Additional details were obtained from the primary source [Tosato et al., 1991].)Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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9 Study 3 : Acute toxicity study in Daphnia magna ( Marchini et al., 1993 )

Title: Comparison of the susceptibility of daphnids and fish to benzene derivatives

This st udy is: Adequate Not Adequate

This study is not adequate because t he duration of exposure is 24 hours, which is shorter than the

48

- hour duration specified by the test rule guideline, ASTM E 729

- 96. In addition, study details are limited; missing information includes concentrations tested, measurements of dissolved oxygen, pH, and temperature during the test, and mortality at each test concentration.

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9 ( referred to as benzophenone in study description)

Remarks: > 99% pure

METHOD

Method/guideline followed: Not specified

Test type: Acute static daphnid test

GLP compliant?: Not specified

Year study was performed: 199 3

Test species: Water flea ( C eriodaphnia dubia ); < 24 hours old ; supplier: EPA Environmental

Resea r ch Laboratory

– Duluth

Analytical monitoring: Yes

Exposure duration: 24 hours

Concentrations tested: Not specified

Test method/conditions remarks: Dilution water consisted of sand

- filtered, aerated water from Lake Superior. Water was characterized as follows: temperature = 25 ± 1 °C, pH = 7.6 ± 0.6, conductivity = 111 ± 9 μΩ - 1 , dissolved oxygen = 7.3 ± 1 mg/L, alkalinity = 41 ± 5 mg

CaCO 3 /L, and hardness = 45.5 ± 1 mg CaCO 3 /L

.

Daphnids were exposed in a static system to five concentrations of the test substance, with a

dilution factor of 0.65 and two replicates per concentration . Five daphnids per replicate were exposed in 25 mL of test solution in a tightly closed chamber t o avoid chemical volatilization during exposure. Measurements at the beginning and end of the test were conducted in oneFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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10 vessel at each concentration and included: toxicant concentration, temperature, pH, and dissolved

oxygen.

Water samples for analytica l measurements of test substance concentrations were collected into reagent bottles containing a known volume of hexane, followed by stirring for 45 minutes to facilitate extraction and subsequent concentration. Chemical analysis was conducted using high

performance liquid chromatography using 70

- 80% acetonitrile in water as mobile phase, a C 18 reverse phase column, and a UV

- visible variable wavelength detector. Exposure concentrations were determined using linear regression analysis of the peak area resp onses versus four external

standards.

The trimmed Spearman

- Karber method was used to estimate LC 50 values and confidence limits.

RESULTS

Endpoint value(s): 24

- hour L C 50 = 7.6 mg/L (use of nominal or measured concentrations not specified)

Results rem arks: Daphnia magna were significantly more sensitive (by a factor of 1.4 log units) than Ceriodaphnia to b enzophenone.

CONCLUSIONS

The 24

- hour L C 50 for Ceriodaphnia dubia was 7.6 mg/L.

STUDY RELIABILITY

[ 3 ] Not r eliable. The duration of exposure is 24 hours, which is shorter than the 48

- hour duration specified by the test rule guideline, ASTM E 729

- 96. In addition, study details are limited; missing information includes concentrations tested, measurements of dissolved oxygen

, pH , and

temperature dur ing the test, and mortality at each test concentration.

REFERENCE

Marchini, S., Hoglund, M.D., Broderius, S.J., and Tosato, M.L. 1993. Comparison of the susceptibility of daphnids and fish to benzene derivatives. The Science of the Total Environment, Supplement 1993, pp. 799

- 808. (In a submission dated March 8, 2011

, Cytec Industries [a member of the Benzophenone HPV Consortium ] presented the results of this study. Additional details were obtained from the primary source [ Marchini et al., 199 3 ].)Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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11 S tudy 4 : Acute toxicity study in Daphnia magna ( Ministry of the Environment, Japan, 1998 )

Title: Not available

This study is: Adequate Not Adequate

This study is not adequate because study details were not provided . Missing details included water quality of test solutions (e.g., pH, temperature, water hardness, and dissolved oxygen), test substance purity, details regarding analytical monitoring, experimental conditions (e.g., number of replicates, number of daphni ds per replicate, chamber volume

, whether chambers were sealed to prevent evaporation of test substance, and use of static, static renewal, or flow

- through conditions), and results for individual replicates. According to Japan’s Ministry of the

Environmen t, “because most of these data have not been evaluated by experts, confirmation of

test results is needed if these data are used for assessment” and “tests conducted before FY 2002 need confirmation of test results, because some of these tests were conduct ed using a dispersant”. Therefore, evaluation of the full study report would be necessary before a reliability rating other than 4 (not assignable) could be designated

.

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9 (referred to as be nzophenone in study description)

Remarks: Purity not provided

METHOD

Method/guideline followed: OECD TG 202

Test type: Daphnia sp., Acute Immobilisation Test

GLP compliant?: Yes

Year study was performed: 199 8

Test species: Water flea ( species not specified)

Analytical monitoring: Not specified

Exposure duration: 48 hours

Concentrations tested: Not specified

Test method/conditions remarks: None specifiedFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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12 RESULTS

Endpoint value(s): 48

- hour E C 50 > 10 mg/L (use of nominal or measured c oncentrations not specified)

Results remarks: None specified

CONCLUSIONS

The 48

- hour L C 50 for daphnids was > 10 mg/L.

STUDY RELIABILITY

[4] Not assignable. Study details were not provided in the summaries. Missing details included water quality o f test solutions (e.g., pH, temperature, water hardness, and dissolved oxygen), test substance purity, details regarding analytical monitoring, experimental conditions (e.g., number of replicates, number of daphnids per replicate, chamber volume, whether c hambers were sealed to prevent evaporation of test substance , and use of static, static renewal, or flow

- through

conditions ), and results for individual replicates. According to Japan’s Ministry of the Environment, “because most of these data have not bee n evaluated by experts, confirmation of

test results is needed if these data are used for assessment” and “tests conducted before FY 2002 need confirmation of test results, because some of these tests were conducted using a dispersant”. Therefore, evaluat ion of the full study report would be necessary before a reliability rating other than 4 (not assignable) could be designated

.

REFERENCE

In a submission dated M arch 8, 2011, Cytec Industries ( a member of the Benzophenone HPV

Consortium ) presented the res ults of this study. In a submission dated January 17, 2012, t he Benzophenone HPV Consortium provided a link to a summary of this study at the website for Japan’s Ministry of the Environment ( http://w ww.env.go.jp/chemi/sesaku/02e.pdf ) ; summaries of this study are also available at websites for Japan’s National Institute of Technology and

Evaluation ( http:/ /www.safe.nite.go.jp/english/sougou/view/ComprehensiveInfoDisplay_en.faces ) and the European Chemicals Agency ( http://echa.europa.eu/ ; Exp WoE Short

- term toxicity to aquatic

invertebrates.002 , second row of the “Search results” table resulting from a “Chemical Substance

Search” for CASRN 119

- 61

- 9 )

. None of the summaries contain sufficient data to evaluate study adequacy.

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorise d provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) ech a.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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13 C

- 3

. Toxicity to Plants (Algae) : Test Requirement C2 Under Final Test Rule Dated January 7, 2011

Summary of endpoint: Not Adequate

NOTE: Toxicity to plants (algae) data supplied by the Benzophenone HPV Consortium ( Study

1 , below) were inadequate to fulfill this endpoint. The Toxicity to Plants (Algae) endpoint remains a data gap; the Benzophenone HPV Consortium needs to conduct a study following

ASTM E 1218

- 04 to address this data gap.

Study 1: Toxicity to Pseudokirchneriella su bcapitata ( Ministry of the Environment, Japan,

1998 )

Title: Not available

This study is: Adequate Not Adequate

This study is not adequate because s tudy details were not provided. Missing details included

water qua lity of test solutions (e.g., pH, temperature, water hardness, and dissolved oxygen), test substance purity, details regarding analytical monitoring, experimental conditions (e.g., light intensity, number of replicates, chamber volume, and whether chambers were sealed to prevent evaporation of test substance ), and results for individual replicates. According to Japan’s Ministry of the Environment, “because most of these data have not been evaluated by experts,

confirmation of test results is needed if thes e data are used for assessment” and “tests conducted before FY 2002 need confirmation of test results, because some of these tests were conducted using a dispersant”. Therefore, evaluation of the full study report would be necessary before a reliability r ating other than 4 (not assignable) could be designated

.

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9 (referred to as benzophenone in study description)

Remarks: Purity not provided

METHOD

Method/guideline followed: OECD TG 20 1

Test type: Freshwater Alga and Cyanobacteria, Growth Inhibition Test

GLP compliant?: Yes

Year study was performed: 1998

Test species: Freshwater green algae ( Pseudokirchneriella subcapitata )Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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14 Analytical monitoring: No t specified

Exposure dura tion: 72 hours

Concentrations tested: Not specified

Test method/conditions remarks: No ne specified

RESULTS

Endpoint value(s): 72

- hour EC 50 (growth rate) = 3.5 mg/L; 72

- hour NOEC (growth rate) = 1 mg/L; 72

- hour EC 50 (biomass) = 1.8 mg/L; 72

- hour NO EC (biomass) = 0.46 mg/L (use of nominal or measured concentrations not specified)

Results remarks: None specified

CONCLUSIONS

The 72

- hour EC 50 s for growth rate and biomass were 3.5 and 1.8 mg/L, respectively. The 72

- hour NOEC s for growth rate and biomass were 1 and 0.46 mg/L , respectively

.

STUDY RELIABILITY

[ 4] Not assignable

. Study details were not provided in the summaries

. Missing details included water quality of test solutions (e.g., pH, temperature, water hardness, and dissolved oxyge n), test substance purity, details regarding analytical monitoring, experimental conditions (e.g., light intensity, number of replicates, chamber volume, and whether chambers were sealed to prevent evaporation of test substance ), and results for individual replicates. According to Japan’s Ministry of the Environment , “because most of these data have not been evaluated by experts,

confirmation of test results is needed if these data are used for assessment” and “tests conducted

before FY 2002 need confirmat ion of test results, because some of these tests were conducted using a dispersant”. Therefore, evaluation of the full study report would be necessary before a reliability rating other than 4 (not assignable) could be designated

.

REFERENCE

In a submissi on dated M arch 8, 2011, Cytec Industries ( a member of the Benzophenone HPV

Consortium ) presented the results of this study. In a submission dated January 17, 2012, the Benzoph enone HPV Consortium provided link s to summar ies of this study at the website s f or Japan’s Ministry of the Environment ( h ttp://www.env.go.jp/chemi/sesaku/02e.pdf ) and the European Chemicals Agency ( http://apps.echa.europa.eu/registered/data/dossiers/DISS

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- c262ccb1985dFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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15 ; Exp Key Toxicity to aquat ic algae and cyanobacteria.001); a summar y of this study is also

available at the website for Jap an’s National Institute of Technology and Evaluation ( http://www.safe.nite.go.jp/english/sougou/view/ComprehensiveInfoDisplay_en.faces ). None of

the summarie s contain sufficient data to evaluate study adequacy.

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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16 C

- 4

. Acute Toxicity

Summary of endpoint: Adequate

Study 1: Acute oral toxicity study in mice ( C aprino et al., 197 6

)

Title: Toxicological studies of photosensitizer agents and photodegradable polyolefins

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

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- 9

Re marks: Purity not provided

METHOD

Method/guideline followed: S imilar to OECD TG 401

Test type: Acute Oral Toxicity

GLP compliant?: Not applicable (pre

- GLP)

Year study performed: 197 5

Test species: Swiss mice

Number of animals/sex/dose: 8/dos e (sex not specified)

Route of administration: Oral gavage

Vehicle: 5% Gum arabic

Doses/concentrations tested: Not specified

Statistical methods used: The LD 50 was calculated using probit analysis.

Test method/conditions remarks: Swiss mice, fast ed for 16 hours, were administered by gavage with the test material suspended in 5% gum Arabic. The animals were observed for 7 days. Necropsies were performed on all animals at death or at the end of the study. The LD50 was calculated by probit analysis

. A so lvent control was also tested. Groups of eight animals were tested, but it is not clear how many groups were tested. The dose levels were not provided.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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17 RESULTS

Endpoint value(s): LD 50 = 2895 mg/kg

Results remarks: Sedation, progressive depress ion of motor activity, unstable gait, tremors, and respiratory impairment were noted at lethal doses. No lesions or abnormalities were noted grossly in the visceral organs at necropsy.

CONCLUSIONS

The oral LD 50 for mice was 2895 mg/kg (95% C.L. 2441

- 343 3 mg/kg). The acute oral LD 50 was reported as >10,000 mg/kg in the rat and the acute dermal LD 50 was reported to be 3535 mg/kg in the rabbit ( no additional details ; Opdyke, D.L.J. 1979. Benzophenone. Monographs on Fragrance Raw Materials. Pergamon Press. p. 124).

STUDY RELIABILITY

[2] Reliable with restrictions. The post

- dosing observation period was 7 days, rather than the 14

- day period required by OECD TG 401. Missing details included test substance purity , doses tested, sex of test animals , and eff ects observed at each dose level.

REFERENCE

Caprino, L., Togna, G., and Mazzei, M. 1976. Toxicological studies of photosensitizer agents and photodegradable polyolefins. European Journal of Toxicology 9: 99

- 103. As summarized in

HPVIS and at http://echa.europa.eu/ (Exp Key Acute toxicity: oral.001 , second row of the “Search results” table resulting from a “Chemical Substance Search” for CASRN 119

- 61

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.

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communic ation Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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18 C

- 5

. Repeated

- Dose Toxicity

Summary of endpoint: Adequate

Study 1: Repeated

- dose oral toxicity study in rats ( NTP, 2000 )

Title: NTP Technical Report on the toxicity studies of benzophenone (CAS No. 119

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ad ministered in feed to F344/N rats and B6C3F1 mice

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

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- 9

Remarks: > 99% pure

METHOD

Method/guideline followed: S im ilar to EPA 870.3100

Test type: 90

- Day Oral Toxicity in Rodents (dietary)

GLP compliant?: Yes

Year study performed: 2000

Test species: Fischer 344 rats (male and female)

Number of animals/sex/dose: 10

Route of administration: Oral

– dietary

Ve hicle: None

Exposure duration: 14 weeks

Doses/concentrations tested: 0, 1250, 2500, 5000, 10,000, 20,000 ppm (equivalent to 75, 150, 300, 700, or 850 mg/kg/day for males and 80, 160, 300, 700, or 1000 mg/kg/day for females)

Statistical methods used: Not available

Test method/conditions remarks: Groups of 10 rats/sex/group were given test material in diet for 14 weeks. The rats were observed daily for clincial signs of toxicity and were weighed weekly. At sacrifice, blood, tissues, and organs wer e removed for gross and histopathological

examination.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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19 Endpoint value(s): LOAEL = 1250 ppm based on hypertrophy and cytoplasmic vacuolization in

the liver , increased bile salts, and increased CYPIIB activity, as well as decreased body weights

in females ; NOAEL = not established

Results remarks: All 20,000 ppm rats were terminated for humanitarian reasons before the end of the study. Significantly decreased body weights were found for all treated female rats and for male rats receiving >1250 ppm. The l iver and kidney were identified as the target organs and the weight of both organs were increased in all treated animals. In the liver of all treated rats, hypertrophy and/or cytoplasmic vacuolization were found. In the kidney of 2500 ppm males and

femal es of the 10,000 and 20,000 groups, unique lesions were observed that were well

demarcated, wedge

- shaped areas of prominent tubule dilitation. Bile salts were increased in all treated groups, consistent with hepatic congestion. CYPIIB activity was increa sed in all groups.

CONCLUSIONS

Under the conditions of the study, the target organs of toxicity were the liver and kidney. The test material induced the formation of renal tubule adenomas in male rats, and there was equivocal evidence for increased inci dences of mononuclear cell leukemia and histiocytic

sarcoma in females.

STUDY RELIABILITY

[ 1 ] Reliable with out restrictions.

REFERENCE S

National Toxicology Program (NTP Report) Apr. 2000. NTP Technical Report on the toxicity studies of benzophenone (CAS No. 119

- 61

- 9) administered in feed to F344/N rats and B6C3F1

mice. NIH Publication No. 00

- 3943, NTP Report No. 61. As summarized in HPVIS.

Supporting Information: NTP Report No. TR

- 533. 2004. Toxicological and carcinogenesis studies on benzophen one (CAS 119

- 61

- 9) in F344/N rats and B6C3F1 mice (feed studies).

Burdock, G.A., D.H. Pence, and R.A. Ford. 1991. Safety evaluation of ben zophenone. Fd

Chem. Toxic. 29 : 741

- 750.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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20 C

- 6

. Genetic Toxicity

– Bacterial Reverse Mutation

Summary of endpoint : Adequate

Study 1: Mutagenicity study in Salmonella typhimurium ( Mortelmans et al., 1986 )

Title: Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

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- 9

Remarks : Supplied by Aldrich; according to the vendor it was 99% pure.

METHOD

Method/guideline followed: Similar to OECD TG 471

Test type: Bacterial Reverse Mutation Test

G LP c ompliant?: No data

Year study performed: 1986

Test species: Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537

Metabolic activation: With and without

Concentrations tested: 0, 3, 10, 33, 100, 166, 333, and 1000 μg/plate (Not all concentra tions were used in every trial.)

Statistical methods used: None specified

Test method/conditions remarks: The method was similar to OECD TG 471. A preincubation

assay was used, as described earlier in Haworth et al . (1983), but with some differences a s noted

below. Test chemical dilution or solvent (0.05 m L ), overnight Salmonella culture (0.05 m L ),

and S

- 9 mix or buffer (0.50 m L ) were combined, mixed, and incubated for 20 minutes at 37°C, without shaking. Then 2.0 m L of molten (45°C) top agar supplem ented with 0.5 mM L

- histidine

and 0.5 mM D

- biotin was added. The contents of the tubes were mixed and poured onto the surface of 15 x 100 mm Petri dishes that contained Vogel

- Bonner minimal glucose bottom agar. After the top agar solidified, the plates w ere inverted. The histidine

- revertant (his+) colonies that arose on these plates were counted after two days of incubation at 37°C.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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21 The test chemical was initially tested in a preliminary cytotoxicity test using TA100 to determine the appropriate conce ntration range for the mutagenicity assay. Toxic concentrations were those that produced his+ pinpoint colonies, a decrease in the number of his+ colonies, or thinning or absence of the background lawn. Cytotoxic chemicals like this one were tested up to a concentration that elicited some degree of toxicity. All tests used triplicate plating, and results were presented as the mean number of his+ revertant colonies for three plates and the standard

error o f the mean. Chemicals that were poorly soluble we re tested up to concentrations defined by their solubilities. Chemicals with good solubility and no cytotoxicity were tested up to a limit concentration of 10 mg/plate. Concurrent solvent and positive controls were run with every trial.

Experiments we re repeated no less than one week following the initial experiment. The S

- 9 (9,000g supernatant) fractions were derived from livers of Aroclor 1254

- induced male Sprague

Dawley rats and male Syrian hamsters. The S

- 9 fractions were mixed with appropriate c o

factors immediately prior to each assay, and they all contained 10% S

- 9. All chemicals were tested without exogenous metabolic activation and with 10% rat and hamster S

- 9. Because the chemical was provided as a coded sample, the laboratory did not know what chemical it was testing. At least 5 concentrations of the test chemical were tested in every trial.

Strain text description: TA98, TA100, TA1535, and TA1537

Vehicle used: Yes

Vehicle Name: DMSO

Criteria for Postive Results: Requires reproducible c oncentration

- related response in replicate

trials in at least one strain

It was not necessary for a response to reach two

- fold over background for a chemical to be considered mutagenic. Initial classification of a response as mutagenic, nonmutagenic, or equivocal was made at the testing laboratory, but Errol Zeiger, who was the project officer, made

the final classification. The chemical was then decoded. When, as was the case here, only the results of the second experiment were displayed in the paper, it is implied that those results confirmed the results of the first experiment at each laboratory.

Positive Control Substance s : Without metabolic activation: 9

- aminoacridine with TA97, 4

- nitro

o

- phenylenediamine with TA98, and sodium azide with TA100 and TA1535. With metabolic

activation: 2

- aminoanthracene with all 4 strains.

Negative Control Substance Remarks: The solvent control was DMSO, with a maximum of 0.05

mL added to each plate.

RESULTS

Genotoxicity result: Negative with and without metaboli c activation

Cytotoxic concentration (if applicable): 166 μg/plate without S

- 9; 1000 μg/plate with S

- 9

Results remarks: The test chemical showed no indication of induction of mutations with or without metabolic activation in any of the four strains tes ted. Solvent and positive controls gaveFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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22 appropriate responses. Thus

, none of the 24 trials gave any indication of induction of mutations; half of those results were not displayed in the paper. Precipitate was not seen on any plates. In

the absence of m etabolic activation, slight cytotoxicity, as evidenced by slight clearing of the background lawn and a reduction in the number of his+ revertants, was seen in all strains at 166 μg/plate, which was the highest concentration tested under that test condition

. With rat S

- 9 mix, slight cytotoxicty was seen in all strains at 1000 μg/plate. The highest concentration tested with

hamster S

- 9 mix was 333 μg/plate, and it caused no cytotoxicity.

CONCLUSIONS

The test chemical does not induce gene mutations in bact eria either with or without metabolic

activation.

STUDY RELIABILITY

[ 2 ] Reliable with restrictions. This was not a guideline study. However, it was an excellent study with a clear result. The details of the study were clearly presented.

REFERENCES

M ortelmans, K., Hayworth, S., Lawlor, T., Speck, W., Tainer, B., and Zeiger, E. 1986.

Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ. Mutagen. 8 (Suppl. 7): 1

- 119. As summarized in HPVIS.

Supporting Reference (dis plays some additional data from the same experiment): NTP. 2000. NTP technical report on the toxicity studies on benzophenone (CAS No. 119

- 61

- 9) administered in feed to F344/N rats and B6C3F1 mice. Toxicology Report Series No. 61.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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23 C

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. Genetic Toxici ty

– Chromosomal Aberrations

Summary of endpoint: A dequate

Study 1: Micronucleus assay in mice ( NTP, 2000 )

Title: NTP technical report on the toxicity studies on benzophenone (CAS No. 119

- 61

- 9)

administered in feed to F344/N rats and B6C3F1 mice

Th e study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

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Remarks: The sample was obtained from Aldrich Chemical Company. The supplier indicated that the sample had puri ty greater than 99% based on gas chromatographic analysis.

METHOD

Method/guideline followed: Similar to OECD TG 474

Test type: Mammalian Erythrocyte Micronucleus Test ( in vivo )

GLP compliant?: No data

Year study performed: 200 0

Test species: B6 C3F1 male mice

Number of animals/sex/dose: 5 males /dose

Route of administration: Intraperitoneal

Vehicle: Corn oil

Exposure duration: 72 hours

Doses tested: 0, 200, 300, 400, and 500 mg/kg bw

Statistical methods used: The frequencies of micro nucleated PCEs were compared statistically using a software package (ILS, 1990) that tested for increasing trend over the dose groups by using a one

- tailed Cochran

- Armitage trend test, followed by pairwise comparisons between each dose group and the solven t control. A binomial dispersion test was included that adjusted for excess binomial variation. Statistical significance was initially declared for an individual trial if

the trend test P

- value was less than or equal to 0.025 or if the P

- value for any si ngle dose groupFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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24 was less than or equal to 0.025 divided by the number of dose groups. The NTP scientific staff makes the final determination if a result is positive based on statistical analysis, the reproducibility of any effects observed, and the magnit ude of those effects.

Test method/conditions remarks: The method was similar to OECD TG 474. It followed NTP’s standard protocol, which was described in detail by Shelby et al. (1993). There was a preliminary range

- finding study, and for the test che mical the limiting factor was toxicity. The test chemical was dissolved in corn oil and injected intraperitoneally into male mice three times

at 24

- hour intervals. The total dosing volume each time was 0.4 mL. Mice were killed 24 hours

after the final i njection, and bone marrow was extracted from their femurs to make blood smears.

Those smears were air

- dried, fixed, and stained. Two thousand polychromatic erythrocytes (PCEs) from each mouse were examined for the presence of micronuclei. Results were t abulated as the mean and the standard error of the mean for the pooled results of all 5 animals within each group. Nothing was specified about the ratio of polychromatic erythrocytes to normochromatic erythrocytes (PCE:NCE), which is used as a measure of bone marrow toxicity.

Positive Control Substance: Cyclophosphamide at 25 mg/kg bw Negative Control Substance: Corn oil at 0.4 mL per injection

One limitation of this experiment was that there was no testing of females. The testing in

females becomes m uch less important when toxicity is similar between the sexes, and there were ample data available within the same report to show that such is the case. However, this issue was never dealt with in the presentation regarding this assay.

Criteria for Posit ive Results: Must be significantly above the solvent control, with a significant

dose

- response relationship

RESULTS

Genotoxicity result: Negative

Cytotoxic dose: No data

Results remarks: The test chemical did not induce a statistically significant increase in micronuclei in bone marrow PCEs under the conditions of this assay. The positive and vehicle controls gave appropriate responses. Only t he treated group that was injected three times with 400 mg/kg bw (i.e., the next to highest dose) gave an y suggestion of an increase in the frequency of micronucleated PCEs, and for it the pairwise P

- value was 0.043. According to the statistical test used, this value would have had to be less than 0.006 to reach statistical significance. The

numbers of micr onucleated PCEs per 1000 PCEs in the solvent control and in the 400 mg/kg bw group were 1.2 ± 0.4 and 2.2 ± 0.7, respectively.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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25 CONCLUSIONS

The test chemical does not appear to have the potential to induce chromosomal aberrations in

somatic cells in vivo

.

STUDY RELIABILITY

[ 2 ] Reliable with restriction s

. This was not a guideline study. However, it was a good study with a clear result. The details of the study were clearly presented and the conclusions are solid.

REFERENCE

NTP. 2000. NTP technical re port on the toxicity studies on benzophenone (CAS No. 119

- 61

- 9)

administered in feed to F344/N rats and B6C3F1 mice. Toxicology Report Series No. 61. As

summarized in HPVIS

.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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26 C

- 8

. Reproductive Toxicity

Summary of endpoint: Adequate

Study 1: Two

- g eneration reproductive toxicity study in rats ( Hoshino et al., 2005 )

Title : A two

- generation reproductive toxicity study of benzophenone in rats

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Met hanone, diphenyl

- , CASRN 119

- 61

- 9 (referred to as benzophenone in study description)

Remarks: ≥ 99.98% purity; lot/batch no. 112D2013

METHOD

Method/guideline followed: OECD TG 416

Test type: Two

- generation Reproduction Toxicity

GLP compliant?: Not specified

Year study performed: 200 5

Test species: Crj:CD(SD) rats ; supplier: Charles River Japan, Inc. ; age at initiation: 5 weeks (P) or 3 weeks (F1)

Number of animals/sex/dose: 24

Route of administration: Oral feed

Vehicle: None

Exposure duration: P males were exposed for 10 weeks; P females were exposed for at least 10 weeks during p re

- mating, mating, gestation, lactation, and weaning of the F1 offspring (until postnatal day [PND] 21); F1 animals were exposed for the same duration as the P generation, starting at the time of weaning (three weeks old)

Doses/concentrations tested: 0, 100, 450, and 2000 ppm in diet (nominal concentrations) ; approximately equivalent to 0, 6.4, 29, and 130 mg/kg for the F0 male parents, 0, 8. 4 , 38, and

16 7 mg/kg for the F0 female parents, 0, 7.8, 3 5 , and 159 mg/kg for the F1 male parents, and 0,

8. 8 , 4 1

, and 179 mg/kg for the F1 female parents, respectivelyFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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27 Statistical methods used: Data concerning effects on the offspring until their weaning were based on values calculated per litter as the specimen unit. Using weights of bilateral organs, the

sums of the left and right organs were employed for statistical analysis. Metric data were analyzed for homogeneity of variance by Bartlett’s method (Bartlett, 1937). When the variance was homogeneous, one

- way ANOVA was carried out. When not homogeneous, on the other hand, a Kruskal

- Wallis’s test (Kruskal and Wallis, 1952) was performed. When a significant

inter

- group difference was found, Dunnett’s method (Dunnett, 1955) or a Dunnett type multiple

comparison method (Dunnett, 1964) was applied. For some examin ation items, the Kruskal

Wallis test was applied first, and when a significant inter

- group difference was found, Dunnett type multiple

- comparison method was conducted. Numerical data were analyzed by the Fisher’s exact probability method (Fisher, 1955). The level of statistical significance was basically set at

5%.

Test method/conditions remarks:

Test Animals

- Source: Charles River Japan, Inc. (Astugi breeding Center )

- Age at study initiation: (P) 5 wks; (F1) 3 wks

- Housing: Polycarbonate cages

- Di et: ad libitum

- Water: ad libitum

- Acclimation period: 5 days

Environmental Conditions

- Temperature (°C): 19.0

- 25.0

- Humidity (%): 35

- 75

- Air changes (per hr): 12

- Photoperiod: 12 hrs dark /12 hrs light

Details on Mating Procedure

- M/F ratio per c age: 1:1

- Length of cohabitation: 2 weeks

- Proof of pregnancy: vaginal plug and /or sperm in vaginal smear referred to as day 0 of

pregnancy

- Further matings after two unsuccessful attempts: no

- Any other deviations from standard protocol: none known

Administration of F0 parental animals started from an age of 5 weeks and continued in males for 10 weeks. For females, administration lasted through 10 weeks or more of the pre

- mating, mating, gestational, lactational and during weaning of the F1 offspri n g (PND 21). Administration to F1 parental animals was started from the time of weaning (three weeks old); in F1 males it was continued until necropsy through 10 weeks or more of the pre

- mating and mating periods, and in F1 females until necropsy through 1 0 weeks or more of the pre

- mating, mating, gestational, lactational periods, and during weaning of the F2 offspring (PND 21).

Frequency of treatment: continuous through diet Control animals: plain dietFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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28 Dose selection rationale: B ased on the results of a preliminary dose

- range finding study over 4 weeks with dietary concentrations of 0, 600, 2000, 6000 or 20000 ppm, the highest dose for the definite study was set at 2000 ppm

.

PARENTAL ANIMALS: OBSERVATIONS AND EXAMINATIONS Cage

- side observations : Yes ( Ti me schedule: once daily )

D etailed clinical observations : No data

B ody weight : Yes

- Time schedule for examinations: on gestation days 0, 7, 14 and 20, on lactation days 0, 4, 7, 14 and at necropsy

F ood consumption and compound intake :

- Food consumption f or each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

- Compound intake calculated as time

- weighted averages from the consumption and body weight gain data: Yes Estrous cyclicity (Parental animals) :

- Vagin al smears were collected from female animals everyday in the morning to examine the

estr o us cycle during the two weeks before mating, starting from 13 weeks of age for the F0 parents and from 11 weeks for the F1 parents. Sperm parameters (Parental animals) : Parameters examined in F0 and F1 male parental generations:

- In 10 animals of the control and 2000 ppm group, the number of homogenization

- resistant spermatids in the testis and number of sperms in the cauda epididymal were counted.

LITTER OBSERVATIONS

Standardi z ation o f Litters :

- Performed on day 4 postpartum: yes

- Maximum of 8 pups/litter (4)/sex/litter as nearly as possible; excess pups were killed and

discarded.

Parameters Examined : The following parameters were examined in [F0 / F1 / F2] offsprin g:

- number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other: reflex tests Gross Examination Of Dead Pups : yes

POSTMORTEM EXAMINATIONS (PARENTAL ANIMALS)

Sacrifice :

- Male animals: All surviving animals as soon as possible after the last litters in each generation were produced

- Maternal animals: All surviving animals after the last litter of each generation was weaned Gross Necropsy :

- Gross necropsy c onsisted of: no data Histopathology / Organ Weights :

- Organ weights in all F0 and F1 parental animals: brain, pituitary gland, thyroid including parathyroid, liver, kidneys, adrenal glands, spleen, testes, epididymes, prostate, semin al vesicle,

ovaries an d uterusFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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29 - Histopathological examinations were conducted for the following organs from all males and females of the control and 2000 ppm groups in the F0 and F1 parents. The brain, pituitary gland, thyroid and parathyroid, liver, kidneys, adrenal glands, spleen, testes, epididymes, seminal vesicles (including coagulating glands), prostate (ventral lobe), ovaries, uterus (including the cervical region), vagina, and mammary glands. Furthermore, the liver and kidneys in the 100 and 450 ppm groups in the F0 a nd F1 parent animals and any macroscopically abnormal site s were also histopathologically examined. Also , any animals that died during the course of the study or were sacrificed upon becoming moribund w ere examined to investigate the causes.

POSTMORTEM E XAMINATIONS (OFFSPRING)

Sacrifice :

- Excluding the pups that died before selection on PND 4 or the pups not selected on PND 4 (when their numbers were adjusted), all the remaining pups were necropsied when they were

sacrificed or were found dead.

Gross Nec ropsy :

- Gross necropsy consisted of external and internal examinations including the cervical, thoracic,

and abdominal viscera. Organ weights (at weaning) :

- The brain, thymus, and spleen of one F1 and F2 male and female pups each selected from each

litt er were weighed on PND 21.

REPRODUCTIVE INDICES No. of days until copulation Mating index (%) = (Number of males and females showing evidence of copulation / number of males and females used for mating) × 100. Fertility index (%) = (Number of pregnant fe males / number of copulated females) × 100. Gestation length (days) = Number of days from GD 0 until the delivery day. Gestation index (%) = (Number of females with normal delivery / number of pregnant females) ×

100. Sex ratio = Total number of male pups delivered / total number of the pups delivered.

OFFSPRING VIABILITY INDICES Birth index (%) = (Number of live pups delivered / number of implantations) × 100. Viability rate on PND 21 (weaning rate) (%) = (Number of live pups on PND 21 / number of live

pu ps on PND 4) × 100. Viability on PND 4 (the survival rate on day 4) (%) = (Number of live pups on PND 4 / number of live pups on PND 0) × 100.

RESULTS

Endpoint value(s): The LOAEL for parental toxicity was 100 ppm ( 6.4

- 7.8 and 8.4

- 8.8 mg/kg/day for male s and females, respectively; lowest dose tested) , based on hypertrophy of centrilobular hepatocytes . The NOAEL for parental toxicity was not established . The N OAEL for reproductive toxicity was 2000 ppm (130

- 159 and 167

- 179 mg/kg/day for males and female s, respectively; highest dose tested), based on no effects at the highest dose tested. The LOAEL for developmental toxicity in F1 and F2 pups was 2000 ppm (130

- 179 mg/kg/day), based onFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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30 inhibition of pup body weights and body weight gain during lactation

. The NOAEL for developmental toxicity was 450 ppm (29

- 41 mg/kg/day)

.

Results remarks:

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)

No effects

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS) Treatment at 450 ppm or 2000 ppm inhibited body weight gain and food consumption in both F0

and F1 males and females

.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS) The mean daily intakes of the test substance in the group receiving the concentrations (doses) of 0, 100, 450, and 2000 ppm were equivalent to 0, 6.44 5, 29.01, and 130.0 mg/kg for the F0 male parents, 0, 8.379, 38.15, and 166.5 mg/kg for the F0 female parents, 0, 7.785, 34.60, and 159.4 mg/kg for the F1 male parents, and 0, 8.776, 40.52, and 179.2 mg/kg for the F1 female parents, respectively.

REPRODUC TIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS) Effects were not found in any dose group of the F0 and F1 females

.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) In both F0 and F1 male parents, no effects of treatment were found, even in the 200 0 ppm groups, on the sperm motility rate, number of homogenization

- resistant spermatids in the testis and number of sperm in the cauda epididymis, or on the frequency of morphologically abnormal

sperm

.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)

There wer e no effects of treatment to the reproduct ive performance in any of the t ested groups

.

ORGAN WEIGHTS (PARENTAL ANIMALS) 100 ppm: the relative hepatic weights increased significantly in the F0 females, but there was no difference in the absolute weights no r was there a significant difference in absolute hepatic weights found in the F1 females. 450 ppm: a significant increase was also evident for both the absolute and relative hepatic weights and the relative renal weights in both F0 males and females; this was also the case for the absolute renal weights in F0 males, and the relative liver and kidney weights in both the F1

males and females. 2000 ppm group: significantly elevated values were found for both the absolute and relative weights of the liver and kidneys in F0 and F1 males and females.

GROSS PATHOLOGY (PARENTAL ANIMALS) No changes related to treatment were found in either F0 or F1 males or females.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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31 HISTOPATHOLOGY (PARENTAL ANIMALS) 100 ppm group:

- hypertrophy of centrilobular hepatocytes in th e parental F0/F1 males and females

. 450 ppm or 2000 ppm groups:

- dilation of renal proximal tubules was observed in both F0 and F1 males and females. Regeneration of the proximal tubular epithelium was also apparent in all groups of F0 and F1

males and fe males, including the control group. The incidence of the renal change was higher in the males receiving 450 ppm or 2000 ppm and in the females given 2000 ppm as compared with the control, and cases with moderate or marked change were included only in the former groups. Regeneration of tubular epithelium was more remarkable in males than females, and was pathologically prevalent around the dilated tubules

.

OTHER FINDINGS (PARENTAL ANIMALS)

Serum hormone levels 100 ppm group (or higher):

- testosterone lev els in the F0 males showed a tendency to be elevated, while values for F1 males were not significantly different from the control, so that no consistent trend was apparent. In the F0 and F1 males, no effects were found with regard to the mating index or t he fertility index

. Furthermore, when testosterone levels were compared between the F0 and F1 males, the treatment was found to have had no biologically significant effect. The change observed in F0 males was judged to be due to the low value in one cont rol male. With serum levels of FSH, LH and estradiol, no change related to BZP treatment was found in any dose groups of F0 and F1

animals of either sex. In addition, no abnormalities were found in the hormone levels measured

in three F1 control and one 100 ppm F1 animals , all of which were non

- copulating or non

pregnant.

VIABILITY (OFFSPRING) No changes related to treatment were found in the number of F1 and F2 pups delivered, the viabilities on PNDs 0, 4 and 21, and the other parameter s examined.

CLIN ICAL SIGNS (OFFSPRING) In the F1 and F2 offspring, no changes related to treatment were found in clinical signs in any dose group.

BODY WEIGHT (OFFSPRING) 100 ppm group: N ormal body weight changes as shown in the control were observed in both F1

and F2 m ale and female offspring. 450 ppm group: T he F2 male offspring showed significantly elevated body weights on PND 0. 2000 ppm group: A significant elevation was noted for body weights on PND 0 in F1 male and F2 male/female offspring, while significantly low values were found as follows: for body weights on PNDs 14

- 21 in the F1 and F2 male/female offspring and for body weight gain on

PNDs 7

- 21 in F1 male/female and F2 female offspring.

SEXUAL MATURATION (OFFSPRING)

No eff ec ts noted in sexual maturationFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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32 O RGAN WEIGHTS (OFFSPRING) In the 2000 ppm group, significantly elevated relative brain weights were observed in both male and female F1/F2 pups, and lower absolute spleen weights were found in both F1 sexes. These changes were considered due to inhibition of the body weight gain induced by treatment

. In the groups treated with 450 ppm or less, no substance related changes were found.

GROSS PATHOLOGY (OFFSPRING) No changes related to treatment were observed in any dose group of F1 and F2 pups.

HISTOPATH OL OGY (OFFSPRING)

No t performed

, as no macroscopic changes were observed

.

CONCLUSIONS

With regard to the effects of benzophenone on the F0 and F1 parental animals, inhibition of body weight gain and food consumption, significantly elevated renal weights, d ilatation of the renal proximal tubules, and regeneration of the proximal tubular epithelium were recognized at doses of 450 ppm and 2000 ppm, along with an increase in hepatic weight and centrilobular hepatocytic hypertrophy, considered as vital adaptive changes, at the doses of 100 ppm or more. Obvious effects on the endocrine system and reproductive toxicological effects were not found even at the dose of 2000 ppm in the F0 or F1 parent. There were no test substance

- related changes in the estrous cycle , reproductive capability, delivery and lactation, sperm parameters, serum hormone levels, or necropsy findings. As for effects on the offspring, inhibition of body weight gain was observed in both the F1 and F2 males and females of the 2000 ppm group. N o effects of treatment were recognized in the number of male and female F1 or F2 pups delivered, viability, anogenital distance, physical development, the results of reflex and response tests, or

on the observation results of external abnormalities.

STUDY RELIABILITY

[1] Reliable without restriction.

REFERENCE

Hoshino, N., Tani, E., Wako, Y., and Takahashi, K. 2005. A two

- generation reproductive toxicity study of benzophenone in rats. The Journal of Toxicological Sciences 30 : 5

- 20

. As

summarized a t http://echa.europa.eu/ (Exp Key Toxicity to reproduction .00 1 for CASRN 119

- 61

- 9

, second row of the “Search results” table resulting from a “Chemical Substance Search” for

CASRN 119

- 61

- 9 ).

Copyright Notice: © Europe an Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notificat ion is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

33 C

- 9

. Developmental Toxicity

Summary of endpoint: Adequate

Study 1: Developmental toxicity study in rabbit s ( NTP, 2004 )

Title: Final study report developmental toxicity evaluati on for benzophenone (CAS No. 119

- 61

- 9) administered by gavage to New Zealand White rabbits on gestational days 6 through 29

The study is: Adequate Not Adequate

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CAS RN 119

- 61

- 9

Remarks: > 99% pure

METHOD

Method/guideline followed: OPPTS 870.3700

Test type: Prenatal Developmental Toxicity Study

GLP compliant?: Yes

Year study performed: 2004

Test species: New Zealand White rabbits

Number of animals/sex/dose : 24 females /dose

Route of administration: Oral gavage

Exposure duration: Daily on gestation days 6

- 29 (total of 24 days)

Doses/concentrations tested: 0, 5, 25, and 45 mg/kg

- bw /day

Vehicle: 0.5% Ethylcellulose

S tatistical methods used: No data

Te st method/conditions remarks: Groups of 24 naturally mated New Zealand W hite rabbits were administered 0, 5, 25, or 45 mg/kg

- bw /day in 0.5% ethylcellulose by gavage on gestation day (GD) 6

- 29. Animals were observed daily for general condition and 1

- 2 hou rs post

- dosing for clinical signs of toxicity. Body weight was recorded on GD 0, 3, and 6

- 30. Food consumption was measured on GD 3, 6, 9, 12, 15, 18, 21, 24, 27, 29, and 30.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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34 Animals were sacrificed on GD 30 and subjected to gross necropsy. The liver, pair ed kidneys,

and gravid uterus were weighed. The number of corpora lutea on each ovary was counted. Uterine contents were examined for number of implants, resorptions, dead fetuses, and live fetuses. Live fetuses were weighed and examined for externa l abnormalities, including cleft palate. Approximately one

- half of the fetuses were decapitated and the heads fixed in Bouin's solution for examination by free

- hand sectioning. All carcasses were sexed and examined for visceral abnormalities using fresh dissection. The carcasses were eviscerated and stained for

skeletal examination.

RESULTS

Endpoint value(s): LOAEL (maternal toxicity) = 25 mg/kg

- bw/day based on mortality, reduced body weight gain and food consumption, and early termination of preganacy ; NOAEL (maternal toxicity) = 5 mg/kg

- bw/day ; LOAEL (developmental toxicity) = 45 mg/kg

- bw/day based on reduced fetal body weight ; N OAEL (developmental toxicity) = 25 mg/kg

- bw/day

Results remarks:

Maternal Effects: No adverse effects were noted in low

- d ose animals. Two mid

- dose and five high

- dose animals were found dead or sacrificed moribund between GDs 24

- 30. Additionally,

three mid

- dose and seven high

- dose does aborted during this same time period. Body weight gain during the treatment interval was significantly less for the mid

- (39% of control) and high

dose (net loss of 4.8 g) groups compared with controls (+320.8 g). Overall food consumption by

the mid

- and high

- dose groups was 86 and 83%, respectively, of the control group level during

the tre atment period.

Fetal Effects: Number of corpora lutea/doe, number of implantations/doe, percent of pre

- and

post

- implantation losses, number of live fetuses/litter, and fetal sex ratio were similar between the treated and control groups. Fetal body weig ht was significantly less than controls for male and female fetuses in the high

- dose group.

No treatment

- related external, visceral, or skeletal malformations were observed.

CONCLUSIONS

The LOAELs for maternal and developmental toxicity in rabbits were 25 and 45 mg/kg

- bw/day, respectively.

STUDY RELIABILITY

[ 1 ] Reliable with out restrictions.

REFERENCES

NTP (National Toxicology Program). 2004. Final study report developmental toxicity evaluation for benzophenone (CAS No. 119

- 61

- 9) administered by g avage to New Zealand White rabbits on gestational days 6 through 29. NTIS PB2004

- 105387. 95 pp. As summarizedFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

35 in abstract ( http://ntp.niehs.nih.gov/index.cfm ?objectid=07313273

- FB82

- 4032

- AAE7B779BD397F5D ) and HPVIS.

Supporting study: NTP (National Toxicology Program). 2002. Final study report developmental toxicity evaluation for benzophenone (CAS No. 119

- 61

- 9) administered by gavage to Sprague

- Dawley (CD) rats on gestational days 6 through 19. NTIS PB2003

- 101281. 132 pp.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

36 D. SUPPLEMENTAL DATA (NON

- SIDS ENDPOINTS)

D

- 1. Skin Irritation

Study 1: Dermal irritation study in rabbits ( From ECHA website, Exp Key Skin

irritation/corrosion.001 )

Title: Not pr ovided

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: White to pale yellowish crystals; lot/batch no. 50391499; expiration date: December 1999; stored in dark refrigerator; test substance ID: HR 98/660032 ; purity not provi ded

METHOD

Method/guideline followed: OECD TG 404 and EU Method B.4

Test type: Acute Dermal Irritation/Corrosion

GLP compliant?: Yes

Year study performed: 19 98

- 1999

Test species: MOL:Russian rabbit

Number of animals/sex/dose: 4 animals total , s ex not indicated

Route of administration: Dermal

Vehicle: Ethanol 96% and Diethyl phthalate in a ratio of 1:1

Doses/concentrations tested: 0.5 mL of 2, 5, 10, 25 and 100%

Statistical methods used: None

Test method/conditions remarks:

TEST ANIMALS

- Source: M&B, Ejby, DK

- 4623 Lille Skensved, Denmark

- Weight at study initiation: 2.2

- 2.4 kg

- Housing: indi vidual in PPO/HIPS cages

- Diet : ad libitum

- Water: ad libitumFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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- 9

37 - Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 20 ± 3° C

- Humidity (%): 55 ± 15%

- Air changes (per hr): 10/hour

- Photoperiod (hrs dark / hrs light): 12/12

IN

- LIFE DATES: 14 Dec 1998 t o 01 January 1999

TEST SYSTEM Type of coverage : semiocclusive Preparation of test site : shaved

Vehicle : Ethanol 96% an d Diethyl phthalate in a ratio of 1:1

Amount of test material applied: 0.5 g of the test item was moistened with 0.5 mL vehicle, or

0.5 mL of the test article soluti on (if diluted), were applied

Concentration : 2, 5, 10, 25 and 100%

Vehicle a mount applie d: 0.5 mL Duration of treatment/exposure : 4 hours Observation period : 1, 24, 48, and 72 hours after exposure period

Number of animals: 4

Test site

- Area of exposure: 10x10 cm, 6 sit es were selected on this area Type of wrap if used: gauze patches se cured with 2.5 cm adhesive tapes Removal of test substance: washing wi th lukewarm water and mild soap at 4 hours after start of

exposure Scoring system : Erythema and Eschar formation: Score 0 to 4; Oedema formation: Score 0 to 4

RESULTS

Endpoint value(s ): Not irritating; scores at 24, 48

, and 72 hours were 0.

Results remarks: All treated skin sites were scored with 0, i.e. no signs of irritation were observed at any of the tested concentrations.

CONCLUSIONS

The test substance was not irritating to r abbit skin.

STUDY RELIABILITY

[ 2 ] Reliable with restrictions

. The primary source of the study is not identified and the purity of the test substance is not provided.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

38 REFERENCE

Study available from ECHA website, htt p://echa.europa.eu

, second row of the “Search results” table resulting from a “Chemical Substance Search” for CASRN 119

- 61

- 9 . Study indicated as Exp Key Skin irritation/corrosion.001

. The data source is referred to as a “study report”, with a report dat e of 1999

- 01

- 07. No other reference information is provided.

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

39 Study 2: Dermal irritation study in rabbits ( Calas et al., 1977 )

Title: Not provided

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: Purity not provided

METHOD

Method/guideline followed: Draize (1944) method

Test type: Acute Dermal Irritation/Corrosion

GLP compliant?: Not applicable (pre

- GLP)

Year study performed: 1977

Test species: New Zealand White rabbit

Number of animals/sex/dose: 6 animals total , sex not indicated

Route of administration: Dermal

Vehicle: Olive oil

Doses/concentrations tested: 0.5 mL of 2 0% solution

Statistical methods used : None

Test method/conditions remarks: The test substance was applied to scratched and non

scratched test sites. The vehicle was olive oil. 0.5 mL of a 200 g/L (20%) test solution was applied to each test site. Treated sites were scored for erythema a nd edema at 24 and 72 hours

post

- administration using the Draize (1944) method.

RESULTS

Endpoint value(s): Moderately irritating; primary dermal irritation index (PDII) = 2.0

.

Results remarks: Erythema and edema were most often slight, but were moder ate in 1/6

animals and intense in 1/6 animals. Histolo patholo g ical changes consisted of focal necrosis with and without dyskeratosis.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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40 CONCLUSIONS

Benzophenone, applied to the scratched or unscratched rabbit skin, had a medium irritating

response. The p rimary irritation index was at 2.0

.

STUDY RELIABILITY

[2] Reliable with restrictions. Test details are limited; missing details include test substance purity, description of test sites and wrap used to cover sites, and individual irritation scores

.

REF ERENCE

Calas

, E

. , Castelain

, P

. Y

. , Lapointe

, H

. R

. , Ducos

, P

. , Cavelier

, C

. , Duprat

, P ., and Pottou

, P

. 1977

. Allergic contact dermatitis to a photom erizable resin used in printing. Contact Dermatitis

3: 186

- 194. As summarized at http://echa.europa.eu/ ( Exp Supporting Skin

irritation/corrosion.00 2 , second row of the “Search results” table resulting from a “Chemical

Substance Search” for CASRN 119

- 61

- 9 ).

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Re production is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communicat ion Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

41 D

- 2

. Eye Irritation

Study 1: Eye irritation study in rabbits ( Eastman Kodak Co., 1984)

Title: Letter from Eastman Kodak to USEPA RE: Chemicals listed in the '83 list of chemicals selected for review by TSCA ITC ( 48 FR 5152) w/attachments

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: Purity not provided

METHOD

Method/guideline followed: Not specified

Test type: Acute Eye Irritation

GLP compliant?: Not specified

Year study performed: 19 84

Test species: R abbits (strain and sex not specified)

Number of animals/sex/dose: 6 total , sex not indicated

Route of administration: Ocular

Vehicle: None

Doses/concentrations tested: Several crystals (not further specified)

Stat istical methods used: None specified

Test method/conditions remarks: Several crystals of the compound were placed into the conjunctival sac of 6 rabbit eyes (3 rinsed/not rinsed each).

RESULTS

Endpoint value(s): Slightly irritating

Results remarks: The treatment caused only slight eye irritation in all animals.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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42 CONCLUSIONS

The test substance was slightly irritating to rabbit eyes.

STUDY RELIABILITY

[ 4 ] Not assignable

. Many s tudy details were not provided. Missing details include test

substance purity, volume of test material administered, duration of observation period, individual

irritation scores and observations , and primary irritation index.

REFERENCE

Eastman Kodak Co. 1984. Initial submission: Letter from Eastman Kodak to USEPA RE:

Che micals listed in the '83 list of chemicals selected for review by TSCA ITC (48 FR 5152) w/attachments, dated 07/04/84. NTIS OTS0001156, FYI

- OTS

- 0794

- 1156. As summarized at http://echa.europa.eu/ (Exp WoE Eye irritat ion.00 1 , second row of the “Search results” table resulting from a “Chemical Substance Search” for CASRN 119

- 61

- 9 ).

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

43 D

- 3

. Skin Sensitization

Study 1: Der mal sensitization study in guinea pigs (Sharp, 1978 )

Title: The sensitization potential of some perfume ingredients tested using a modified Draize procedure

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: Purity not specified; t he test item used was from commercial batches which had passed quality control checks

METHOD

Method/guideline followed: Similar to OECD TG 406 (modified Draize test)

Test type: Skin sensitization

GLP compliant?: No

Year study performed: 1978

T est species: Dunkin

- Hartley g uinea p igs

Number of animals/sex/dose: 10 test animals and 4 challenge control animals (sex distribution not specified , both males and females used )

Route of administration: Induction: intradermal; Challenge: intradermal and epicutaneous

Vehicle: Not specified

Doses/concentrations tested: Intradermal injection induction concentration = 1%; Topical challenge concentration = 20%; Intradermal i njection challenge concentration = 0.25%

Test method/conditions remarks: Test animals were obtained from an in

- house inbred colony and weigh ed 350 g at study initiation.

RANGE

- FINDING TESTS Intradermal injection: Four animals of the same sex were each injected intradermally on the shaved flanks with 0.1 mL aliquots of a range of concentrations of test item in a suitable solvent. The reactions were examined for size, erythema and oedema 24 hours later and the concentration giving slight but perceptible irritation with no oedema was selected as the injection challenge

concentration (IIC). Topical application: Aliquots (0.1 mL) of a range of concent r a tions of the test item in a suitableFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

44 solvent were applied in small circular areas to the shaved flanks of 4 guinea pigs of the same sex. The reactions were examined 24 hours later for ery thema and the highest concentration which caused no irritation was selected as the application challenge conc entration (AAC).

MAIN STUDY Induction Exposure : At Day 0, in 10 animals, 0.1 mL aliquots of the test item at 1% ( 2.5 times

the IIC ) were injected intradermally at 4 sites which overlie the 2 a u xilla ry and inguinal lymph

nodes.

Challenge Exposure : Fourteen days after induction, each animal was challenged intradermally in one flank and topically in the other with 0.1 mL aliquots of the test item at the respective ICC (0.25%) and ACC (20%)

. T he topical chall e nge was made by spreading 0.1 mL of the test

substance onto the shaved flank in a small circular area which was not covered. Twenty

- four

hours later

, the reactions were scored and apparent seni tization reactions confirmed 7 days later by a second challenge with controls included. In the absence of sensitization reactions at first challenge, the induction and challenge procedures were repeated on days 35 and 42 , but this time

a co n firmatory chal lenge with controls was included irrespective of any apparent sensitization reactions at the previous challenge.

Challenge controls : At each challenge with controls, 4 previously untreated animals of the same sex and similar weight to the test animals we re treated intradermally and topically on opposite flanks with 0.1 mL aliquots of test substance at the ICC and ACC respectively. Positive control substance(s) : no

Scoring: Each injection reaction was given a total score based on size (2 largest diamet ers), erythema and oedema. Individual reactions were considered positive when their total score was significantly greater than the average for total score for control reactions. Application reactions

were scored on a 0 to +++ scale and individual reactio ns were considered positive if they were a) + or greater and b) there were no erythema reactions in controls.

RESULTS

Endpoint value(s): Not sensitizing

Results remarks: None specified

CONCLUSIONS

The test article was not sensitizing in guinea p igs.

STUDY RELIABILITY

[ 2 ] Reliable with restrictions

. P ositive control s were not used. Missing test details include purity of test substance and individual scores. Although 4 (instead of 10) intradermal injections were used in the induction phase in this modified Draize test, the test modification as compared to the original Draize method was validated by the performing laboratory

.Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

45 REFERENCE

Sharp, D.W. 1978. The sensitization potential of some perfume ingredients tested using a

modified Draize procedure. Toxicology 9: 261

- 271. As summarized at http://echa.europa.eu/ (Exp Key Skin sens i tisation.001 for CASRN 119

- 61

- 9

, second row of the “Search results” table resulting from a “Chemical Substance Search” for CASRN 119

- 61

- 9 ).

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa .europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

46 Study 2 : Dermal sensitization study in guinea pigs ( Calas et al. , 197 7 )

Title: Allergic contact dermatitis to a photomerizable resin u sed in printing

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: Purity not specified

METHOD

Method/guideline followed : OECD TG 406

Test type: Skin sensitization

GLP compliant?: Not applicable (pre

- GLP)

Year study perfor med: 1977

Test species: Hartley guinea pigs

Number of animals/sex/dose: 2 0 females

Route of administration: Induction: intradermal and epicutaneous ; Challenge: epicutaneous (open)

Vehicle: Olive oil, Freund’s adjuvant

Doses/concentrations teste d: Intradermal injection induction concentration = 1%; Topical

induction concentration = 1 0%; Intradermal injection challenge concentration s = 1 and 5 %

Test method/conditions remarks: Test animals weigh ed 400 g at study initiation.

MAIN STUDY

Induction Exposure :

- No. of exposures: 2 intra dermal injections in olive oil (1%); 2 intra dermal injections of Freund's complete adjuvant (50% in distilled water) and 2 intra dermal injections of suspended test item in Freund's adjuvant (1%)

- Exposure period: Afte r one week, a topical application was applied at a 10% concentration for

48 hours

- Test groups: 1

- Control group: none

Challenge Exposure :

- No. of exposures: 1Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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- 9

47 - Day(s) of challenge: 2 weeks after dermal induction

- Exposure period: 48 hours

- Test gro ups: 1

- Control group: none

- Site: same as induction

- Concentrations: 1 and 5%

- Evaluation (hr s after challenge): 24 and 48 hours

Positive control substance(s) : no

RESULTS

Endpoint value(s): Not sensitizing

Results remarks: At 24 hours after t he challenge exposure, 0/20 animals displayed positive

reactions.

CONCLUSIONS

The test article was not sensitizing in guinea pigs.

STUDY RELIABILITY

[2] Reliable with restrictions. Positive controls were not used. Missing test details include purity of test substance and individual scores.

REFERENCE

Calas, E., Castelain, P.Y., Lapointe, H.R., Ducos, P., Cavelier, C., Duprat, P., and Pottou, P. 1977. Allergic contact dermatitis to a photomerizable resin used in printing. Contact Dermatitis

3: 1 86

- 194. As summarized at http://echa.europa.eu/ (Exp Supporting Skin sensitisation .002

, second row of the “Search results” table resulting from a “Chemical Substance Search” for

CASRN 119

- 61

- 9 ).

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written not ification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

48 D

- 4 . Carcinogenicity

Study 1 : Carcinogenicity study in rats (NTP, 200 6 )

Title: Toxicology and carcinogenesis studies of benzophenone (CAS 119

- 61

- 9) in F344/N rats

and B6C3 F1 mice (feed studies)

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: > 99% pure

METHOD

Method/guideline followed: NTP study equivalent to EPA 870.4300

Test type: 2

- Year Oral Toxicity in Rodents (dietary)

GLP complia nt?: Yes

Year study performed: 200 6

Test species: Fischer 344 rats (male and female)

Number of animals/sex/dose: 5 0

Route of administration: Oral

– dietary

Vehicle: None

Exposure duration: 2 years

Doses/concentrations tested: 0, 312, 625, an d 1250 ppm (equivalent to average daily doses of approximately 15, 30, and 60 mg /kg body weight to males and 15, 30, and 65 mg/kg to females)

Test method/conditions remarks: Groups of 50 male and 50 female rats were fed diets containing 0, 312, 625, or 1 250 ppm benzophenone (equivalent to average daily doses of approximately 15, 30, and 60 mg benzophenone/kg body weight to males and 15, 30, and 65 mg/kg to females) for 105 weeks.

Carcinogenic effect: Yes

Results remarks: Survival of 1250 ppm males was significantly less than that of controls. Mean body weights of 1250 ppm males were markedly less than those of the controls during year 2 of the study, and weights of exposed females were consistently less than controls throughoutFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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49 the study. Feed consum ption by 1250 ppm males was less than that by the controls after week 70; feed consumption by 1250 ppm females was generally less than that by the controls throughout the study.

There was a positive trend in the incidences of renal tubule adenoma in male s, and the incidences in 625 and 1250 ppm males exceeded the historical control range for all routes; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Due to these findings, additional kidney sections wer e evaluated; results indicated additional renal tubule adenomas in all groups of males and renal tubule hyperplasia in all groups of males and

females. The incidences of pelvic transitional epithelium hyperplasia and the severity of nephropathy were signi ficantly increased in all exposed groups of male rats.

Increased incidences of mononuclear cell leukemia in all exposed groups of females exceeded the historical control range from feed studies, and the incidence in 625 ppm females was significantly grea ter than that in the controls. Male rats exposed to 312 or 625 ppm had significantly increased incidences of mononuclear cell leukemia. One 625 ppm female and two 1250 ppm females had histiocytic sarcomas, and the incidence in the 1250 ppm group exceeded the range in the historical controls.

Liver lesions included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of males and females, cystic degeneration in 625 and 1250 ppm males, and bile duct hyperplasia in all exposed groups of females.

Incidences of mammary gland fibroadenoma in females exposed to 625 or 1250 ppm were lower than expected after adjusting for body weight.

CONCLUSIONS

Under the conditions of th is 2

- year stud y , there was some evidence o f carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma; mononuclear cell leukemia in male F344/N rats may have been related to benzophenone

exposure. There was equivocal evidence of carcinogenic a ctivity of benzophenone in female F344/N rats based on the marginally increased incidences of mononuclear cell leukemia and histiocytic sarcoma. Administration of benzophenone in feed resulted in increased incidences and/or severities of nonneoplastic les ions in the kidney and liver of male and female rats

. D ecreased incidences of mammary gland fibroadenoma in female rats were related to

b enzophenone exposure.

STUDY RELIABILITY

[ 1 ] Reliable with out restrictions.

REFERENCE

NTP Report No. TR

- 533. 200 6

. Toxicolog y and carcinogen e sis studies of benzophenone (CAS

119

- 61

- 9) in F344/N rats and B6C3F1 mice (feed studies).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

50 Study 2 : Carcinogenicity study in mice (NTP, 200 6 )

Title: Toxicology and carcinogenesis studies of benzophenone (CAS 119

- 61

- 9) in F 344/N rats and B6C3F1 mice (feed studies)

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks: > 99% pure

METHOD

Method/guideline followed: NTP study equivalent to EPA 870.4300

Test type: 2

- Year Oral Toxicity in Rodents (di etary)

GLP compliant?: Yes

Year study performed: 2006

Test species: B6C3F1 mice (male and female)

Number of animals/sex/dose: 50

Route of administration: Oral

– dietary

Vehicle: None

Exposure duration: 2 years

Doses/concentrations tested: 0 , 312, 625, and 1250 ppm (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg body weight to males and 35, 70, and 150 mg/kg to females)

Test method/conditions remarks: Groups of 50 male and 50 female mice were fed diets containing 0 , 312, 625, or 1250 ppm benzophenone (equivalent to average daily doses of approximately 40, 80, and 160 mg/kg body weight to males and 35, 70, and 150 mg/kg to females) for 105 weeks. Survival of all exposed groups of mice was generally similar to that o f the control groups. Mean body weights of exposed females were less than vehicle controls. Feed consumption by exposed males and females was similar to that by the controls.

Carcinogenic effect : Yes

Results remarks: In male mice, there were signific antly increased incidences of hepatoce llular

adenoma in the 625 and 1 250 ppm groups, and these incidences exceeded the historical controlFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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51 range. All hepatocellular neoplasms combined occurred with a positive trend. In female mice, the incidences of hepat ocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. Incidences of centrilobular hepatocyte hypertrophy were significantly increased in all exposed groups of males and femal es. All exposed groups of male mice had significant increases in the incidences of multinucleated hepatocytes and chronic active inflammation. The incidences of cystic degeneration of hepatocytes in 625 and 1250 ppm males were significantly increased. T he incidence of histiocytic sarcoma in 625 ppm females was significantly increased and exceeded the historical control range.

The incidences of kidney nephropathy and mineralization in exposed groups of females and the severity of nephropathy in exposed g roups of males were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm males and

females. The incidences of hyperplasia of lymphoid follicles in the spleen were significantly

increas ed in all exposed groups of males and in 312 and 625 ppm females.

CONCLUSIONS

Under the conditions of this 2

- year study, there was some evidence of carcinogenic activity of benzophenone in male B6C3F 1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in

female B6C3F 1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F 1 mice may have been related to benzophenone

exposure. Administration of benzophenone in feed resulted in increased incidences and/or severities of nonneoplastic lesions in the liver, kidney, nose, and spleen of male and female mice.

STUDY RELIABILITY

[1] Reliable without restrict ions.

REFERENCE

NTP Report No. TR

- 533. 2006. Toxicology and carcinogenesis studies of benzophenone (CAS

119

- 61

- 9) in F344/N rats and B6C3F1 mice (feed studies).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

52 D

- 5. Genetic Toxicity

– Other

Study 1: DNA Damage and Repair Study in Escherichia co li ( Fluck et al., 19 7 6)

Title: Evaluation of a DNA polymerase

- deficient mutant of E. coli for the rapid detection of carcinogens

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks : Purity not provided

METHOD

Method/guidelin e followed: None specified

Test type: DNA damage and/or repair ( in vitro )

GLP compliant?: Not applicable (pre

- GLP)

Year study performed: 19 7 6

Test species: Escherichia coli : W3110 (Pol A+) and p3478 (Pol A

- )

Metabolic activation: With and without (rat liver extract)

Concentrations tested: 500 μg

Statistical methods used: None specified

Test method/conditions remarks: The procedure is based on the finding that cells exposed to agents that modify their DNA tend to protect themselves by excising the altered DNA portion and then resynthesizing the correct sequence. DNA polymerase has been implicated in this repair process. Bacterial mutants deficient in DNA polymerase (pol A

- ) have been isolated. These strains are exceedingly sensitive to UV ra diations, radiomimetic agents, and agents known to react with cellular DNA; moreover, they exhibit an increased rate of mutation. Advantage was taken of these properties of pol A

- strains to devise a screening procedure for detecting agents that modify ce llular DNA.

Portions (0.1 m L ) of exponentially growing bacterial cultures [Escherichia coli W3110 (pol A+) or its pol A

- derivative p3478)] were added to 3 mL of soft (0.75%) agar, which were then poured onto the surface of a hard (1.5%) agar plate (25 mL ). For the growth of bacteria, solid as well as liquid media contained Medium HA (18) supplemented with 5 μg of thymine/mL. When the soft agar had solidified, a sterile disc impregnated with the test substance, dissolved preferably in water, was placed a t the center of each plate. (Alternatively, 0.1 mL of theFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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53 bacterial cultures was applied directly to the surface of the hard agar plates.) After incubation at 37°C for 16 hrs the diameters of the zones of growth inhibition were measured.

Vehicle: W ater or acetone (if unsoluble) Negative controls: A mpicillin and colistin

Positive control: D imethyl sulfate

Solvent control: N o data

Evaluation criteria: Zones of inhibition were measured on inoculated plates.

RESULTS

Genotoxicity result: Negative wi th and without metabolic activation

Cytotoxic concentration (if applicable): No data

Results remarks: Positive and negative controls were valid. Zones of inhibition were 0 (for Pol A+) and 1 mm for Pol A

-
.

CONCLUSIONS

In a DNA repair test, Benzophe none did not reveal a positive result.

STUDY RELIABILITY

[2] Reliable with restrictions. This was not a guideline study.

REFERENCE

Fluck, E.R., Poirier, L.A., and Ruelius, H.W. 1976. Evaluation of a DNA polymerase

- deficient

mutant of E. coli for th e rapid detection of carcinogens

. Chem Biol Interactions 15 : 219

- 231

. As

summarized at http://echa.europa.eu/ (Exp Key Genetic toxicity in vitro.002 , second row of the “Search results” table resulting from a “Chemic al Substance Search” for CASRN 119

- 61

- 9 ).

Copyright Notice: © European Chemicals Agency, 2007

- 2011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Communication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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54 Study 2 : DNA Damage and Repair Study in Salmonella typhimurium ( Takemoto et al.,

2002 )

Title: Genotoxic activat ion of benzophenone and its two metabolites by human cytochrome

P450s in SOS/ umu assay

TEST SUBSTANCE

Identity: Methanone, diphenyl

- , CASRN 119

- 61

- 9

Remarks : > 99% pure; supplier: Wako Pure Chemicals

METHOD

Method/guideline followed: None spec ified

Test type: DNA damage and/or repair ( in vitro SOS/ umu assay )

GLP compliant?: No data

Year study performed: 2002

Test species: Salmonella typhimurium TA 1535 pSK1002

Metabolic activation: With ( liver microsomes )

Concentrations tested: 1

- 1000 μM

Statistical methods used: None specified

Test method/conditions remarks: The genotoxicity of benzophenone was determined by measuring the induction of umu gene expression in Salmonella typhimurium TA1535/pSK1002

or O

- acetyltransferase

- overexpressin g strain NM2009. Overnight cell cultures of tester strain were grown in 1% bactotryptone, 0.5% sodium chloride, 0.2% glucose containing 50 μ g/m L ampicillin until the OD600 of the bacterial culture was ~ 0.2. The resulting bacterial suspension

was incubat ed with benzophenone and its metabolites dissolved in dimethylsulfoxide at 37°C for

2 h. The expressed beta

- galactosidase activity in the tester strain was determined using o

nitrophenyl

- ß

- D

- galactopyranoside as a substrate. The P450

- dependent activation of benzophenone and its metabolites causing an induction of umu gene expression was carried out

with liver microsomes or recombinant P450/NPR in insect cells or E. coli membranes expressing

human P450 and NPR. Incubation mixtures (final volume 1.0 mL) co nsisted of P450 enzyme

sources with chemicals in 0.25 m L of 200 mM potassium buffer containing an NADPH

generating system and 0.75 m L of bacterial suspension. In separated experiments, liver 9000 *g supernatant fraction (20

– 60 μ g/m L ) was used instead of l iver microsomes, or liver cytosol (30

μ g/m L ) was added to the liver microsomes. For inactivation of the enzyme activities, heat treatment (at 100°C for 2 min) was carried out. The umu gene expression was monitored byFinal HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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55 measuring beta

- galactosidase activiti es as described above and expressed as units/(min nmol)

P450 or NPR.

The concentrations of P450 and protein were determined spectrally. NADPH

– cytochrome c reductase activities were determined using an assumed specific activity of 3.0 umol cytochrome

redu ced/(min nmol) NPR based on purified human NPR preparations. The molar ratios for P450
1A1/NPR, 1A2/NPR, 1B1/NPR, 2A6/NPR, 2B6/NPR, 2C8/NPR, 2C9/NPR, 2C19/NPR, 2D6/NPR, 2E1/NPR, 3A4/NPR, and 3A5/NPR membranes used in this study were 0.70, 0.28, 0.65, 1.94 , 0.80, 0.14, 1.95, 1.40, 0.95, 1.05, 1.10, and 0.36, respectively.

Metabolites: benzhydrol and p

- benzoylphenol

- Supplier: Wako Pure Chemicals and Pfaltz & Bauer (Waterbury, CT)

Target gene: umu gene expression in Salmonella typhimurium TA1535/pSK1002 or O

acetyltransferase

- overexpressing in NM2009

Vehicle: DMSO

RESULTS

Genotoxicity result: Positive with activation

Cytotoxic concentration (if applicable): No data

Results remarks: The umu gene expression of benzophenone catalyzed by P450 2A6/NP R membranes was increased at substrate concentrations up to 200μM. This activation was dependent on P450 concentrations.

CONCLUSIONS

In the present study, benzophenone, benzhydrol and p

- benzylphenol induced umu gene expression after metabolic activation by human P450s, including P450 2A6 and P450 family 1

enzymes. The bioactivation reaction was dependent on the substrate and P450

- concentrations.

STUDY RELIABILITY

[2] Reliable with restrictions. This was not a guideline study. No details are provided on the use

of controls.

REFERENCE

Takemoto, K., Yamazaki, H., Nakajima, M., and Yokoi, T. 2002. Genotoxic activation of benzophenone and its two met abolites by human cytochrome P450s in SOS/ umu assay

. Mutat

Res 519 : 199

- 204

. As summarized at http://echa.europa.eu/ (Exp Key Genetic toxicity in

vitro.00 5 , second row of the “Search results” table resulting from a “Chemical Substance

Search” for CASRN 119

- 61

- 9 ).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

- 61

- 9

56 Copyright Notice: © European Chemicals Agency, 2007

- 2 011. Reproduction is authorised provided the source is fully acknowledged in the form "Source: European Chemicals Agency, http://echa.europa.eu/ ", and provided written notification is given to the ECHA Co mmunication Unit (info (at) echa.europa.eu).Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119

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57 E. DATA ADEQACY SUMMARY TABLE

Endpoint Study Information

Available Acceptable Data Gap

Aquatic Effects Acute Toxicity to Fish Yes Yes No Acute Toxicity to Daphnia Yes Yes No Toxicity to Plants (Algae) Ye s No Yes

Health Effects Acute Toxicity Yes Yes No Repeated

- Dose Toxicity Yes Yes No

Gene Mutation Yes Yes No

Chromosomal Aberrations Yes Yes No

Reproductive Toxicity Yes Yes No Developmental Toxicity Yes Yes No