# August 16 , 2013

U.S. Environmental Protection Agency

Office of Pollution Prevention and Toxics

Confidential Business Information Center (CBIC) – TS7407M

Attention: Audrey Binder

EPA East Building, Room 6428

1201 Constitution Avenue, NW

Washington, DC 20004-3302

Dear Ms. Binder:

Reference: PMN P-12-0425

Submission Report Number –

Update of Attachment 1 (Toxicity Testing Summary)

Please also find attached an updated version of At tachment 1 (confidential copy and public copy).

A new study has been added for the PMN substance.

The study will be conducted in compliance with the Good Laboratory Practice Standards. An

OECD Guideline OECD, Section 4 (Part 412): Subacute Inhalation Toxicity: 28-Day Study,

Guideline for the Testing of Chemicals (2009) has been scheduled for the test substance. The

objective of this study is to evaluate the potential cumulative toxicity of the test substance when

administered 6 hours per day, 5 days per week by inhalation to male and female rats for a period

of approximately 28 days.

Male and female rats will be exposed to the test substance via inhalation to the test substance 6

hours per day, 5 days per week for 28 days, and then sacrificed. Additional satellite recovery

groups will be sacrificed after an approximate 28 -day recovery period. The following parameters

will be used to assess the potential toxicity: body weight, food consumption,

mortality/moribundity, clinical observations, ophthalmological evaluations, neurobehavioral

evaluations, and anatomic and clin ical pathology evaluations.

Dose levels will be selected based on previous repeat ed dose oral toxicity studies (up to 90 days in

duration) and an acute inhalation study where th e rat whole-body 4-hour LC50 was greater than

15,000 ppm (the highest achievable vapor concentration). In this study, anesthetic effects were

observed at concentrations greater than or equal to 9700 ppm and the no-observed-adverseeffect-level (NOAEL) for CNS effects during ex posure was 5000 ppm. There were no other

abnormal clinical signs of toxicity observed in any rats when they were removed from the

exposure chamber or throughout the 14-day reco very period. The NOAEL for histopathological

changes of the respiratory tract, liver and kidneys was 15,000 ppm.

# Please contact me if you have any questions about this submission or need further clarification.

Via eTSCA Client (attachm ents)

cc: Rebecca von dem Hagen (EPA, Office of Air and Radiation, Stratospheric Protection

Division)

# EPAX130816959911761 

# X

PPXP120622354273551 D1493P P120425

Jun 22, 2012

CDX



# X

XXX XXX

XXX XXX

XXX XXX

XXX

XXX XXX XXX



# X

XXX XXX

XXX XXX

XXX XXX

XXX

XXX XXX XXX

XXX XXX



# X SANITIZED SUBMISSION

# X

XXX SANITIZED SUBMISSION

# 001 EPA Letter (P-12-0425) (New Study - 26-Day

Inhalation) (8-16-2013) (public) EPA Letter (P-12-0425) (New

Study - 26-Day Inhalation) (8-16- 2

002 P-12-0425 Toxicity Testing Summaries (Updated

8-16-2013 (public) P-12-0425 Toxicity Testing

Summaries (Updated 8-16-2013) 4 SANITIZED SUBMISSION

# ATTACHMENT HEADER SHEET

Attachment Number 001

Attachment Name

EPA Letter (P-12-0425) (New Study - 26-Day Inhalation) (8-16-2013) (public)



# Associated PMN Section Number

N/A

Does not contain CBI



# Report Number

EPAX130816959911761 SANITIZED SUBMISSION

# ATTACHMENT HEADER SHEET

Attachment Number 002

Attachment Name

P-12-0425 Toxicity Testing Summaries (Updated 8-16-2013 (public)



# Associated PMN Section Number

N/A

Does not contain CBI



# Report Number

EPAX130816959911761 SANITIZED SUBMISSION15-Jun-2012; UPDATED 12-Nov-2012, 7-May-2013; 16-August-2013Test TypeReport #Test SystemCommentsResultsAcute Oral (LD50)RatGLP;GuidelineThe female rat oral LD50 was greater than 5000 mg/kg (limit dose). There were nodeaths during the exposure recovery period.Acute Inhalation (4-hr LC50)Rat, whole-bodyGLP;NotGuidelineThe male and female rat, whole-body inhalation 4-hr LC50 was greater than 15,000ppm (the highest achievable vapor concentration). There were no deaths during the exposureor recovery period. Anesthetic effects were observed at concentrations greater than or equalto 9700 ppm and the no-observed-adverse-effect-level (NOAEL) for CNS effects duringexposure was 5000 ppm. There were no abnormal clinical signs of toxicity observed in anyrats when they were removed from the exposure chamber or throughout the 14-day recoveryperiods. The NOAEL for histopathological changes of the respiratory tract, liver and kidneysis also 15,000 ppm.Acute Inhalation (4-hr LC50)Rat, nose-onlyGLP;GuidelineThe test substance was an azeotrope blend containing.The azeotrope blend male and female rat, nose-only inhalation 4-hr LC50 was 31,000 ppm(140 mg/L).Acute Dermal (LD50)RatGLP;GuidelineThe male and female rat dermal LD50 was greater than 5000 mg/kg (limit dose).There were no deaths during the exposure recovery period.Dermal IrritationRabbitGLP;Guidelinewas not a dermal irritant when tested in rabbits. No clinical signs of toxicity wasobserved in the study.Dermal SensitizationMouseGLP;Guidelinewas not a dermal sensitizer when tested in mice. No clinical signs of toxicity wasobserved in the study.Eye IrritationRabbitGLP;Guidelinewas not an eye irritant when tested in rabbits. No clinical signs of toxicity wasobserved in the study.Bacterial Reverse Mutation Assay(Ames)BacteriaGLP;Guidelinewas not mutagenic in the Bacterial Reverse Mutation Assay (Ames) test usingSalmonellastrains TA98, TA100, TA1535, and TA1537 andE. colistrain WP2uvrA eitherin the presence or absence of an S9-activated test system.In Vitro Chomosome AberrationChinesehamster ovary(CHO) cellsGLP;Guidelinedid not produce structural or numerical chromosome aberrations in anin vitromammalian chromosome aberration test using Chinese hamster ovary (CHO) cells either inthe presence or absence of an S9-activated test system.In Vivo MicronucleusRatGLP;GuidelineMale and female rats were exposed to a single oral dose of 0, 500, 1000, or 2000 mg/kg. No clinical signs of toxicity or mortality was observed in the study. did notinduce biologically relevant increases in micronucleated reticulocytes in peripheral bloodcells.28-Day OralRatGLP;GuidelineMale and female rats were exposed to 0, 250, 500 or 1000 mg/kg via oral gavagefor 28 days. No test substance-related adverse effects were observed in clinical or anatomicalpathology assessments. The no-observed-adverse-effect level (NOAEL) was 1000mg/kg/day.Completed Studies (PMN Substance)28-Day Oral with FOB(a)P100578RatGLP;GuidelineMale and female rats were exposed to 0, 100, 250, or 1000 mg/kg via oral gavagefor 28 days. No test substance-related adverse effects were observed in clinical,neurobehavioral, or anatomical pathology assessments. The no-observed-adverse-effect level(NOAEL) was 1000 mg/kg/day.90-Day Oral with FOBDuPont 18157-1026 RatGLP;GuidelineMale and female rats were exposed to 0, 250, 500 or 1000 mg/kg via oral gavagefor 90 days. No test substance-related adverse effects were observed in clinical,neurobehavioral, or anatomical pathology assessments in females. A slight increase inseverity, but not incidence, of chronic progressive nephropathy (CPN) and associated clinicalpathology changes was observed in males at all dose levels. The no-observed-adverse-effectlevel (NOAEL) for female rats was 1000 mg/kg/day. The NOAEL was not determined formale rats.Pre-natal Oral Developmental DuPont 18157-841 RatGLP;GuidelineFemale rats were exposed to 0, 250, 500, or 1000 mg/kg per day via oral gavageduring gestation day (GD) 6-20. No test substance-related maternal or developmental toxicitywas observed at any dose level. The no-observed-adverse-effect level (NOAEL) for maternaland fetal effects was 1000 mg/kg.Intravenous Tolerability Study DuPont 18157-1231 RatNot GLP;NotGuidelineMale and female rats were exposed to to a single intravenous injection of 0, 1, or 5 mg/kg. No deaths, clinical signs, or body weight losses occurred in any animal after 4days of observation.Toxicokinetics Test (Absorption)(e)DuPont 18157-1389(China report numberZWY2012HD006)RatNot GLP;NotGuidelineMale rats were administered 10 mg/kg by a single intravenous injection, 1500 or30,000 mg/kg by a single oral gavage, or 1500 mg/kg by oral gavage for 14consecutive days. Blood was withdrawn at various timepoints by direct venous puncture andthe concentration of in the blood was measured by GC-MS. may havelimited cumulative effects in rats after repeated exposure.Bioconcentration Study(b)A100071 FishGLP;GuidelineMedaka were exposed to 0.005 or 0.05 mg/L in a continuous flow-through dilutionsystem for 60 days followed by a 14-day depuration period. The steady-state BCF valuesranged from 1100 to 2210 for the 0.05 mg/L level and from 1560 to 2850 for the 0.005 mg/Llevel. The concentration of in the fish decreased with time during the depurationperiod. The biological half-lives ranged from 3.1 to 6.6 days for the 0.05 mg/L level andfrom 2.5 to 4.7 days for the 0.005 mg/L level. Average BCF for 12 datapoints = 1990±460.Algae Growth Inhibition Test(b)A100360 Green algaeGLP;GuidelineThe green algae 72-hr ErC50 was greater than 0.000477 mg/L (the highestconcentration tested). The no observed effect concentration (NOECr) at 72 hours was0.000477 mg/L (the highest dose tested). The concentration was the time-weighted mean ofthe limit of solubility (0.16 mg/L) after 72-hours. During the course of the study, it wasdetermined that the test substance was volatilized from the test solutions due to a largeHenry's law constant of 4.75E6 m3/mol.Algae Growth Inhibition TestDuPont 18157-315RV1Green algaeNot GLP;NotGuidelineThe green algae 72-hr ErC50 was greater than 120 mg/L (the highest concentrationtested).Fish Acute Toxicity Test(b)A100362 MedakaGLP;GuidelineThe Medaka 96-hr LC50 was greater than 0.0.960 mg/L (the highest concentrationtested). The concentration was the time-weighted mean of the limit of solubility (0.1 mg/L)after 96-hours. The test solution was renewed every 24 hours.Fish Acute Toxicity TestDuPont 18157-295RV1FatheadMinnowNot GLP;NotGuidelineThe fathead minnow 96-hr LC50 was greater than 120 mg/L (the highestconcentration tested).Daphnia Acute Immobilization Test(b)DaphniamagnaGLP;GuidelineThe Daphnia magna 48-hr EC50 was greater than 0.157 mg/L (the highestconcentration tested). The concentration was the time-weighted mean of the limit ofsolubility (0.17 mg/L) after 48-hours. The test solution was renewed after 24 hours.Daphnia Acute Immobilization TestDaphniamagnaNot GLP;NotGuidelineThe Daphnia magna 48-hr EC50 was greater than 120 mg/L (the highestconcentration tested).Daphnia Reproduction Test(c)DaphniamagnaGuidelineThe 21-day NOAEL (reproduction and body length) = 100 mg/L (measured concentrationwas 0.107 mg/L based on solubility) - highest concentration tested; LOAEC > 100 mg/LZebrafish 14-day Growth Study(c)Zebrafish GuidelineThe 14-day NOAEC (lethality) = 100 mg/L (measured concentration was 0.08851 mg/Lbased on solubility) - highest concentration tested; LOAEC > 100 mg/LEarthworm Acute Toxicity Test(c)EiseniafoetidaGLP;GuidelineThe Eisenia foetida 14-day LC50 was greater than 1011 mg/kg dry soil (the highestand only concentration tested).Activated Sludge RespirationInhibition TestMicrobialGLP;GuidelineThemicrobial respiration inhibition EC50 was greater than 1000 ppm (highestdose tested). No inhibition was noted at any concentration.Adsorption Coefficient (Log Koc)NAGLP;GuidelineThe study was conducted using the HPLC Method for determining a substance's absorptioncoefficient (soil organic carbon/water) on soil and sewage sludge. The adsorption coefficient(log Koc) value of the test substance was calculated to be 4.50 on soil and 4.43 on sewagesludge.LogKow (modelled)NANot GLP;NotGuidelineKOWWIN v1.68 was used to estimate LogKow. components failed to satisy thetraining set's structural domain requirements completely, however, other evidence by way ofrelated analogues and water solubility information provide corroborating evidence that theestimates made by the model are reasonable. LogKow prediction ranged from 4.57 to 5.22for . A weighted average based on the typical component percentages and theirestimated LogKow values was calculated to be approximately 4.97.LogKow (measured)(b)NA GuidelineThe average log Kow ranged from 4.5 to 4.9 among 5 components.Ready Biodegradability(b)NAGLP;Guidelineis not readily biodegradable. No transformation product was generated under theconditions of the test.Inherent Biodegradability Test(d)NAGLP;Guidelineis inherently biodegradable.Biodegradation was 44.3% after 28 days under theconditions of the test.28-Day InhalationRatGLP;GuidelineMale and female rats will be exposed to via inhalation 6 hours per day, 5 days perweek for approximately 28 days. The objective of this study is to evaluate the potentialcumulative toxicity of the test substance.On-going Studies (PMN Substance)