### SAT Report PMN Number: P-14-0756 SAT Date: 8/8/2014 Print Date: 2/3/2015

Related cases : CBI : Yes

Concern levels : Type of Concern: Health Eco Comments Level of Concern: 1-2 3

Persistence Bioaccum Toxicity Comments 2 11

Exposure Based Review : Health: N o Ecotox: N o

Routes of exposure : Health: Dermal Inhalation Ecotox: All releases to water Fate: ;
Keywords : Keywords: UNSERT BLOOD

Summary of Assessment :

Fate : Fate Summary: P-14-0756 FATE: Solid with MP = 147-151 C (M) log Kow = 3.60 (M) S = 1 mg/L at 25 C (M) VP < 1.0E-6 torr at 25 C (E) BP = Dec. 249 C (M) H < 1.00E-8 (E) log Koc = 3.86 (E) log Fish BCF = 2.04 (E), 1.55-2.12 (M) log Fish BAF = 2.03 (E)POTW removal (%) = 15 via sorption and biodeg; OECD 301F(Mano Resp): 2% (avg)/28d, -1%(avg)/67d; OECD 301D( Closed Btl): 1.44%/28d; OECD 302C(Mano Resp): -6% (avg)/28d, -7% (avg)/31d; OECD111(Hydrolysis): t1/2( p H 4, 7,9): <10% after 120 hrs; OECD 305(Bioconcentration): 131.8 (low), 35.9 (high)/28d. Time for complete ultimate aerobic biodeg ≥ mo Sorption to soils/sediments = moderate PBT Potential: P2B1 *CEB FATE: Migration to ground water = moderate

Health : Health Summary: N ot absorbed through the skin as neat material, moderate absorption through the skin if in solution, moderate through the GI tract and lungs based on
p hysical/chemical properties. There is uncertain concern for blood toxicity based on the submitted data. Test Data: Ames test Salmonella and E. coli negative with and without activation. Mouse Micronucleus Assay (oral) - negative Acute dermal – LD50 > 2000 mg/kg-bw Acute oral – LD50 > 2000 mg/kg-bw Acute (4 hr) inhalation rats – LD50 > 5.7 mg/L Eye irritation in rabbit – non-irritating Dermal irritation in rabbit – non-irritating OECD 429 Skin Sensitization Local Lymph Nodes Assay (reviewed)

– negative 5-day dietary repeated dose range finding test – lower food consumption and lower body weight at 200, 500, and 1000 mg/kg/day. 14-day dietary repeated dose – NOAEL 500 mg/kg/day. At 1000 mg/kg/day (next dose) - hematological changes, no was detected in the blood. OECD 408 repeated dose, dietary 90day – authors proposed NOAEL was 1000 mg/kg/day. Some changes in hematology and clinical chemistry were observed at 100, 300, and 1000 mg/kg/day. in vitro assay to detect potential release with rat and human primary liver cells (4 hr incubation)

– at 250 μM cells toxic effect was observed; human hepatocytes converted 1.2% of PMN into

Ecotox :

Test Organism Test Type Test End Point Predicted Measured Comments

fish 96-h LC50 0.60 > 0.823 >0.03-0.15

daphnid 48-h LC50 0.34 1.02 green algal 96-h EC50 0.060 > 1.03

fish

_ chronic value 0.009daphnid

_ chronic value 0.048 0.102 Predicted from Measured using 10 algal

_ chronic value 0.18 N OEC = 1.03 LOEC > 1.03 Sewage Sludge 3-h EC50

_ Sewage Sludge

_ Chronic Value _

Ecotox Values Comments: Predictions are based on SARs for ; SAR chemical class = ; log Kow = 4.68 (EPI); solid with mp = 151 C (M); S = 0.164 mg/L at 20 C (P); 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 Data Results: Case Number: P-14-0756 N ame:

Initial Data Review

Fish Toxicity Summaries: (1) conducted a 96-hour acute toxicity test in rainbow trout (Oncorhynchus mykiss) with P-14-0756 (> 99% p urity) under semi-static conditions with daily renewal. This study was reported to follow OECD Test Guideline No. 203 (1992) and EC Method C.1 (1992). Based on the results of a formulation trial, the limit of aqueous solubility of the test substance in dechlorinated tap water was approximately 1.2 mg/L. Following a range-finding test, single replicates of seven O. mykiss were exposed to a dilution water control (dechlorinated tap water), a solvent control ( or the test substance at nominal concentrations of 0.427, 0.939, 2.07, 4.54 or 10.0 mg/L. Corresponding geometric mean measured concentrations of the test substance were 0.0408, 0.0921, 0.197, 0.403 and 0.823 mg/L, as determined by analysis (LOQ = 0.02 mg/L; LOD = 5 ng/mL). An aqueous preparation of the test substance was prepared by dissolving the test substance (1 g) in ; 10 mL). The contents of the flask were shaken vigorously before an (2 mL) was dispersed in the diluent water (ca. 2.5 L) in a volumetric flask (5 L). This intermediate dilution was treated by ultrasound for 20 minutes, with mixing at 5 minute intervals, checking after each interval that the temperature remained below 50°C, before being adjusted to volume (5 L) in the flask. The contents of the flask were poured into a glass aspirator containing diluents water (10 L) and were stirred overnight in the dark. On the cessation of stirring, the contents of the aspirator were filtered (0.2 μm pore size, and the resultant (saturated) solution was either used directly or was further diluted to
p rovide the test media at the four lower concentrations. At all concentrations, the test media were clear and colorless. Over the course of testing, temperature ranged from 14.2

– 15.3°C, p Hranged from 7.80

– 8.45 and dissolved oxygen ranged from 84

– 102% ASV. The dilution water hardness was 174

– 176 mg/L as CaCO3 and the TOC was 0.87 mg C/L. A loading rate of 0.92 g fish/L was reported. N o mortalities occurred during the study. Treatment-related effects were observed at concentrations ≥ 0.197 mg/L. These effects included the following: loss of orientation, nose pointing down; dark body and eye orbital area; hyperactive, erratic swimming; lethargy (on base of vessel); overturned but mobile; overturned but immobile; trailing feces with mucus and reduced opercular movement. Based on geometric mean measured concentrations, the 96-hour LC50 was > 0.823 mg/L. 96-hour LC50 > 0.823 mg/L

(2) conducted a 96-hour acute toxicity test in zebra fish with P-14-0756 ( p urity not provided) under semi-static conditions with daily renewal. This study was reported to follow OECD Test Guideline No. 203 (1992). The water solubility of the test substance was reported to be 1 mg/L. Following a range-finding test, two replicates of ten B. rerio were exposed to a dilution water control (dechlorinated tap water) or the test substance at a nominal concentration of 100 mg/L. A corresponding mean measured concentration of the test substance was 0.03~0.15 mg/L, as determined via analysis. The test medium with a loading rate of 100 mg/L was prepared by weighing 300 mg of test substance into 3 L of test water. The test substance was mixed into the test water as homogenously as possible by stirring for 4 hours at room temperature in the dark to dissolve a maximum concentration of the test substance in the dispersion. The supersaturated stock dispersions of the test substance were filtered through the 0.45 μm of membrane filter. The were used as test medium. Over the course of testing, temperature was maintained at 23.0-23.2°C, p H ranged fro m 7.85

– 8.21 and dissolved oxygen ranged from 75.1

–

95.3% ASV. The dilution water hardness ranged between 10 - 250 mg/L as CaCO3. A loading rate of 0.4 g fish/L was calculated. N o mortalities occurred during the study. Based on mean measured concentrations, the 96-hour LC50 was greater than 0.03~0.15 mg/L. 96-hour LC50 > 0.03~0.15 mg/L

Daphnid Toxicity Summary: . conducted a 48-hour immobilization test in water fleas (Daphnia magna) with P-14-0756 (> 99% p urity) under static conditions. This study was reported to follow OECD Test Guideline No. 202 (2004) and EC Method C.2 (1992). Based on the results of a formulation trial, the limit of aqueous solubility of the test substance in test medium was approximately 1.2 mg/L. Following a range-finding test, four replicates of five D. magna were exposed to a dilution water control ), a solvent control or the test substance at nominal concentrations of 0.625, 1.25, 2.5, 5 or 10 mg/L. Corresponding geometric mean measured concentrations of the test substance were 0.0735, 0.150, 0.304, 0.588 and 1.20 mg/L, as determined by analysis (LOQ = 0.05 mg/L; LOD = 5 ng/mL). An aqueous preparation of the test substance was prepared by dissolving the test substance (1 g) in 10 mL). The contents of the flask were shaken vigorously before an aliquot (0.2 mL) was dispersed in the dilution medium (ca. 1900 mL) in a 2-L volumetric flask. This intermediate dilution was treated by ultrasound for 20 minutes, with mixing at 5 minute intervals, before the contents of the flask were adjusted to the base of flask neck. The contents of the flask were stirred overnight in the dark and on cessation of stirring it was made up to volume (2 L) and the contents filtered (0.2 μm pore size,). The resultant (saturated) solution was either used directly or was further diluted to provide the test media at the four lower concentrations . Each vessel was loosely covered with a watch-glass. Over the course of testing, temperature ranged from 20.1

– 20.6°C,
p H ranged fro m 7.37

– 8.10 and dissolved oxygen ranged from 96

– 103% ASV. The dilution water hardness was 224 mg/L as CaCO3. A loading rate of 50 daphnids/L was calculated. N o immobilization was observed at mean measured concentrations ≤ 0.588 mg/L, and 70% immobilization was observed at 1.20 mg/L. Based on geometric mean measured concentrations, the 48-hour EC50 was 1.02 mg/L. 48-hour EC50 = 1.02 mg/L

Algae Toxicity Summary: . conducted a 72-hour algal growth inhibition assay in green algae with P-14-0756 (> 99% p urity) under static conditions. This study was reported to follow EC Method C.3, OECD Test Guideline No. 201 (1984) and the
p roposal for updating OECD Guideline No. 201, document 2-2, revision 2 (2004). Based on the results of a formulation trial, the water solubility of the test substance was approximately 1.2 mg/L. Following a range-finding test, six replicates of P. subcapitata (1.19 x 104 cells/mL) were exposed to a dilution medium control (OECD medium), a solvent control and OECD medium) or the test substance at a nominal concentration of 10 mg/L. The corresponding mean measured test concentration was 1.03 mg/L, as determined by analysis (LOQ = 0.05 mg/L; LOD = 0.025 mg/L). The algae were illuminated at a light intensity of 6750

– 6810 lux with constant shaking. An aqueous preparation of the test substance was
p repared by dissolving the test substance (1 g) in ; 10 mL). The contents of the flask were shaken vigorously before an aliquot (0.1 mL) was dispersed in sterile algal medium (ca. 700 mL) in a volumetric flask (1 L). This intermediate dilution was treated by ultrasound for 20 minutes, with mixing at 5 minute intervals, before the volume in the flask was adjusted to the base of the flask neck. The contents of the flask were stirred overnight in the dark and on cessation of stirring it was made up to volume (1 L) and the contents were filtered (0.2 μm pore size, . The resultant (saturated) solution was used directly as the test medium. Test flasks were loosely plugged with a foam bung. On day the day of
p reparation, the test medium was clear and colorless. Over the course of testing, temperature ranged from 22.7

– 23.8°C and pH ranged from 7.92

– 9.62. The mean cell density in control cultures was increased by a factor of 142 within 72 hours. Compared to the solvent control cultures, neither the area under the growth curve nor the average specific growth rate was significantly reduced in cultures exposed to the test substance. Based on the mean measured test concentration, the 72-hour EC50 value for growth rate and biomass was > 1.03 mg/L. The 72-hour NOEC and LOEC values were 1.03 mg/L and > 1.03 mg/L, respectively. 72-hour EC50 (growth rate and biomass) > 1.03 mg/L 72-hour NOEC (growth rate and biomass) = 1.03 mg/L 72-hour LOEC (growth rate and biomass) > 1.03 mg/L

Earthworm Toxicity Summary: conducted a 14-day acute toxicity test in earthworms (Eisenia foetida) with P-14-0756 (99.2% p urity). This study was reported to follow: The guidelines for the testing of chemicals, 153-2004); The guidelines for the testing of chemicals,(2004); EC Method C.8 (2008); OECD Test Guideline No. 207 (1984); OPPTS Method 850.6200 (1996). Following a range -finding test, a definitive test was
p erformed in (cation exchange capacity: 29.76 cmol(+)/kg; p H: 8.45; organic matter: 28.73 g/kg; character: clay) and (cation exchange capacity: 10.6 cmol(+)/kg; p H: 5.29; organic matter: 9.94 g/kg; character: clay). For each soil, three replicates of ten were exposed to a blank control or the test substance nominal concentrations of 100 or 1000 mg/kg-soil. Seven-hundred fifty grams (750 g) of test soil, 150 mL of distilled water and test substance were added to each test container of the treatment group. Only soil and water were added to containers of the control group. The test substrate in all containers was mixed thoroughly before the introduction of the test worms. The containers were sealed with
p lastic films. The test temperature was 20±1°C with humidity of 80

– 85%. N o mortalities or abnormalities were observed during the study. Based on nominal concentrations, the 14-day LC50 was > 1000 mg/kgsoil in both

. 14-day LC50 > 1000 mg/kgsoil

submitted five ecotoxicity studies (two on fish, one daphnia, one green algae, and one earthworm) on PMN substance, P-14-0756. The submitted studies on PMN (P-14-0756) are considered to be acceptable. The test results will be used to calculate the concentrations of concern for P-14-0756. For comparative purposes, the QSAR- p redicted acute fish, Daphnia, and algae values for P-14-0756 are 0.60 mg/L, 0.34mg/L, and 0.06 mg/L, respectively. The predicted chronic values for fish, Daphnia, and algae are 0.009 mg/L, 0.048 mg/L, and 0.18 mg/L, respectively.

The acute for P-14-0756 is 204 p pb (1020 p pb÷5(uncertainty factor)), based on the experimentally-derived 48-hour EC50 of Daphnia. The chronic for P-14-0756 is 0.9 p pb ( ≈ 1 p pb) (9 p pb÷10 (uncertainty factor)), based on the QSAR predicted fish chronic value.

The reason for using this fish chronic value for calculating chronic is that the treatment-related effects were observed at concentrations ≥ 0.197 mg/L in one acute fish test. The observed effects included the following: loss of orientation, nose pointing down; dark body and eye orbital area; hyperactive, erratic swimming; lethargy (on base of vessel); overturned but mobile; overturned but immobile; trailing feces with mucus and reduced opercular movement. Therefore, although no lethality was observed in the acute study, the observed effects cannot be discarded for possible chronic effects. In addition, no chronic study either on fish or Daphnia has been submitted, indicating a chronic data gap.

Acute = 204 p pb Chronic = 1 p pb

Ecotox Reviewer: Anne Kim August 20, 2014

Factors Values Comments Assessment Factor10 Concentration of Concern ( p pb) 1

SARs SAR Class Ecotox Category N one

Ecotox Factors Comments:

SAT Chair: Viktor Morozov