SRC TR-12-031

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 16, 2012
Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119-61-9

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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 Requirement 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 ENDPOINTS)........................................................ 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.............................................................................. 57
Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119-61-9

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A. INTRODUCTION

This document evaluates a submission by the Benzophenone HPV Consortium of the American 

Chemistry Council received by EPA1 in response to the final test rule, “Testing of Certain High 

Production Volume Chemicals; Second Group of Chemicals” (76 FR 1067, January 7, 2011; 

referred to here as HPV2) for methanone, diphenyl- (CASRN 119-61-9). In this submission, the 

Benzophenone HPV Consortium supplied data for required aquatic toxicity tests. 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 adequacy 

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 information 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 TESTING REQUIRED BY TEST RULE

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

that a log Kow of 3.18 has been measured by Hansch et al. (1995),3 the use of Test Group 1, 

which applies to chemicals with log Kow < 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 requirement; 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 address 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.
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C. DATA FOR SIDS ENDPOINTS

C-1. Acute Toxicity to Fish

Summary of endpoint: Adequate

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

Title: Lethal and sublethal toxicity of benzene derivatives to the fathead minnow, using a shortterm 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 survival and growth as the endpoints.

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. 
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The toxicant concentration in the stock solution and in each exposure tank was analyzed before 

starting the tests and two or three times during the test. 

Alkalinity was 39 mg CaCO3/L, water hardness was 44.5 to 46.5 mg CaCO3/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 LC50s at 96 hours and at 7 

days.

RESULTS

Endpoint value(s): 96-hour LC50 = 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 LC50 was 9.64 to 12.31 mg/L.

CONCLUSIONS

The 96-hour LC50 for fathead minnow was 10.89 mg/L. 

STUDY RELIABILITY

[1] Reliable without restrictions. Data appeared in a peer-reviewed journal article. 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 minnow, using a shortterm test. Environmental Toxicology and Chemistry 11: 187-195. As summarized in HPVIS.
Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119-61-9

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

January 7, 2011

Summary of endpoint: Adequate

NOTE: Acute toxicity 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 

test 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 invertebrates.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-static)

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 aqueous stock solution. The stock solution (50.1 mg test item/L) was prepared in dilution 
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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 CaCO3/L. The 

water temperature ranged between 20.3°C and 20.7°C. The pH values throughout the test 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 hours. Samples of 

aged test media were analyzed after 24 hours and at the end of the test. All test concentrations 

and the control were analyzed.

Due to recovery rates outside the range of 80 – 120 % of nominal for the highest treatment, mean 

measured concentrations were applied for effect assessment.

K2Cr2O7 was used as a reference substance (positive control).

RESULTS

Endpoint value(s): 48-hour EC50 = 6.784 mg/L (based on mean measured 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, corresponding with 100, 95, 85, 79, and 75 % of the nominal loading.

Confidence limits of the 48-hour EC50 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. 

Immobilization 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 EC50 for Daphnia magna was 6.784 mg/L.

STUDY RELIABILITY

[2] Reliable with restrictions. The summary does not 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.
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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”, with 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).
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Study 2: Acute toxicity study in Daphnia magna (Tosato et al., 1991) 

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

This study is: Adequate Not Adequate

This study is not adequate because 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 information includes concentrations tested, 

measurements of dissolved oxygen and pH during the test, and immobilization counts 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: OECD TG 202

Test type: Daphnia sp., Acute Immobilization Test and Reproduction Test: Part I – 24h EC50

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 duration: 24 hours

Concentrations tested: Not specified

Test method/conditions remarks: Dilution 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 CaCO3/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 determined 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; volume 
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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 performed 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 EC50 was estimated by the Litchfield and Wilcoxon method.

RESULTS

Endpoint value(s): 24-hour EC50 = 0.28 mg/L (use of nominal or measured concentrations not 

specified) 

Results remarks: Confidence limits of the 24-hour EC50 were 0.21-0.37 mg/L.

CONCLUSIONS

The 24-hour EC50 for Daphnia magna was 0.28 mg/L.

STUDY RELIABILITY

[3] Not reliable. 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 information 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 

chemical hazards. Framework and application. 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 January 17, 2012, 

the Benzophenone HPV Consortium provided a link to a summary of this study at 

http://apps.echa.europa.eu/registered/data/dossiers/DISS-9c7935fb-2f34-5de5-e044-

00144f67d249/AGGR-04cb11d3-db50-4fbf-84b1-084d82237941_DISS-9c7935fb-2f34-5de5-

e044-00144f67d249.html#GEN_RESULTS_HD. Additional details were obtained from the 

primary source [Tosato et al., 1991].)

 
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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 study is: Adequate Not Adequate

This study is not adequate because 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 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: 1993

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

Research 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 

CaCO3/L, and hardness = 45.5 ± 1 mg CaCO3/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 to avoid chemical volatilization 

during exposure. Measurements at the beginning and end of the test were conducted in one 
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vessel at each concentration and included: toxicant concentration, temperature, pH, and dissolved 

oxygen.

Water samples for analytical 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 highperformance liquid chromatography using 70-80% acetonitrile in water as mobile phase, a C18

reverse phase column, and a UV-visible variable wavelength detector. Exposure concentrations 

were determined using linear regression analysis of the peak area responses versus four external 

standards.

The trimmed Spearman-Karber method was used to estimate LC50 values and confidence limits.

RESULTS

Endpoint value(s): 24-hour LC50 = 7.6 mg/L (use of nominal or measured concentrations not 

specified) 

Results remarks: Daphnia magna were significantly more sensitive (by a factor of 1.4 log 

units) than Ceriodaphnia to benzophenone.

CONCLUSIONS

The 24-hour LC50 for Ceriodaphnia dubia was 7.6 mg/L.

STUDY RELIABILITY

[3] Not reliable. 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 during 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., 1993].)
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Study 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 daphnids 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 

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 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 rating 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 202 

Test type: Daphnia sp., Acute Immobilisation Test

GLP compliant?: Yes

Year study was performed: 1998

Test species: Water flea (species not specified)

Analytical monitoring: Not specified

Exposure duration: 48 hours

Concentrations tested: Not specified 

Test method/conditions remarks: None specified
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RESULTS

Endpoint value(s): 48-hour EC50 > 10 mg/L (use of nominal or measured concentrations not 

specified) 

Results remarks: None specified

CONCLUSIONS

The 48-hour LC50 for daphnids was > 10 mg/L.

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 oxygen), test 

substance purity, details regarding analytical monitoring, experimental conditions (e.g., number 

of replicates, number of daphnids 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 

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 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 rating other 

than 4 (not assignable) could be designated.

REFERENCE

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 January 17, 2012, the 

Benzophenone HPV Consortium provided a link to a summary of this study at the website for 

Japan’s Ministry of the Environment (http://www.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 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).
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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 subcapitata (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., 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 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 rating 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 201

Test type: Freshwater Alga and Cyanobacteria, Growth Inhibition Test

GLP compliant?: Yes

Year study was performed: 1998

Test species: Freshwater green algae (Pseudokirchneriella subcapitata)
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Analytical monitoring: Not specified

Exposure duration: 72 hours

Concentrations tested: Not specified

Test method/conditions remarks: None specified

RESULTS

Endpoint value(s): 72-hour EC50 (growth rate) = 3.5 mg/L; 72-hour NOEC (growth rate) = 1

mg/L; 72-hour EC50 (biomass) = 1.8 mg/L; 72-hour NOEC (biomass) = 0.46 mg/L (use of 

nominal or measured concentrations not specified) 

Results remarks: None specified

CONCLUSIONS

The 72-hour EC50s for growth rate and biomass were 3.5 and 1.8 mg/L, respectively. The 72-

hour NOECs 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 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 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, evaluation 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 March 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 

Benzophenone HPV Consortium provided links to summaries of this study at the websites for 

Japan’s Ministry of the Environment (http://www.env.go.jp/chemi/sesaku/02e.pdf) and the 

European Chemicals Agency (http://apps.echa.europa.eu/registered/data/dossiers/DISS9875cc3a-73ed-5dcf-e044-00144f67d031/AGGR-83a4ad65-b0f5-4029-8d5ec262ccb1985d_DISS-9875cc3a-73ed-5dcf-e044-00144f67d031.html#AGGR-83a4ad65-b0f5-

4029-8d5e-c262ccb1985d
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; Exp Key Toxicity to aquatic algae and cyanobacteria.001); a summary of this study is also 

available at the website for Japan’s National Institute of Technology and Evaluation 

(http://www.safe.nite.go.jp/english/sougou/view/ComprehensiveInfoDisplay_en.faces). None of 

the summaries 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).
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C-4. Acute Toxicity

Summary of endpoint: Adequate

Study 1: Acute oral toxicity study in mice (Caprino et al., 1976)

Title: Toxicological studies of photosensitizer agents and photodegradable polyolefins

The study is: Adequate Not Adequate

TEST SUBSTANCE 

Identity: Methanone, diphenyl-, CASRN 119-61-9

Remarks: Purity not provided

METHOD

Method/guideline followed: Similar to OECD TG 401

Test type: Acute Oral Toxicity

GLP compliant?: Not applicable (pre-GLP)

Year study performed: 1975

Test species: Swiss mice

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

Route of administration: Oral gavage

Vehicle: 5% Gum arabic

Doses/concentrations tested: Not specified

Statistical methods used: The LD50 was calculated using probit analysis.

Test method/conditions remarks: Swiss mice, fasted 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 solvent 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.
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RESULTS

Endpoint value(s): LD50 = 2895 mg/kg

Results remarks: Sedation, progressive depression 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 LD50 for mice was 2895 mg/kg (95% C.L. 2441-3433 mg/kg). The acute oral LD50 was 

reported as >10,000 mg/kg in the rat and the acute dermal LD50 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 effects 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 119-61-9.

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).
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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. 119-61-9) 

administered in feed to F344/N rats and B6C3F1 mice

The study is: Adequate Not Adequate

TEST SUBSTANCE 

Identity: Methanone, diphenyl-, CASRN 119-61-9

Remarks: > 99% pure

METHOD

Method/guideline followed: Similar 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

Vehicle: 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 were removed for gross and histopathological 

examination. 
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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 liver 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 

females of the 10,000 and 20,000 groups, unique lesions were observed that were welldemarcated, wedge-shaped areas of prominent tubule dilitation. Bile salts were increased in all 

treated groups, consistent with hepatic congestion. CYPIIB activity was increased 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 incidences of mononuclear cell leukemia and histiocytic 

sarcoma in females.

STUDY RELIABILITY

[1] Reliable without restrictions. 

REFERENCES

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 benzophenone 

(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 benzophenone. Fd 

Chem. Toxic. 29: 741-750.
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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 119-61-9

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

GLP compliant?: 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 concentrations 

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 as noted 

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

and S-9 mix or buffer (0.50 mL) were combined, mixed, and incubated for 20 minutes at 37°C, 

without shaking. Then 2.0 mL of molten (45°C) top agar supplemented 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 were inverted. The histidine-revertant (his+) colonies that 

arose on these plates were counted after two days of incubation at 37°C. 
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The test chemical was initially tested in a preliminary cytotoxicity test using TA100 to determine 

the appropriate concentration 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 of the mean. Chemicals that were poorly soluble were 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 were 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 SpragueDawley rats and male Syrian hamsters. The S-9 fractions were mixed with appropriate cofactors 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 concentration-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 Substances: Without metabolic activation: 9-aminoacridine with TA97, 4-nitroo-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 metabolic 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 tested. Solvent and positive controls gave 
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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 metabolic 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 bacteria 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

Mortelmans, 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 (displays 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.
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C-7. Genetic Toxicity – Chromosomal Aberrations

Summary of endpoint: Adequate 

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

The study is: Adequate Not Adequate

TEST SUBSTANCE 

Identity: Methanone, diphenyl-, CASRN 119-61-9

Remarks: The sample was obtained from Aldrich Chemical Company. The supplier indicated 

that the sample had purity 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: 2000

Test species: B6C3F1 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 micronucleated 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 solvent 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 single dose group 
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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 magnitude 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 chemical 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 injection, 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 tabulated 

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 much 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 Positive 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 the treated group that was injected three times with 

400 mg/kg bw (i.e., the next to highest dose) gave any 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 micronucleated 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.
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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 restrictions. 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 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. As 

summarized in HPVIS.
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C-8. Reproductive Toxicity

Summary of endpoint: Adequate

Study 1: Two-generation 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: Methanone, 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: 2005

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 pre-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 

167 mg/kg for the F0 female parents, 0, 7.8, 35, and 159 mg/kg for the F1 male parents, and 0, 

8.8, 41, and 179 mg/kg for the F1 female parents, respectively
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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 multiplecomparison method (Dunnett, 1964) was applied. For some examination items, the KruskalWallis 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

- Diet: 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 cage: 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 offspring (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 10 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 diet
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Dose selection rationale: Based 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 (Time schedule: once daily)

Detailed clinical observations: No data

Body weight: Yes 

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

and at necropsy

Food consumption and compound intake:

- Food consumption for 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):

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

estrous 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

Standardization of 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] offspring:

- 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 consisted 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, seminal vesicle, 

ovaries and uterus
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- 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 and F1 parent animals and any macroscopically abnormal sites 

were also histopathologically examined. Also, any animals that died during the course of the 

study or were sacrificed upon becoming moribund were examined to investigate the causes.

POSTMORTEM EXAMINATIONS (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 Necropsy:

- 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 

litter 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 females / 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 

pups 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 males and females, respectively; lowest dose tested), based on hypertrophy of 

centrilobular hepatocytes. The NOAEL for parental toxicity was not established. The NOAEL 

for reproductive toxicity was 2000 ppm (130-159 and 167-179 mg/kg/day for males and females, 

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 on 
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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, 6.445, 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.

REPRODUCTIVE 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 2000 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 were no effects of treatment to the reproductive performance in any of the tested 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 nor 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.
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HISTOPATHOLOGY (PARENTAL ANIMALS)

100 ppm group:

- hypertrophy of centrilobular hepatocytes in the 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 females, 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 levels 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 the 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 control 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 nonpregnant.

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 parameters examined.

CLINICAL 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: Normal body weight changes as shown in the control were observed in both F1 

and F2 male and female offspring.

450 ppm group: The 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 effects noted in sexual maturation
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ORGAN 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.

HISTOPATHOLOGY (OFFSPRING)

Not 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, dilatation 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. No 

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 at http://echa.europa.eu/ (Exp Key Toxicity to reproduction.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

33

C-9. Developmental Toxicity 

Summary of endpoint: Adequate

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

Title: Final study report developmental toxicity evaluation 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-, CASRN 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

Statistical methods used: No data

Test method/conditions remarks: Groups of 24 naturally mated New Zealand White 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 hours 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 119-61-9

34

Animals were sacrificed on GD 30 and subjected to gross necropsy. The liver, paired 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 external 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; NOAEL (developmental toxicity) = 25 mg/kg-bw/day

Results remarks:

Maternal Effects: No adverse effects were noted in low-dose 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 highdose (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 treatment 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 weight 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 without restrictions. 

REFERENCES

NTP (National Toxicology Program). 2004. Final study report developmental toxicity 

evaluation for benzophenone (CAS No. 119-61-9) administered by gavage to New Zealand 

White rabbits on gestational days 6 through 29. NTIS PB2004-105387. 95 pp. As summarized 
Final 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.
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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 provided

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 provided

METHOD

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

Test type: Acute Dermal Irritation/Corrosion

GLP compliant?: Yes

Year study performed: 1998-1999

Test species: MOL:Russian rabbit

Number of animals/sex/dose: 4 animals total, sex 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: individual in PPO/HIPS cages

- Diet: ad libitum

- Water: ad libitum
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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 to 01 January 1999

TEST SYSTEM

Type of coverage: semiocclusive 

Preparation of test site: shaved 

Vehicle: Ethanol 96% and 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 solution (if diluted), were applied

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

Vehicle amount applied: 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 sites were selected on this area

Type of wrap if used: gauze patches secured with 2.5 cm adhesive tapes

Removal of test substance: washing with 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 rabbit 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.
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REFERENCE

Study available from ECHA website, http://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 date 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 20% solution

Statistical methods used: None

Test method/conditions remarks: The test substance was applied to scratched and nonscratched 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 and 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 moderate in 1/6 

animals and intense in 1/6 animals. Histolopathological changes consisted of focal necrosis with 

and without dyskeratosis.
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40

CONCLUSIONS

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

response. The primary 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.

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: 186-194. As summarized at http://echa.europa.eu/ (Exp Supporting Skin 

irritation/corrosion.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 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

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: 1984

Test species: Rabbits (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)

Statistical 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 119-61-9

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CONCLUSIONS

The test substance was slightly irritating to rabbit eyes.

STUDY RELIABILITY

[4] Not assignable. Many study 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: 

Chemicals 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 irritation.001, 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: Dermal 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; the 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

Test species: Dunkin-Hartley guinea pigs

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 injection challenge concentration = 0.25%

Test method/conditions remarks: Test animals were obtained from an in-house inbred colony 

and weighed 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 concentrations of the test item in a suitable 
Final 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 erythema and the highest concentration which 

caused no irritation was selected as the application challenge concentration (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 auxillary 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%). The topical challenge 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 senitization 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 confirmatory challenge 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 were 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 diameters), 

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 reactions 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 pigs.

STUDY RELIABILITY

[2] Reliable with restrictions. Positive controls 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

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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 sensitisation.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., 1977)

Title: Allergic contact dermatitis to a photomerizable resin used 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 performed: 1977

Test species: Hartley guinea pigs 

Number of animals/sex/dose: 20 females 

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

(open)

Vehicle: Olive oil, Freund’s adjuvant

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

induction concentration = 10%; Intradermal injection challenge concentrations = 1 and 5%

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

MAIN STUDY

Induction Exposure:

- No. of exposures: 2 intradermal injections in olive oil (1%); 2 intradermal injections of 

Freund's complete adjuvant (50% in distilled water) and 2 intradermal injections of suspended 

test item in Freund's adjuvant (1%)

- Exposure period: After 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: 1
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- Day(s) of challenge: 2 weeks after dermal induction

- Exposure period: 48 hours

- Test groups: 1

- Control group: none

- Site: same as induction

- Concentrations: 1 and 5%

- Evaluation (hrs after challenge): 24 and 48 hours

Positive control substance(s): no 

RESULTS

Endpoint value(s): Not sensitizing 

Results remarks: At 24 hours after the 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: 186-194. 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 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

48

D-4. Carcinogenicity 

Study 1: Carcinogenicity study in rats (NTP, 2006)

Title: Toxicology and carcinogenesis studies of benzophenone (CAS 119-61-9) in F344/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 (dietary)

GLP compliant?: Yes

Year study performed: 2006

Test species: Fischer 344 rats (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 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 1250 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 throughout 
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49

the study. Feed consumption 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 males, 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 were 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 significantly 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 greater 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 this 2-year study, there was some evidence of 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 activity 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 lesions in the kidney and liver of male and female rats. 

Decreased incidences of mammary gland fibroadenoma in female rats were related to 

benzophenone exposure.

STUDY RELIABILITY

[1] Reliable without restrictions. 

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

50

Study 2: Carcinogenicity study in mice (NTP, 2006)

Title: Toxicology and carcinogenesis studies of benzophenone (CAS 119-61-9) in F344/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 (dietary)

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 of 

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 significantly increased incidences of hepatocellular 

adenoma in the 625 and 1250 ppm groups, and these incidences exceeded the historical control 
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range. All hepatocellular neoplasms combined occurred with a positive trend. In female mice, 

the incidences of hepatocellular 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 females. 

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. The 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 groups 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 

increased 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 B6C3F1 mice based on increased incidences of hepatocellular neoplasms, 

primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in 

female B6C3F1 mice based on increased incidences of histiocytic sarcoma; the incidences of 

hepatocellular adenoma in female B6C3F1 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 restrictions. 

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). 
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D-5. Genetic Toxicity – Other

Study 1: DNA Damage and Repair Study in Escherichia coli (Fluck et al., 1976)

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/guideline followed: None specified

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

GLP compliant?: Not applicable (pre-GLP)

Year study performed: 1976

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 radiations, 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 cellular DNA.

Portions (0.1 mL) 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 at the center of each plate. (Alternatively, 0.1 mL of the 
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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: Water or acetone (if unsoluble)

Negative controls: Ampicillin and colistin

Positive control: Dimethyl sulfate

Solvent control: No data

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

RESULTS 

Genotoxicity result: Negative with 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, Benzophenone 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 the 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 “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

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

2002)

Title: Genotoxic activation 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 specified

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-overexpressing strain NM2009. Overnight cell cultures of tester strain 

were grown in 1% bactotryptone, 0.5% sodium chloride, 0.2% glucose containing 50 μg/mL

ampicillin until the OD600 of the bacterial culture was ~ 0.2. The resulting bacterial suspension 

was incubated 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 onitrophenyl-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) consisted of P450 enzyme 

sources with chemicals in 0.25 mL of 200 mM potassium buffer containing an NADPHgenerating system and 0.75 mL of bacterial suspension. In separated experiments, liver 9000 *g 

supernatant fraction (20–60 μg/mL) was used instead of liver microsomes, or liver cytosol (30 

μg/mL) 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 by 
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measuring beta-galactosidase activities 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 

reduced/(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 Oacetyltransferase-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/NPR 

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 metabolites 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.005, second row of the “Search results” table resulting from a “Chemical Substance 

Search” for CASRN 119-61-9).
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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 Communication 

Unit (info (at) echa.europa.eu).
Final HPV2 Chemical Data and Protocol Adequacy Review CASRN 119-61-9

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) Yes 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