U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 SCREENING-LEVEL HAZARD CHARACTERIZATION SPONSORED CHEMICAL CI2, Branched Ketones CASRN 68514-41-0 SUPPORTING CHEMICALS Trimethyl 4-nonanone 2-Dodecanone Methylheptenone CASRN 123-18-2 CASRN 6175-49-1 CASRN 409-02-9 The High Production Volume (HPV) Challenge Program1 was conceived as a voluntary initiative aimed at developing and making publicly available screening-level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsored chemicals; sponsorship entailed the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data did not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set l 2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the environment. The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals by developing hazard characterizations (HCs). These HCs consist of an evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. They are not intended to be definitive statements regarding the possibility of unreasonable risk of injury to health or the environment. The evaluation is performed according to established EPA guidance23 and is based primarily on hazard data provided by sponsors; however, in preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor's responses to comments and revisions made to the submission. In order to determine whether any new hazard information was developed since the time of the HPV submission, a search of the following databases was made from one year prior to the date of the HPV Challenge submission to the present: (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS, Merck, etc.), Science Direct and ECHA4. OPPT's focus on these specific sources is based on their being of high quality, highly relevant to hazard characterization, and publicly available. OPPT does not develop HCs for those HPV chemicals which have already been assessed internationally through the HPV program of the Organization for Economic Cooperation and 1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm. 2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm. 3 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 4 European Chemicals Agency, http://echa.europa.eu. ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are presented in an international forum that involves review and endorsement by governmental authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening-level hazard assessments. These hazard characterizations are technical documents intended to inform subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously not readily available to the public. 2 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Sponsored Chemical 68514-41-0 Chemical Abstract Service Registry Number (CASRN) Supporting Chemicals 123-18-2 6175-49-1 409-02-9 Sponsored Chemical C12, Branched Ketones Chemical Abstract Index Name Supporting Chemicals 4-Nonanone, 2,6,8-trimethyl- 2-Dodecanone Heptenone, methyl- Sponsored Chemical ch3 H3C^ yv /V i. ch3 o Representative SMILES:CC(C)CCC(=0)CCCC(C)C Supporting Chemicals Structural Formula ch3 ch3 0 ch3 SMILES: CC(C)CC(=0)CC(C)CC(C)C o SMILES: CCCCCCCCCCC(C)=0 SMILES: CC(C)=CCCC(C)=0 Summary Ketones, C12-branched is a mixture of branched ketones that is a co-product of methyl ethyl ketone (MEK) production and is never isolated from the waste MEK production stream. It is a 3 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 liquid that is expected to have moderate vapor pressure and moderate water solubility. The components of this mixture are expected to have moderate mobility in soil. A representative component of this mixture was not readily biodegradable using a standard OECD test. The rate of degradation is expected to decrease with the degree of branching of the components of this mixture. Volatilization is considered high based on the Henry's Law constant of representative components of this mixture. The rate of hydrolysis is considered negligible since the constituents of this mixture do not contain functional groups that are expected to hydrolyze under environmental conditions. The rate of atmospheric photooxidation is considered moderate for the components of this mixture. The constituents of ketones, C12-branched are expected to have low persistence (PI) with the exception of the most highly branched isomers which may have moderate persistence (P2). All the constituents of this mixture are expected to possess low bioaccumulation potential (Bl). No data are available on the sponsored substance for the human health endpoints. The acute oral toxicity is low for supporting chemicals trimethyl 4-nonanone and methylheptenone in rats. The acute dermal toxicity in rabbits is low for supporting chemical trimethyl 4-nonanone. A combined oral gavage repeated-dose/reproductive/developmental toxicity study in rats with the supporting chemical, methylheptenone, showed decreased motor activity in a functional observational battery and thyroid follicular cell hypertrophy in males at 100 mg/kg-day, decreased food consumption during lactation and thyroid follicular cell hypertrophy in females at 300 mg/kg-day; the NOAEL for systemic toxicity in males is not established and in females is 100 mg/kg-day. Irregular cycles and increased gestation period were observed at 500 mg/kg-day; the NOAEL for reproductive toxicity is 300 mg/kg-day. No treatment-related developmental effects were observed at the highest-dose tested; the NOAEL for developmental toxicity is 500 mg/kg-day. The supporting chemical, methylheptenone, was not mutagenic in bacteria in vitro and did not induce chromosomal aberrations in mammalian cells in vitro. The supporting chemical, methylheptenone, is severely irritating to rabbit skin. No data are available on the sponsored substance for the ecotoxicity endpoints. For the supporting chemical, 2-dodecanone, the 96-h LCso for fish is 1.18 mg/L. For the supporting chemical methylheptenone, the 48-h EC so for aquatic invertebrates is 5.2 mg/L. Toxicity to aquatic plants, based on the supporting chemical methylheptenone, is 16 mg/L and 8 mg/L for growth rate and biomass, respectively. No data gaps were identified under the HPV Challenge Program. 4 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document The sponsor, ExxonMobil Chemical Company, submitted a Test Plan and Robust Summaries to EPA for C12, branched ketones (CASRN 68514-41-0; 9th CI name: Ketones, C12-branched) on December 15, 2009. EPA posted the submission on the ChemRTK HPV Challenge website on January 25, 2010 (http://www.epa.gov/oppt/chemrtk/pubs/summaries/cl2brchketones/cl6825tc.htm). Public comments were received and posted to the website. Justification for Supporting Chemicals The sponsor proposed the use of methylheptenone (C8 ketone; CASRN 409-02-9) as a supporting chemical for both human health and aquatic toxicity endpoints because it and the sponsored chemical comprise two fractions created from the same starting material, methylethyl ketone (MEK), and are formed via the same condensation reaction pathway. Methylheptenone is branched and formed from the condensation of two MEK molecules, while the sponsored chemical is also branched and formed from the condensation of three MEK molecules. Methylheptenone is therefore expected to have similar activities to the sponsored chemical. The sponsor also proposed the use of trimethyl 4-nonanone (CI2 ketone; CASRN 123-18-2) as a supporting chemical for acute human health toxicity endpoints since it is a C12 branched ketone with a C9 carbon backbone containing methyl groups at carbons 2, 6, and 8. EPA agrees that the use of data for both of these two supporting chemicals is justified based on structural similarities. Another proposed supporting chemical for the aquatic toxicity endpoints, 2-dodecanone (C12 ketone; CASRN 6175-49-1), is a linear C12 ketone with the ketone group at the second carbon. Since branching is not considered to be a critical attribute for ecotoxicity testing, EPA agrees that the use of 2-dodecanone as a supporting chemical is justified for the aquatic toxicity endpoints. 1. Chemical Identity 1.1 Identification and Purity Ketones, C12-branched is liquid that is expected to have moderate vapor pressure and moderate water solubility. It is a high-boiling byproduct of the manufacture of methyl ethyl ketone and is not isolated from other byproducts. This mixture of byproducts is subsequently used as a feedstock to produce syngas (50/50 carbon monoxide/ hydrogen blend). 1.2 Physical-Chemical Properties The physical-chemical properties of Ketones, C12-branched are summarized in Table 1. 5 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Table 1. Physical-Chemical Properties of Ketones, C12-branched and Supporting Chemicals1'2 Property SPONSORED CHEMICAL Ketones, C12-branched SUPPORTING CHEMICAL Trimethyl 4-nonanone CASRN 68514-41-0 123-18-2 Molecular Weight 184.32 184.32 Physical State Liquid Liquid Melting Point <0°C (estimated)3 4 <0°C (estimated)3 Boiling Point 220°C (estimated)3 4 217°C (measured)5 Vapor Pressure 0.20 mm Hg at 25°C (estimated)3-4 0.03 mm Hg at 20°C (measured)5; 0.06 mm Hg at 25°C (estimated)6 Dissociation Constant Not applicable Not applicable Henry's Law Constant 0.00128 atm-m3/mol (estimated)3-4 0.00154 atm-m3/mol (estimated)3 Water Solubility 31.9 mg/L (estimated)3-4 22 mg/L (measured)7 Log Kow 4.04 (estimated)3-4 3.96 (estimated)3 ExxonMobil Chemical Company. 2009. Test Plan and Robust Summary for C12, Branched Ketones. Available online at http://www.epa.gov/oppt/chemrtk/pubs/summaries/cl2brcliketones/cl6825tc.htm as of August 16, 2012. 2The sponsor also proposed using heptenone, methyl- and 2-dodecanone as a supporting chemicals. 3U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Enviromnental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of August 16, 2012. 4The sponsor proposed the branched ketone 4-decanone, 2,9-dimethyl- (CASRN unknown not on TSCA) as a typical representative structure for the sponsored chemical. 5The Dow Chemical Company. 2002. Technical Bulletin for ECOSOFT™ solvent IK (2,6,8-Trimethyl-nonan-4- one). Available online at http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh 0119/090lb8038011948e.pdf?filepath=oxvsolvents /pdfs/noreg/327-00050.pdf&fromPage=GetDoc as of August 16, 2012. 6N0M05. 1987. Programs to Enhance PC-Gems Estimates of Physical Properties for Organic Compounds. The Mitre Corp. 7The Dow Chemical Company. 2006. Test Plan and Robust Summary for 4-Nonanone, 2,6,8-Trimethyl-. Available online at http://www.epa.gov/oppt/chemrtk/pubs/summaries/4non268t/cl5003tc.htm as of August 16, 2012. 2. General Information on Exposure 2.1 Production Volume and Use CASRN 68514-41-0 had an aggregated production and/or import volume in the United States between 1 and 10 million pounds during calendar year 2005. Industrial processing and uses for the chemical were claimed confidential. No commercial and consumer uses were reported for the chemical. 2.2 Environmental Exposure and Fate The components of ketones, C 12-branched are expected to have moderate mobility in soil. Though no biodegradation studies could be located for the sponsored mixture, a representative component 6 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document of this mixture - a branched C12 ketone, 4-nonanone, 2,6,8-trimethyl- exhibited 48% degradation over 28 days by biochemical oxygen demand (BOD) using the closed bottle test (OECD guideline 301D). In addition, a C8 ketone fraction was nearly 60% degraded after 28 days using the Manometric respirometry (OECD 30 IF) test. These data suggest that the components of ketones, C12-branched will not be highly persistent in the environment. Volatilization is expected to be high given the estimated Henry's Law constant. Hydrolysis is expected to be negligible since the components of this mixture do not possess functional groups that are expected to hydrolyze under environmental conditions. The rate of atmospheric photooxidation is moderate. The constituents of ketones, C 12-branched are expected to have low persistence (PI) with the exception of the most highly branched isomers which may have moderate persistence (P2). All the constituents of this mixture are expected to possess low bioaccumulation potential (Bl). The environmental fate properties of Ketones, C 12-branched are provided in Table 2. Table 2. Environmental Fate Properties of Ketones, C12-branched and Supporting Chemical1'2 Property SPONSORED CHEMICAL SUPPORTING CHEMICAL Ketones, C12-branched Trimethyl 4-nonanone CASRN 68514-41-0 123-18-2 Photodegradation Half- life 7.3 hours (estimated)3 5.5 hours (estimated)3 Hydrolysis Half-life Stable Stable Biodegradation No data 48% degradation over 28 days by BOD (not readily biodegradable)4 Bioaccumulation Factor BAF = 2.3 (estimated)3 BAF = 2.3 (estimated)3 Log Koc 2.61 (estimated)5 2.55 (estimated)3 Fugacity (Level III Model)5 Air (%) 3.4 3.1 Water (%) 22.5 24.5 Soil (%) 73.6 72.0 Sediment (%) 0.4 0.4 Persistence5 PI (low) to P2 (moderate) PI (low) Bi oaccumul ati on5 Bl (low) Bl (low) ExxonMobil Chemical Company. 2009. Test Plan and Robust Summary for C12, Branched Ketones. Available online at http://www.epa.gov/oppt/chemrtk/pubs/summaries/cl2brchketones/cl6825tc.htm as of August 16, 2012. 2The sponsor proposed the branched ketone 4-decanone, 2,9-dimethyl- (CASRN unknown not on TSCA) as a typical representative structure for the sponsored chemical. 3U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Enviromnental Protection Agency, Washington DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of August 16, 2012. 4The Dow Chemical Company. 2006. Test Plan and Robust Summary for 4-Nonanone, 2,6,8-Trimethyl-. Available online at http://www.epa.gov/oppt/chemrtk/pubs/summaries/4non268t/cl5003tc.htm as of August 16, 2012. ^Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. 7 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Conclusion: Ketones, C12-branched is a mixture of branched ketones that is a co-product of methyl ethyl ketone (MEK) production and is never isolated from the waste MEK production stream. It is a liquid that is expected to have moderate vapor pressure and moderate water solubility. The components of this mixture are expected to have moderate mobility in soil. A representative component of this mixture was not readily biodegradable using a standard OECD test. The rate of degradation is expected to decrease with the degree of branching of the components of this mixture. Volatilization is considered high based on the Henry's Law constant of representative components of this mixture. The rate of hydrolysis is considered negligible since the constituents of this mixture do not contain functional groups that are expected to hydrolyze under environmental conditions. The rate of atmospheric photooxidation is considered moderate for the components of this mixture. The constituents of ketones, C12-branched are expected to have low persistence (PI) with the exception of the most highly branched isomers which may have moderate persistence (P2). All the constituents of this mixture are expected to possess low bioaccumulation potential (Bl). 3. Human Health Hazard A summary of health effects data submitted for SIDS endpoints is provided in Table 3. The table also indicates where data for the supporting chemical are read-across (RA) to the sponsored chemical. Acute Oral Toxicity Trimethyl 4-nonanone (CASRN123-18-2, supporting chemical) Albino rats (10 males/dose; strain not specified) were administered CASRN 123-18-2 (purity not specified) as a 20% dispersion in 1% Tergitol 7 via gavage at 6300, 7950, 10,000 or 12,600 mg/kg and observed for up to 14 days. Mortalities were observed at all dose levels: 3/10 at 6300 mg/kg, 4/10 at 7,900 mg/kg, 6/10 at 10,000 mg/kg and all animals at 12,600 mg/kg. LDso = 8470 mg/kg Methylheptenone (CASRN 409-02-9, supporting chemical) Crl:CD SD rats (5 females/dose) were administered CASRN 409-02-9 in corn oil via the oral route at 2000 mg/kg and observed for 15 days. No mortalities were observed. LD50 > 2000 mg/kg Acute Dermal Toxicity Trimethyl 4-nonanone (CASRN 123-18-2, supporting chemical) Rabbits (10 males/dose; strain not specified) were administered undiluted CASRN 123-18-2 (purity not specified) via the dermal route at 6500, 8180, 10,300 or 12,900 mg/kg under an impervious sheeting for 24 hours and observed for up tol4 days. Mortalities were observed at all dose levels: 2/10 at 7950 mg/kg; 4/10 at 10,000 mg/kg; 5/10 at 12,600 mg/kg, and 9/10 at 15,800 mg/kg. LD50 = 9030 mg/kg 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document Repeated-Dose Toxicity September, 2014 Methylheptenone (CASRN 409-02-9, supporting chemical) In a combined oral gavage repeated-dose/reproductive/developmental toxicity screening test, Crl:CD (SD) rats (10/sex/dose) were administered CASRN 409-02-9 (purity not specified) in corn oil at 0, 100, 300 or 500 mg/kg-day during a pre-mating period and continuing throughout gestation and post-parturition. The high-dose was reduced from 1000 mg/kg-day on day 3. One female in the mid-dose group and one female in the high-dose group were sacrificed early because they failed to litter. One female in the high-dose group was sacrificed following litter death. A single female in the high-dose group was sacrificed due to terminal signs. No additional mortalities were observed in treated animals. Treatment-related effects observed in the high-dose group prior to its reduction at day 3 included reduced activity, partially closed eyelids, piloerection, hunched posture, reduced body tone, prostration for up to 4 hours, mean weight loss and significantly low food consumption. Treatment-related clinical signs were not observed at any dose level following reduction of the highest dose. A significant decrease in absolute body weight was observed in high-dose females during lactation and a slight but not significant decrease in body weight gain was observed in the mid- and high-dose groups. No treatment-related effects were observed on hematological parameters. Treatment-related effects on functional observations in the high-dose group included a high incidence of weak tail pinch response during week 5 of treatment and low forelimb grip strength values in females only. A dose-related reduction in beam scores (cage floor activity) for all male treatment groups was observed during the first 6 minutes of recording during week 5. Treatment-related effects observed at gross pathology included significantly increased liver weights in mid- and high-dose males, increased adjusted ovarian weights in high-dose females and pale kidneys and macroscopically enlarged livers in high-dose males. An increased incidence of aggregations of all alveolar macrophages (minimal grade, excepting a single high- dose male presenting slight grade) was observed in the lungs of all treated male groups and the high-dose female group. The increase in incidence was slight and a dose response was not apparent; therefore, the finding was not considered to be of toxicological significance. Slight hepatocyte centrilobular hypertrophy was observed during histopathological examination of the liver in all treated male and female groups. This finding was considered to be an adaptive change and not a toxic effect of treatment. Increased incidence and minimal to moderate severity of cortical tubular hyaline droplets deposition5, tubular granular casts, cortical tubular basophilia and increased incidence of minimal to slight interstitial inflammation was observed in all treated male groups in conjunction with significantly increased kidney weights. Thyroid follicular cell hypertrophy (minimal severity) was observed in all male treatment groups and in mid- and high- dose females. This finding was not considered to be of toxicological significance to humans. LOAEL (male) = 100 mg/kg-day (based on decreased motor activity in the functional observational battery and thyroid follicular cell hypertrophy) NOAEL (male) = Not Established. LOAEL (female) = 300 mg/kg-day (based on thyroid follicular cell hypertrophy) NOAEL (female) = 100 mg/kg-day 5 The presence of nephropathy in association with the hyaline droplet accumulation in male rats suggests that the nephropathy in the males is occurring by an alpha2U-globulin-mediated mechanism, which appears to be unique to male rats and the response is probably not relevant to humans for purposes of risk assessment. EPA's Risk Assessment Forum has outlined the key events and the data that are necessary to demonstrate this mode of action (Alpha2U- Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Rat, EPA/625/3-91/019F). One of the key events, alpha2U-globulin accumulation, has not been demonstrated. Therefore, the nephropathy is assumed to be relevant to human health and it is concluded that a NOAEL for nephropathy in male rats was not established. 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document Reproductive Toxicity September, 2014 Methylheptenone (CASRN 409-02-9, supporting chemical) In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test that described above no treatment-related effects were observed on pre-coital interval, mating performance and fertility. An increased number of females exhibiting 4/5 day cycles or irregular cycles was observed at the high-dose. A treatment-related shift in the distribution of gestation lengths showing longer gestation periods was observed in the high-dose group; however, the gestation index was unaffected. A significant decrease in food consumption during lactation was observed in mid- and high-dose females on days 1-3 and 1-7, respectively. LOAEL (reproductive toxicity) = 500 mg/kg-day (based on irregular cycles, increased gestation period, and increased ovarian weight) NOAEL (reproductive toxicity) = 300 mg/kg-day Developmental Toxicity Methylheptenone (CASRN 409-02-9, supporting chemical) In a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test that described above developmental parameters unaffected by treatment included litter size, sex ratio, offspring development, survival and body weight performance. NOAEL (developmental toxicity) = 500 mg/kg-day (based on no effects at the highest dose tested) Genetic Toxicity — Gene Mutation In vitro Methylheptenone (CASRN 409-02-9, supporting chemical) Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and Escherichia coli strain WP2 uvrA (pKMlOl) were exposed to CASRN 409-02-9 (purity not specified) in dimethylsulfoxide (DMSO) at seven concentrations ranging from 5 to 5000 |ig/plate with and without metabolic activation. Positive and solvent controls were included; however, control response was not indicated. No cytotoxity was observed. No information was provided with respect to observations of precipitation. No substantial increases in revertant colony numbers over control counts were obtained in any of the tester strains following exposure to the test substance at any concentration up to 5000 [j,g/plate, with or without metabolic activation. Methylheptenone was not mutagenic in this assay. Genetic Toxicity — Chromosomal Aberrations In vitro Methylheptenone (CASRN 409-02-9, supporting chemical) Human lymphocytes were exposed to CASRN 409-02-9 (purity not specified) at concentrations ranging from 25 to 200 |ig/ml without metabolic activation or 50 to 1000 |ig/mL with metabolic 10 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document activation. Positive and solvent (DMSO) controls were included. An appropriate response was observed in the positive control. A statistically significant increase in chromosomal aberrations was observed at the 600 |ag/m L dose only in the first study with metabolic activation. No statistically significance increase in chromosomal aberrations was observed in the second test at any dose level with or without metabolic activation. Methylheptenone did not induce chromosomal aberrations in this assay. Additional Information Skin Irritation Trimethyl 4-nonanone (CASRN123-18-2, supporting chemical) In the acute dermal toxicity test described previously, erythema and occasional necrosis was observed in rabbits following dermal exposure to CASRN 123-18-2. Trimethyl 4-nonanone was severely irritating to rabbit skin in this assay. Conclusion: No data are available on the sponsored substance for the human health endpoints. The acute oral toxicity is low for supporting chemicals trimethyl 4-nonanone and methylheptenone in rats. The acute dermal toxicity in rabbits is low for supporting chemical trimethyl 4-nonanone. A combined oral gavage repeated-dose/reproductive/developmental toxicity study in rats with the supporting chemical, methylheptenone, showed decreased motor activity in a functional observational battery and thyroid follicular cell hypertrophy in males at 100 mg/kg-day, decreased food consumption during lactation and thyroid follicular cell hypertrophy in females at 300 mg/kg- day; the NOAEL for systemic toxicity in males is not established and in females is 100 mg/kg- day. Irregular cycles and increased gestation period were observed at 500 mg/kg-day; the NOAEL for reproductive toxicity is 300 mg/kg-day. No treatment-related developmental effects were observed at the highest-dose tested; the NOAEL for developmental toxicity is 500 mg/kg-day. The supporting chemical, methylheptenone, was not mutagenic in bacteria in vitro and did not induce chromosomal aberrations in mammalian cells in vitro. The supporting chemical, methylheptenone, is severely irritating to rabbit skin. 11 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 Table 3. Summary Table of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Human Health Data Endpoints SPONSORED CHEMICAL C12, branched ketones (68154-41-0) SUPPORTING CHEMICAL Trim ethyl 4- nonanone (123-18-2) SUPPORTING CHEMICAL Heptenone, methyl- (409-02-9) Acute Toxicity Oral LDso (mg/kg-bw) No Data 8470 (RA) 8470 >2000 Acute Toxicity Dermal LD50 (mg/L) No Data 9030 (RA) 9030 - Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) No Data NOAEL = Not Established LOAEL = 100 (RA) - NOAEL = Not Established LOAEL = 100 Reproductive Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) No Data NOAEL = 300 LOAEL = 500 (RA) - NOAEL = 300 LOAEL = 500 Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) NOAEL = 500 (hdt) (RA) - NOAEL = 500 (hdt) Genetic Toxicity - Gene Mutation In vitro No Data Negative (RA) - Negative Genetic Toxicity - Chromosome Aberrations In vitro No Data Negative (RA) - Negative Additional Information Skin Irritation - Severely Irritating - Bold = measured data (i.e., derived from experiment); (RA) = Read Across; - endpoint not addressed for this chemical 12 ------- U.S. Environmental Protection Agency Hazard Characterization Document September, 2014 4. Hazard to the Environment A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4. The table also indicates where data for the supporting chemical are read-across (RA) to the sponsored chemical. Acute Toxicity to Fish 2-Dodecanone (C12) (CASRN 6175-49-1, Supporting Chemical) Fathead minnow (Pimephales promeIas\ twenty fish per treatment) were exposed to an analog substance CASRN 6175-49-1 for 96 hours under unspecified condition to nominal concentrations of 0, 0.9, 1.38, 2.12, 3.26, and 5.01 mg/L. Corresponding mean, measured concentrations were 0, 0.33, 0.55, 0.66, 1.06, and 2.43 mg/L, respectively. Water quality parameters were the following: temperature=24.8 °C; DO = 6.8 mg/L; pH = 7.6. Mortality was 45 % in the 1.06 mg/L treatment and 100 % in the 2.43 mg/L treatment. 96-hour LCso = 1.18 mg/L Acute Toxicity to Aquatic Invertebrates Methylheptenone (C8) (CASRN 409-02-9, Supporting Chemical) Daphnids (Daphnia magna) were exposed under unspecified conditions to the analog substance methyl heptanone for 48 hours according to OECD 202 with WAF prepared nominal concentrations of 0, 0.75, 2.0, 3.9, 9.1, and 22 mg/L. Measured concentrations were analyzed using HSGC-FID but no values were reported. Water quality parameters were the following: temperature= 20.7 - 20.9 °C, DO = 8.2-8.4, pH =7.6 - 7.8, hardness = 142 mg/L as CaC03, and TOC of the dilution water was 0.54 mg/L. Mortality was 100% at 48 hours in the 9.1 and 22 mg/1 treatment groups 48-hour EC50 = 5.2 mg/L Toxicity to Aquatic Plants Methylheptenone (C8) (CASRN 409-02-9, Supporting Chemical) Green algae (Pseudokirchneriella subcapitata) were exposed under static conditions to the analog substance methyl heptanone for 72 hours according to OECD 201 with WAF prepared nominal concentrations of 0, 0.8, 1.6, 4.1, 8.8, and 19.9 mg/L. Measured concentrations were 0, 0.715, 1.42, 3.28, 7.71, and 12.9 mg/L. Water quality parameters were the following: temperature= 23.6 to 23.9°C, pH = 7.6 - 8.7, continuous light intensity = 7,700 - 8,400 lux. 72-hour ErCso = 16 mg/L 72-hour NOErC = 3.28 mg/L 72-hour EbCso = 8 mg/L 72-hour NOEbC = 0.715 mg/L 13 ------- U.S. Environmental Protection Agency September, 2014 Hazard Characterization Document Conclusion: No data are available on the sponsored substance for the ecotoxicity endpoints. For the supporting chemical, 2-dodecanone, the 96-h LC50 for fish is 1.18 mg/L. For the supporting chemical methylheptenone, the 48-h EC50 for aquatic invertebrates is 5.2 mg/L. Toxicity to aquatic plants, based on the supporting chemical methylheptenone, is 16 mg/L and 8 mg/L for growth rate and biomass, respectively. Table 4. Summary of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Aquatic Toxicity Data Endpoints SPONSORED CHEMICAL C12, Branched Ketones (68514-41-0) SUPPORTING CHEMICAL 2-Dodecanone (C12) (6175-49-1) SUPPORTING CHEMICAL Methyl heptanone (C8) (409-02-9) Fish 96-h LCso (mg/L) No Data 1.18 (RA) 1.18 - Aquatic Invertebrates 48-h ECso (mg/L) No Data 5.2 (RA) - 5.2 Aquatic Plants 72-h ECso growth rate (mg/L) biomass (mg/L) No Data 16 8 (RA) - 16 8 Bold = measured data (i.e. derived from testing), (RA) = read across, - indicates that endpoint not addressed for this chemical 14 ------- |