### SAT Report PMN Number: P-13-0248 SAT Date: 2/12/2013 Print Date: 8/2/2013

Related cases : Health related cases : Ecotox related cases:

Concern levels : Type of Concern: Health Eco Comments Level of Concern: 2 2

Persistence Bioaccum Toxicity Comments 3 12

Exposure Based Review : Health: N o Ecotox: Yes

Routes of exposure : Health: Dermal Drinking Water Inhalation Ecotox: All releases to water Fate: ;

P 2 Rec Comments : Comment: N o Commen t

Keywords : Keywords: IRR/CORR E,S,L,MM BLOOD THYROID N EURO ACUTE UNCRTN IMMUNO AQUATOX-A,C
Summary of Assessment :

Fate :Fate Summary: P-13-0248 FATE:

VP < 1.0E-6 torr at 25 C (E) BP > 400 C (E) H < 1.00E-8 (E) POTW removal (%) = 0; OECD 301C (MITI): 2% (BOD)/28d NRB; OECD 305 (Biocon): under detectable limit: <11-fold(low), <1-fold(high)/28d. Time for complete ultimate aerobic biodeg > mo Sorption to soils/sediments = low PBT Potential: P3B1 *CEB FATE: Migration to ground water = rapid

Health : Health Summary: Absorption is nil through the skin, and good through the lung and GI tract, based on physical/chemical properties. There are concerns for irritation/ p ossible corrosion to all exposed tissues and acute toxicity, based on information in the PMN MSDS and submitted test data. There also are concerns for blood and thyroid effects and neurotoxicity, as well as uncertain concern for immunotoxicity, based on submitted test data and lithium. Test Data: Submitted with the PMN:

Salmonella negative with and without activation; Chromosome aberration with CHL cells negative with and without activation; E. coli negative with and without activation; Rat repeat dose (28D) oral (gavage) toxicity NOAEL 30 mg/kg (M), 100 mg/kg (F), with signs of neurotoxicity, adverse effects to the thyroid, and blood toxicity; Irritating/corrosive to skin in male rabbits (1hr exposure with occlusive dressing); Rat (F) acute (15D) oral (gavage) toxicity LD50 > 50 <= 300 mg/kg

Ecotox :

Test Organism Test Type Test End Point Predicted Measured Comments

fish 96-h LC50 540 >100 daphnid 48-h LC50 120 71 green algal 96-h EC50 780 >100 fish

_ chronic value 6.7 >10 Acute to Chronic Ratio daphnid

_ chronic value 1.6 7.1 Acute to Chronic Ratio

algal

_ chronic value 190 70.7

Sewage Sludge 3-h EC50

_ Sewage Sludge

_ Chronic

_Value

Ecotox Values Comments: Predictions are based on SARs for lithium salts; SAR chemical class = lithium salt with 3.7% Li; MW 187; p H7; effective concentrations based on 100% active ingredients and mean measured concentrations; hardness <150.0 mg/L as CaCO3; and TOC <2.0 mg/L;

Ecotoxicity Test Data Results for P-13-0248

Acute ecotoxicity tests were conducted with fish , daphnia, and algae in 2010 on P-13-0248 by

The PMN material was a colorless and transparent liquid with an estimated vapor pressure of <1 x 10-6 mm Hg at 25 °C. The sorption to soils and sediments is low and the time to complete ultimate aerobic biodegradation is estimated to be greater than months. These studies complied with OECD guidelines for: 1) O2, p H, temperature, water hardness values and other water quality p arameters; 2) species, age, number of organisms per replicate, and biomass loading rates; and, 3) replicate and overall variability. The tests were performed in a GLP laboratory and a quality assurance statement provided for each test.

Fish Ecotoxicity Test: conducted a 96-hour acute toxicity study in Medaka (Oryzias latipes ) with P-13-0248 ( content: 24.0% aqueous solution) under semi-static conditions (48-hour renewal cycle). The study was reported to follow the “Testing Methods for N ew Chemical Substances” ( N ovembe r 21, 2003; N o. 1121002, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare). Following the results of a range-finding study, a single replicate of seven O. latipes was exposed to a dilution water control (dechlorinated tap water) or the PMN substance at a nominal concentration of 100 mg/L (initial measured concentration of 103 mg/L). To prepare the 100 mg/L test solution, 300 mg of the test substance (1249.8 mg as aqueous solution) was weighed and transferred to a 1000-mL volumetric flask and dissolved in dechlorinated tap water. This solution was transferred into the test chamber and then added 2 L dechlorinated water to prepare the exposure solution. The test substance concentrations in the test solutions ranged from 99.0 to 103% of the nominal concentration during the exposure period, according to LC/MS/MS analysis. Throughout the exposure period, no turbidity or precipitate was observed and the test solutions were clear and transparent. Over the course of testing, temperature was maintained at 22.8

–22.9  ̊ C, p H range d from 7.4-8.0, and dissolved oxygen ranged from 6.5-8.0 mg/L. Dilution water hardness was 60 mg CaCO3/L. A loading rate of 0.23 g fish/L was calculated. N o mortality or abnormal responses were observed during the exposure; therefore, the 96-hour LC50 is greater than 100 mg/L (nominal concentration). 96-hour LC50 > 100 mg/L

Daphnid Ecotoxicity Test: conducted a 48-hour test in water fleas (Daphnia magna ) with P-13-0248 ( content: 24.0% aqueous solution) under static conditions. Thestudy was reported to follow the “Testing Methods for New Chemical Substances” ( N ovembe r 21, 2003; N o. 1121002, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare). Following the results of a range-finding study, four replicates of five daphnids were exposed to a dilution water control (dechlorinated tap water) or the PMN test substance at nominal concentrations of 6.26, 12.5, 25.0, 50.0, and 100 mg/L. Corresponding initial measured concentrations of 6.48, 12.7, 25.5, 53.0, and 105 mg/L (102

–106% of nominal) were determined by LC/MS/MS analysis. To prepare the test solutions, an amount of test substance (417 mg as aqueous solution; 100 mg as LiFSI) was weighed and transferred at a 1000-mL volumetric flask and dissolved in dechlorinated tap water (two solutions were prepared, one was for stock solution and another was for the test solutions). The stock solutions (31.3, 62.5, 125 and 250 mL) were separately transferred to 500-mL flasks and brought to volume with dechlorinated tap water to prepare the test solutions of 6.26, 12.5, 25.0, and 50.0 mg/L, respectively. All test solutions in the exposure and control groups were colorless and transparent during the exposure period. At the end of the exposure period, measured concentrations were determined to be 6.12, 12.3, 25.3, 49.3, and 98.0 mg/L (97.8

–101% of nominal). Over the course of testing, temperature was maintained at 19.6-19.7  ̊ C, p H ranged fro m 7.8-7.9, and dissolved oxygen ranged from 7.3-9.1 mg/L. Dilution water hardness was 55 mg CaCO3/L. A loading rate of 50 daphnids /L was calculated. Abnormal behavior was observed during the exposure duration in the nominal concentrations of 25, 50, and 100 mg/L. One hundred percent immobilization was observed in the highest nominal test concentration resulting in a 48-hour EC50 of 71 mg/L (nominal concentration). 48-hour EC50 = 71 mg/L

Algal Ecotoxicity Test: conducted a 72-hour growth inhibition study in green algae (Pseudokirchneriella subcapitata) with P-13-0248 ( content: 24.0% aqueous solution) under static conditions. The study was reported to follow the “Testing Methods for New Chemical Substances” ( N ovembe r 21, 2003; N o. 1121002, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare). Following the results of a range-finding study, six replicates of P. subcapitata (5000 cells/mL) were exposed to a dilution water (OECD medium) control and three replicates were exposed to the PMN substance at nominal concentrations of 6.25, 12.5, 25.0, 50.0, and 100 mg/L. Algae were illuminated at a light intensity ranging from 69

–86 μE/m2/s with constant shaking. The test solutions were prepared by adding the test substance (624.9 mg; 150 mg as LiFSI) to a 300-mL volumetric flask and dissolved in the OECD medium and the volume was adjusted to prepare a 500 mg/L stock solution. The stock solutions (6.25, 12.5, 25.0, 50.0 and 100 mL) were separately transferred to 500-mL flasks and filled to volume with OECD medium to prepare the test solutions. The concentrations of the test substance in the test solutions were 104-106% of the nominal at the exposure initiation and 99.6-103% of the nominal at the exposure termination, according to LC/MS/MS analysis. Due to problems with the control growth rate in the definitive test, a second definitive test was conducted. The first definitive test was not used by the testing laboratory. The results of the first definitive test were not included in the algal submission. The information provided in this 72-hr algal toxicity test review only reflects results from definitive test number two. The concentrations were stable during the exposure period. Over the course of testing, temperature was maintained at 22.9-23.0  ̊ C, and the pH ranged from 7.9-8.1. The cell density in the control increased by a factor of 172 after 72 hours. The 72-hour EC50 for growthrate is > 100 mg/L. Abnormal algal shapes were observed in the highest test concentration (nominal 100 mg/L). The NOEC and LOEC for growth rate are 50 and 100 mg/L, respectively, and the ChV (geometric mean of the NOEC and LOEC) is 70.7 mg/L. 72-hour EC50 (growth rate) > 100 mg/L 72-hour NOEC = 50 mg/L 72-hour LOEC = 100 mg/L 72-hour ChV = 70.7 mg/L

Conclusions: The fish (96-hour LC50 > 100 mg/L), daphnia (48-hour EC50 = 71 mg/L), and algal (72-hour EC50 (growth rate) > 100 mg/L and 72-hour ChV = 70.7 mg/L) toxicity studies are acceptable for P-13-0248. For comparative purposes, the fish (96-hr LC50), acute daphnia (48-hr EC50), and algal (96-hr EC50) toxicity values, based on SARs for P-13-0248, are 540 mg/L, 120 mg/L, and 780 mg/L, respectively. In addition, based on the same SAR equations, the fish, daphnia, and algal chronic values for P-13-0248 are 6.7 mg/L, 1.6 mg/L, and 190 mg/L, respectively. The acute concentration of concern (CoC) is calculated by dividing the 48-hr acute toxicity value for D. magna by an uncertainty factor of 5 yielding 14,200 p pb (71,000 μg/L / 5). The fish and daphnia chronic values for P-13-0248 are calculated dividing their experimental acute toxicity values by an acute to chronic ratio (ACR) of 10. The fish and aquatic invertebrate chronic values for P-13-0248 are > 10 mg/L and 7.1 mg/L, respectively. The chronic concentration of concern for P-13-0248 is calculated by dividing the lowest aquatic chronic value (D. magna-7.1 mg/L) by an uncertainty factor of 10 yielding 710 μg/L or 710 p pb.

The acute CoC = 14,200 p pb The chronic CoC = 710 p pb

Ecotox Study Reviewer: J. Gallagher February 13, 2013

Factors Values Comments Assessment Factor 10 Concentration of Concern ( p pb) 710

SARs SAR Class Ecotox Category N one

Ecotox Factors Comments:

SAT Chair: J. Kwiat