Final

— July 2, 2015

1 

## Significant New Alternatives Policy Program

Aerosols Sector

Risk Screen on Substitutes in Aerosol Solvents

Substitute: Meth oxytridecafluoroheptene I somers

This risk screen does not contain Clean Air Act (CAA) Confidential Business Information (CBI) and, therefore, may be disclosed to the public.



### 1. INTRODUCTION

Ozone

- depleting substances (ODS) are being phased out of production in response to a series of diplomatic and legislative ef forts that have taken place over the past two decades, including the Montreal Protocol and the Clean Air Act Amendments of 1990 (CAAA). The U.S. Environmental Protection Agency (EPA), as authorized by Section 612 of the CAAA, administers the Significant N ew Alternatives Policy (SNAP) Program, which identifies acceptable and unacceptable substitutes for ODS in specific

end

- uses based on assessment of their health and environmental impacts.

EPA’s decision on the acceptability of a substitute is based on th e findings of a screening assessment of potential human health and environmental risks posed by the substitute in specific applications. EPA has already screened a large number of substitutes in many end

- uses within all of the major ODS

- using sectors, inc luding refrigeration and air conditioning, solvent cleaning, foam blowing, aerosols, fire suppression, adhesives, coatings and inks, and sterilization. The results of these risk screens are presented in a series of Background Documents that are available i n EPA's docket.

The purpose of this risk screen is to supplement EPA’s Background Document on the aerosols sector (EPA 1994) (hereinafter referred to as the Background Docu ment). This risk screen evaluates the potential use of [ ]

. M ethoxytridecafluoroheptene isomers is a mixture of structural and stereo isomers, represented as [ ] . The exact structures of the remaining one percent of isomers are unknown. This

substitute is hereinafter referred to as methoxytridecafluoroheptene isomer s (MPHE) and is proposed as a

substitute in the aerosol solvent end

- use. Table 1 presents information on the composition of the proposed

substitute.

Table 1

. Composition of MPHE

Constituent Chemical

Formula CAS

Number a Range of
Concentration (We ight Percent ) Typical
Concentration ( W

eight Percent )

Potential Impurities

a CAS Registry Numbers for MPHE are not available.Final

— July 2, 2015

2 The potential risks associated with the use of substitutes as aerosol solvent s have been examined at length in the Background Document. The reader is referred to this reference for a detailed discussion of the methodologies use d to conduct this risk screen. This ris k screen addresses flammability risk and assesses the impact of potential releases of MPHE to the atmosphere. Additionally, occupational exposure and

end

- use exposure assessments were performed to ensure that manufacture and applicatio n of the proposed substitute in the proposed end

- uses do not pose unacceptable risk s to workers. Lastly, general population exposure was assessed to ensure that the proposed substitute does not pose an unacceptable r isk to the population at large.

Section 2 of this report summarizes the results of the risk screen for the proposed substitute listed in Table

1

. The remainder of the report is organized into the following sections:

• Section 3 : Atmospheric Assessment

• Section 4 : Volatile Organic Compound Assessment

• Section 5 : Potential Health Effects

• Section 6: Flammability Assessment

• Section 7 : Occupational Exposure Assessment

• Section 8 : End

- Use Exposure Assessment

• Section 9 : General Population Exposure Assessment

• Section 10 : References



### 2. SUMMARY OF RESULTS

MPHE is recommended for SNAP approval as a n aerosol solvent for equipment cleaning and coating applications

. EPA's risk screen indicates that the use of the proposed substitute will be less harmful to the atmosphere than the continued use of ODS and other commonly used aerosol solvents , as it is less harmful to the ozone layer, has lower climate impact, and a shorter atmospher ic lifetime (ALT)

. Given the expected composition of aerosol solvent formulations containing MPHE

, minimal anticipated exposures to the proposed su bstitute are expected during end

- use.

MPHE is regulated as a volatile organic compound (VOC) under CAA regulations (40 CFR 51. 1 00 (s) )

. Based on analysis of potential MPHE emissions , VOC s from the u se of MPHE as an aerosol solvent are

not anticipated to result in greater impacts on local air quality in the United States than other available options. R eleases of the proposed substitute should be controlled using capture and destruction technologies, and vapor in

- air detection systems should be used to furt her minimize potential exposures

, as MPHE is highly volatile

. B ased on the characteristics of the proposed substitute and the proper precautions listed in the manufacturer’s safety data sheet ( SDS ) for MPHE , the proposed substitute is not expected to pose a flammability risk during manufacture or end

- use (see Section 6). Given that personnel will receive proper training, a ppropriate personal protective equipment (PPE) ( e.g., respiratory protection, goggles, impervious gloves, chemical

- resistant clothing and boots) will be available

, and proper procedures according to the SDS will be used during manufacturing, end

- use, and disposal, no significant toxicity risk to workers, end

- users, or the general population is anticipated.



### 3. ATMOSPHERIC ASSESSMENT

This section presents an assessment of the potential risks to atmospheric integrity posed by the us e of

MPHE as a n aerosol solvent

. The ozone depletion potential (ODP)

, global warming potential ( GWP ) , and ALT of the proposed substitute are presented in Table 2

. The proposed substitute is substantially less harmful to the ozone layer, has less climate impact, and a

shorter ALT when compared to CFC

- 113, methyl chloroform, HCFC

- 225ca, and HCFC

- 225cb . In addition, MPHE also has lower climate impact and a shorter ALT than those predicted for otherFinal

— July 2, 2015

3 substitutes examined in the Background Document, as well as commonly utilized substitute s, such as

HFC

- 43

- 10mee and HFC

- 365mfc

. Thus, EPA believes that use of MPHE would result in substantially less harm to the climate and ozone layer than the continued use of ODS and other commonly used ODS

substitutes

.

Table 2

. Atmospheric Impacts of MPHE Compared to Other Aerosol Solvents

Aerosol Solvent Ozone Depleting Potential (ODP) a Global Warming Potential (GWP) b Atmospheric Lifetime in Years (ALT) b

MPHE

CFC

- 113 0.8 5 6

, 1 30 85 Methyl chloroform 0. 1 6 14 6 5

HCFC

- 225ca 0.02 122 1. 9

HCFC

- 225cb 0.03 595 5. 8

HFC

- 43

- 10mee 0 1,640 15.9

HFC

- 365mfc 0 794 8.6

a WMO (2011)

b IPCC 4 th Assessme nt Report (Forster et al. 2007)



### 4

. VOLATILE ORGANIC COMPOUND ASSESSMENT

MPHE is regulated as a VOC under CAA regulations (40 CFR 51.100(s)) . Through regulations and standard industry practices, emissions of MPHE should be controlled.

The submitter intends to manufacture MPHE as a n aerosol solvent for spray cleaning and coating applications

. An assessment was performed to compare the annual VOC emissions from the use of MPHE

as an aerosol solvent to other anthropogenic sources of VOC emissions. Assuming the submitter’s maximum anticipated annual production of MPHE for all proposed aerosol solv ent applications is entirely released (in the absence of controls), approximately [ ] MT of VOCs would be emitted. This is approximately equal to [ ] percent of all anthropogenic VOC emissions in the U.S. in 2014 ; 1 however, the release of total production for all proposed applications of MPHE is extremely unlikely to occur. Thus, an additional analysis was performed to determine more realistic annual VOC emissions from the use of

MPHE in aerosol solvent applications.

For aerosol solvent spray applications that take place in less

- controlled environments , such as a fume

hood or other ventilated areas

, which would vent the aerosol solvent to the atmosphere, an emissions rate

of 74% 2 was applied to the entire intended U.S. annual production of MPHE aerosol solvent in order to estimate the maximum impact on VOC emissions across this end

- use. Assuming 74% of the submitter’s intended annual production is entirely released, approximately [ ] MT of VOCs would be emitted, which

i s approximately equal to [ ] percent of the VOC emissions from the solvent utilization sector in the

United States 3 , or only approximately [ ] percent of all anthropogenic VOC emissions in the United

States

. Although these VOC emissions for aerosol solvent applications are several orders of magnitude l ower than other anthropogenic emissions , it is likely that the VOC emissions estimated here can be further reduced, and in some facilities may already be so reduced. For example, capture an d destruction technologies for fugitive emissions are employed in larger facilities, and hence emissions during use of MPHE may be even less than estimated here. In addition, the majority of the solvent sector utilizing ODS

1 Based on the 2014 annual total VOC emissions for the United States (i.e., approximately 17.1 x 10 6 MT) as reported in the National Emissions Inventory (EPA 2015).

2 Leak rate for non

- medical aerosols from EPA’s Vintaging Model (VM IO file_v4.4_ 10.13.14 ).

3 Solvent Utilization includes consumer and commercial solvent use, degreasing, dry cleaning, graphic arts, industrial surface coating and solvent use, and non

- industrial surface coating.Final

— July 2, 2015

4 substitutes (approximately 74%) is made up of solvents that are considered to be VOCs, such as trichloroethylene and organic solvents, and thus, use of MPHE is not expected to increase VOC emissions relative to these other acceptable substitutes (ICF 2012).

Because MPHE is intended for smaller, niche markets (e.g., spray cleaning and coating ) and is projected to have lower production levels in comparison to the entire solvent sector, use of MPHE would not result in greater impacts on local air quality than other availabl e options.



### 5

. POTENTIAL HEALTH EFFECTS

To assess potential health risks from exposure to this proposed substitute, EPA identified the relevant toxicity threshold values for comparison to modeled exposure concentrations for different scenarios. The

submitte r indicates MPHE has an acceptable exposure limit (AEL) of [ ] ppm. The AEL represents the

maximum 8

- hour time weighted average (TWA) at which a worker can be exposed regularly without

adverse effects. A n AEL of 625 ppm was i ndependently developed for MPHE based on a review of available toxicity studies. EPA’s determination of a 625 ppm AEL and summary of available toxicity studies can be found in Appendix A. Because it is the more conservative value, the submitter’s AEL of [ ] ppm was used in exposure assessments in this risk screen.

According to the SDS

, exposure to MPHE through ocular or dermal absorption, inhalation, or ingestion may be harmful. If MPHE is inhaled, ingested, or absorbed through skin or eyes in large amounts, the affected person(s) sh ould adhere to the first aid measures provided in the SDS . In the case of ocular
exposure, t he SDS for MPHE recommends that person ( s ) should immediately flush their eyes, including under their eyeli d s, with water for 15 minutes . Medical attention should b e sought if irritation persists ( DuPont 2012)

. In the case of dermal exposure to MPHE , the SDS for MPHE recommends that person(s) should immediately remove all contaminated clothing to avoid irritation and wash the affected area with

warm water

. If high concentrations of MPHE are inhaled

, the SDS recommends person ( s ) should be immediately

removed from the contaminated space and exposed to fresh air. The SDS recommends that if breathing is difficult, artificial respiration and/or oxygen may be nece ssary , and medical attention should be so ught. In case of ingestion, the SDS recommends the person ( s ) consult a physician immediately, and refrain from inducing vomiting without medical advice

, as there is a greater hazard associated with aspirating MPHE

i nto the lungs if vomiting is induced.

EPA’s review of the human health impacts of this proposed substitute is contained in the public docket

for this decision. These risks and procedures after exposure are similar for other common aerosol

solvents. The p otential health effects of MPHE can be minimized by following the exposure guidelines

and ventilation and PPE recommendations outlined in the SDS for MPHE and this risk screen

.


### 6. FLAMMABILITY ASSESSMENT

MPHE is considered to be non

- flammable ( DuPont 2012 ). Based on this classification, manufacture, servicing, and use of MPHE is not expected to present a flammability risk in aerosol solvent applications.



### 7. OCCUPATIONAL EXPOSURE ASSESSMENT

MPHE is proposed for use in blends with an average composition of [ ] percent MPHE by weight . The blend formulations vary according to the spray cleaning or coating application (DuPont 2012).

[ ]

. Using EPA’s Chemical Screening Tool for Exposures and Environmental Releases ( ChemSTEER )

, 4

4 EPA’s Chemical Screening Tool for Exposures and Environmental Releases (ChemSTEER) is a computer

- based software program used to estimate workplace exposures and environmental releases for chemicals manufactured and used in industrial/commercial settings.Final

— July 2, 2015

5 the submitter provided estimated exposures during [ ]

. Neither the American Conference of Industrial Hygienists (ACGIH) nor the American Industrial Hygiene Association (AIHA) recommended short

- term exposure limits (STELs) for MPHE . As a result, a STEL for MPHE was developed by EPA based on the

submitter’s AEL of [ ] ppm. The STEL was estimated as three to five times the AEL, which is an established method of estimating a short

- term exposure limit by ACGIH. The results of the submitter’s
exposure assessment are presented in Table 3.

Table 3

. Modeled Occupational Exposure during [ ]

Activity Duration of Potential Exposure (hours /day ) Measured Exposure Concentration ( ppm ) Exposure Limit (ppm)

a EPA

- derived STEL

b 8

- hour AEL

As shown in Table 3, exposure during [ ] activities are significantly less than the STEL. The combined daily exposure is also significantly less than the AEL. If one worker were to perform all activities listed in

Table 3 in an 8

- hour workday, exposure wou ld be [ ] ppm per day (DuPont 2012). This estimate is lower than the AEL and does not pose a concern for occupational exposure during all three activities over an 8

- hour workday.

B ecause ChemSTEER does not consider engineering controls such as local exhaus t ventilation , exposure levels are expected to be lower than the results presented in Table 3

. As summarized in Chapter 5 of the Background Document, exposure to aerosol solvent constituents are generally below 10 ppm and do not exceed 15.5 ppm. The maximum 8

- hour time weighted average concentration obtained by one site visit

was estimated at 67 ppm. As these concentrations are well below the MPHE AEL ( [ ] ppm), and the manufacture process is highly automated with minimal emissions anticipated, exposure during the manufacture of aerosol cans is not expected to present a significant toxicity concern to workers. In addition, MPHE is not expected to pose a risk to workers during transfer, sampling, or laboratory analysis when the engineering controls and PPE guidelines consistent with the Occupational Safety and Health Administration (OSHA) are followed.

In the case of large releases of MPHE

, the proposed substitute should be collected on absorbent material ( e.g ., rags, saw dust, vermiculite, spill pillows, cellulose products ) and transferred to steel drums for recovery or disposal to prevent leakage into sewers, waterways, or low lying areas, as recommended by

the SDS . Once the proposed substitute is adequately removed and clean

- up residues are disposed of in

accordance with the SDS , normal ventilation for standard manufacturing procedures and vapor in

- air detection systems should be used to further minimize potential exposures.

EPA believes that because proper handling and disposal guidelines are followed in accordance with good

in dustrial hygiene and manu facturing practices

, and the substitute’s SDS , there is no significant risk to workers during the manufacture of MPHE

. See the following section, “End

- Use Exposure Assessment” for a discussion of exposure to workers using MPHE duri ng aerosol solvent applications.



### 8

. END

- USE EXPOSURE ASSESSMENT

MPHE is proposed for use as a n ae rosol solvent for spray cleanin g and coating applications

. MPHE is not

intended for direct consumer use.Final

— July 2, 2015

6 The submitter indicates workers use the spray can intermittently with spray time of approximately [ ] seconds for each use. In addition, the submitter notes use of aerosol cans is approximately [ ] per week in the presence of local exhaust ventilation. Ass uming one [ ] aerosol can containing [ ] MPHE by weight is

released in a [ ] ft 3 space wi th a ventilation rate of [ ] ACH

, the submitter estimates that the maximum

concentration reached is [ ] ppm. While this modeled exposure is well below the 8

- hour AEL, it does not account for local exhaust ventilation, which the submitter anticipates will reduce exposures by [ ] percent. Assuming local exhaust ventilation at [ ] percent efficiency is present, the maximum concentration is estimated to be approximately three ppm (DuPont 2012).

As a second approach to assessing risks of short

- term exposure, EPA modeled the use of an aerosol solvent. The analysis is based on a simple box

- model approach that draws assumptions from spray tests performed by aerosol solvent manufacturing companies. In this case, the box

- model approach examines an area surrounding the face of the exposed worker and determines exposure based on the velocity of ventilation present. As the velocity varies, the volume of moving air surrounding t he worker also changes, which in turn changes the level of exposure estimated by the box model.

The modeling was based upon the following assumptions

, described below in Table 4

, regarding usage, area of exposure, ventilation, and the constituents of the s olvent formulation.

Table 4 . Summary of Assumptions for Aerosol Solvent End

- Use Exposure Box

- Model

Parameter Assumption

Usage Entire aerosol can ( 454 grams) sprayed in 3, back

- to

- back 10

- minute periods, or 30

- minutes total a
Solvent Formulation [ ] b

Area of Exposure 18 in ches in equidistant directions around worker’s face (3 ft x 3 ft = 9 ft 2 area around the face of worker)

Ventilation/Air Flow

Rate No mechanical ventilation present; Air flow rate is equal to 450 ft 3 /min

or 12.7 m 3 /min (50 ft/min over 9 ft 2 of area at the face of worker) c

a The submitter indicated that use of the aerosol solvent would typically be intermittent and of short duration using

one can per week ( DuPont 201 2 )

b DuPont ( 2012 )

c EPA ( 1994 )

The exposure point concentration for inhalation exposure is determined by calculating the workplace air

chemical concentration. The indoor air concentration for MPHE was estimated using Equation 1 (EPA

199 4 ):

Equation 1: Workplace Air Concentration

C

a = Y

v x 1000 m g

x 24.45 g

AT x k MW

Where:

C

a = Concentration of the chemical in air (ppm)

Y

v = Mass emission rate of volatile compound released (g/s)

AT = Air flow rate (m 3 /s)

k = Dimensionless room ventilatio n mixing coefficient (assumed as 1 for complete mixing )

24.45 = Factor used to convert from mg/m 3 to ppm

MW = Molecular weight of the proposed substitute ( [ ] g)Final

— July 2, 2015

7 The mixing factor, k , accounts for the slow and incomplete mixing of ventilation air with room air (i.e.,

ventilation effectiveness is reduced by poor dispersion characteristics within the room). In this case

, a small area around the user (the breathing zone) was evaluated, so complete mixing is assumed and a

default value of one is used. The model assumes that the enti re area surrounding the solvent sprayer

contains the same concentration of MPHE , and that the chemicals are completely volatilized into the air after release. This assumption is appropriate given the method of application (aerosol canister). Based on

the assumptions above, the short

- term mass emission rate of solvent is [ ] g/s of MPHE ( 454 gram aerosol can containing [ ] MPHE dispensed over 30

- minutes). Table 5 shows the results of this analysis.

Table 5

. MPHE Ae rosol Solvent End

- Use Exposure (Calculated Using Box Model)

Sampling Location Maximum Short

- Term Concentration (ppm) Short

- Term Exposure
Limit (ppm)

Area around Worker’s Face During Aerosol Spray Application 2 0

a EPA

- derived STEL

Based on the results of this modeling, even with conservative assumptions about ventilation

, the short

term concentration is unlikely to reach the ST EL for MPHE

. Further, under good manufacturing practices, it is un likely that these level s of short

- term exposure would occur, as the proposed substitute will be used fo r industrial applications; where those applications occur indoors, robust mechanisms for containing the aerosol spray and/or for better ventilation, such as a fume hood, will likely be used , and aerosol solvent products will be labeled to ensure that the products are used in areas with adequate ventilation or local exhaust ventilation. Because use of MPHE in aerosol cans is not expected to result in significant emissions and because end

- users of MPHE will follow certain guidel ines ( including training to properly use and handle the proposed substitute ) to ensure that employee work habits are conducted in accordance with good industrial hygiene practices

, EPA does not believe

that MPHE presents a significant toxicity concern to w orkers at end

- use.



### 9

. GENERAL POPULATION EXPOSURE ASSESSMENT

This section screens potential risks to the general population from exposure to releases of MPHE to ambient air, surface water, and solid waste. Because the proper safety and disposal precaution s, as listed in the remainder of this section, are followed, MPHE is not expected to cause a significant risk to the environment and human health in the general population when manufactured o r used for aerosol solvent

end

- uses

.

9. 1 Ambient Air

MPHE is hig hly volatile [ ] , and a erosol solvents is a highly emissive end

- use. As such, a ccidental release measures, handling and storage, engineering controls, and waste disposal must be followed per the proposed substitute’s SDS to avoid significant releases to air. Given that aerosol solvents end

- uses will take place indoors with good manufacturing practices, such as employment of capture and destruction technologies, releases are not expected to result in significant exposure to the gene ral population

. Furthermore , the aerosol sector is relatively small compared to other ODS sectors, and use of MPHE in replacement of other, more toxic alternatives, is not expected to present a significant concern to the general population.

9 .2 Surface Wat er

Due to the near

- insolubility of MPHE in water [ ]

, MPHE is not likely to accumulate in surface water ( DuPont 20 12 ). For the proposed end

- uses, the product will be handled indoors with waste or accidental spills collected in steel drums or take n up with an absorbent material, such as vermiculite or spill pillows

.Final

— July 2, 2015

8 Water contaminated with MPHE should not be dumped into sewers, on the ground, or into any body of water, in accordance with the SDS

.

9 .3 Solid Waste

Although the constituents of MPHE are not listed as Resource Conservation and Recovery Act ( RCRA ) hazardous wastes, spent solvent may collect metals and other chemical compounds during cleaning applications , which may cause the spent solvent to display characteristics of hazardous waste ( e.g., ignitability, corrosivity, reactivity, toxicity) . A ny solid waste displaying these characteristics or having a specific waste code (e.g., F001) is considered to be a hazardous waste (40 CFR Part 261). Waste regulated as RCRA hazardous waste is subje ct to the requirements of the Subtitle C program (including storage, treatment, and disposal requirements), which EPA believes are sufficient to control human health and environmental risks. In addition, because solid materials used during end

- use or clean

- up procedures that may be absorbed with MPHE ( e. g.
, rags, vermiculite, and spill pillows ) are disposed of in accordance

with the MPHE SDS , EPA does not expect general population exposure to MPHE through solid waste to

occur.Final

— July 2, 2015

9 

### 10

. REFERENCES

DuPont Chemi cals & Fluoroproducts (now The Chemours Company ). 2012. Premanufacture Notice and Significant New Alternatives Policy Program Submission to the Environmental Protection Agency for Methoxytridecafluoroheptene Isomers to the United States Environmental Prote ction Agency. June 22,

2012.

EPA 201 5 . National Emissions Inventory Air Pollutant Emissions Trends Data. Accessed 1 3 March 201 5

. Updated March 201 5 . Available at: http://www.epa.gov/ttnchie1/trends/.

EPA 1994. Significant New Alternatives Policy Technical Background Document: Risk Screen on the

Use of Substitutes for Class I Ozone

- depleting Substances : Aerosols . Stratospheric Protection Division. March, 1994.

Forster, P., V. Ramaswamy, P. Artaxo, T. Berntsen, R. Betts, D.W. Fahey, J. Haywood, J. Lean, D.C. Lowe, G. Myhre, J. Nganga, R. Prinn, G. Raga, M. Schulz and R. Van Dorland. 2007. Changes in Atmospheric Constituents and in Radiative Forcing. In: Climate Change 2007: The Physical Science Basis. Contribution of Working Group I to the Fourt h Assessment Report of the Intergovernmental Panel on Climate Change [Solomon, S., D. Qin, M. Manning, Z. Chen, M. Marquis, K.B. Averyt, M.Tignor and H.L. Miller (eds.)]. Cambridge University Press, Cambridge, United Kingdom and New York, NY, USA.

ICF Int ernational. 2012. Solvent Sector VOC Analysis for ODS Substitutes. Prepared for EPA’s Stratospheric Ozone Protection Division. February 12, 2012.

WMO (World Meteorological Organization), 2011. Scientific Assessment of Ozone Depletion: 2010

, Global Ozone Research and Monitoring Project

— Report No. 52, 516 pp., Geneva, Switzerland.Final

— July 2, 2015

10 

## Appendix A

Determination of an Acceptable Exposure Limit ( AEL ) for MPHE

Recommended AEL: 625 ppm (8

- hour time

- weighted average)

Basis and Endpoints: NOAEC 5 : 2,500 ppm (dehydration; clinical chemistry; microscopic changes in the teeth)

Critical Study: 28

- day inhalation (whole body) study (DeLorme 2014)

Doses: 0; 1,000; 2,500; 5,100 ppm

NOAEC: 2,500 ppm

HEC 6 : 2,500 ppm x 6 hr/d / 8 hr/d = 1,875 ppm

Uncertainty Factors: 3

– animal to human extrapolation

5 No Observable Adverse Effect Concentration (NOAEC)

6 Human Equivalent Concentration (HEC)Final

— July 2, 2015

11 

## I. Introduction

MPHE [ ] has been proposed as a replacement for CFC

- 113, HCFC

- 225ca/cb, and methyl chloroform in many solvent cleaning uses, as well as in carrier fluid and heat transfer fluid applications. Several studies assessing the potential toxicity of MPHE have been conducted, inclu ding the following:

• An acute inhalation study in rats;

• a sub

- acute (28 day) inhalation study in rats;

• four genotoxicity studies in bacterial and mammalian cells; and

• four gavage ( oral ) studies in rats.

The results of these studies are discussed in t he following sections to inform an assessment of the potential health risks from human exposure to the study compound in the intended end

- uses.



## II. Summary of Toxicity Studies

The toxicological studies reviewed for the determination of an AEL for MPHE are summarized below in Table 1. The toxicity database is rather comprehensive, but is focused primarily on gavage (oral) exposure studies, which are of limited usefulness for the determination of an occupational AEL based on the expected inhalation expos ures (as discussed in the latter portion of Section IV).Final

— July 2, 2015

12 

### Table 1. Select MPHE Toxicological Studies

a All values NOAEL/NOAEC unless otherwise reported; NOAEL/NOAEC = No observed adverse effect level/concentration (commonly used for oral or dermal/inhalation exposures) ; wt

– weight Principal Studies Concentrations NOAEC (L) a Effects

Acute (inhalation; whole body; rat) 0; 2,000; 5,000; 9,700; 15,000 ppm LC 50 >15,000

ppm Anesthetic effects at ≥5,000 ppm including 

### ↓ activity 10 min. into exposure; rats were motionless at 45 min. into exposure.

28

- day (inhalation; whole body; rat) with 14

- day

recovery 0; 1,000; 2,500; 5,100 ppm 2,500 ppm Diuresis

- induced dehydration; chang es in clinical chemistry parameters; degeneration of tooth epithelium in 1 male at 5,100. Adaptive liver effects

acute (oral; female rat) 0; 5,000 mg/kg LC 50 >5,000 mg/kg No clinical findings or gross pathology.

28

- day (oral; rat) 0; 250; 500, 1,000 mg/kg 1,000 mg/kg Sig. ↑ absolute, relative liver wt in males and females; sig. ↑ absolute, relative

kidney wt in males. Hepatocellular hypertrophy in 2/10 males at 1,000 mg/kg; considered adaptive effect. No histopathology in kidneys in males. Some
clin ical chemistry changes at ≥500 mg/kg.

28

- day with FOB (oral; rat) 0; 100; 250; 1,000 mg/kg 1,000 mg/kg Sig. ↑ absolute, relative liver wt in males. Hepatocellular hypertrophy in both sexes at 250 and 1,000 mg/kg; considered adaptive

effect.

90

- day (oral; rat) with 30

- day recovery 0; 250; 500, 1,000 mg/kg Not identified (males); 1,000 mg/kg (females) Evidence of chronic progressive nephropathy in males at all doses, including 7/10 control animals; no similar

effects in females. Sig. ↑ absolute,

re lative liver weights in both sexes at all
doses. Developmental toxicity (oral; rat) 0; 250; 500; 1,000 mg/kg 1,000 mg/kg No exposure

- related adverse effects.

Supporting Studies Doses NOAEL Effects

In vitro bacterial reverse mutation assay ≤ 5,000 μg/plate 5,000 μg/plate Negative

In vitro chromosomal aberration assay , CHL
cells ≤ 3621 μg/mL 3621 μg/mL Negative

In vivo micronucleus 0, 500; 1,000; 2,000 mg/kg 2,000 mg/kg Negative

In vivo micronucleus 0, 1,000; 2,500; 5,100 ppm 5,100 ppm NegativeFinal

— July 2, 2015

13 

## III. Development of the AEL for MPHE

The body of data indicates that MPHE induces anesthetic effects in rodents at concentrations ≥ 5,000 ppm in inhalation exposures lasting 4 hours; however, no neurotoxic effects were noted in the 28

- day inhalation study. Tox icity from repeated inhalation exposure is limited to diuresis

- induced dehydration, increased serum levels of albumin, globulin and total proteins, and decreased body weight, in male rats only at 5,100 ppm. Further, one male rat at 5,100 ppm exhibited dege neration/atrophy of the ameloblastic epithelium (the enamel

- producing cells of the teeth). Hepatocellular hypertrophy was noted in both sexes at 5,100 ppm and in males at 1,000 and 2,500 ppm, but this effect is due to an adaptive increase in metabolic enzy mes and commonly occurs in response to many xenobiotics. Thus, it was not considered adverse. Oral toxicity appears to be limited to adaptive effects in the livers and kidneys of primarily male rats. No effects in the kidneys other than increased absolut e and relative weight were present in the 28

- day gavage study, whereas, kidney lesions (i.e., chronic progressive nephropathy [CPN]) were present in

the 90

- day study.

Because of the high incidence of CPN in control male rats in the 90

- day gavage study, h owever, the effect cannot be ascribed specifically to oral exposure to the study compound. The problematic kidney data limits the usefulness of the oral studies for establishing an occupational exposure limit. Another limitation

of the studies is that the gavage ( oral) pathway used to expose the rodents to MPHE is not relevant for worker exposure. Although the submitter argues that inhalation toxicity is unlikely to be a significant pathway of exposure (DuPont 2013), the vapor pressure for the compound ( [ ] mm Hg) and boiling point ( [ ] oC ) are comparable to those of perchloroethylene (18.6 mm Hg; 121.1oC), and the compound is generally classifiable as volatile or likely to be volatile (Mackay et al. 1993). It is reasonable to expect

that MPHE will enter t he vapor phase during vapor degreasing and if it is used as an aerosol solvent. Further, exposure to high concentrations identified in the acute inhalation exposure study resulted in clinical signs indicative of anesthetic effects. This contrast between th e acute inhalation study and the oral studies indicates that there are differences in activity in the compound between exposure routes, and thus the oral studies will not serve as a basis for development of an exposure limit that is protective of occupatio nal health. For this reason, the 28

- day inhalation exposure study has been chosen as the appropriate toxicity study.

ICF calculated the AEL using the following equations:

2,500 ppm x (6 hr/8 hr) = 1,875 ppm

1,875 ppm x 1/3 = 625 ppm

A HEC was determined by adjusting the identified NOAEC of 2,500 ppm in the 28

- day inhalation study by the ratio of rat exposure duration per day to that of an occupational worker (6 hours/8 hours). No further exposure duration adjustment was necessary. A t otal uncertainty factor (UF) of 3 was applied to account for pharmacodynamic differences between rats and humans as the guidelines for developing

Reference Concentration ( RfC ) values ( U.S. EPA, 1994 ) were followed.Final

— July 2, 2015

14 

## IV. Principal Toxicity Studies

Inhalation Exposure

Acute Study

In the acute study (Kegelman 2011), five young adult Sprague

- Dawley rats per sex were exposed via inhalation (whole

- body exposure) to MPHE in measured concentrations of 0 ; 2,000; 5,000 ; 9,700 ; or 15,000 ppm for 4 hours. During the exp osure
, the rats were reportedly assessed for response to stimuli (startle response) three times. Rats were sacrificed 14 days following exposure and assessed for gross pathological effects; rats in control and 15,000 ppm groups were assessed for histopatho logy in the respiratory tract, livers, and kidneys.

According to the study summary and discussion sections, 5/5 rats of both sexes at 9,700 ppm exhibited decreased activity within 10 minutes of the start of exposure, and within 30 minutes of exposure, th e rats
became motionless and remained motionless throughout the rest of the exposure period. The only exception is that the rats did exhibit a normal startle response when challenged. All male and female rats at 15,000 ppm exhibited increased activity leve l from 10 minutes until 45 minutes of exposure, which included the following: rapid head

- bobbing and ear twitching, chewing motions, excessive grooming, and an increased startle response. All rats were motionless within 20 minutes of the start of exposure . The anesthetic symptoms were gone 5 minutes (9,700 ppm) or 6 minutes (15,000 ppm) post

- exposure, indicating that the study compound was exhaled quickly and did not persist in the bloodstream to cause any adverse clinical signs (DuPont 2013a). No abnormal clinical signs were reported during the 14

- day recovery period in any exposure group.

Four of five male rats at 9,700 ppm, 5/5 male rats at 15,000 ppm, and 2/5 female rats at all levels exhibited weight loss after the first day of exposure (≤ 10 grams), but normal weight gain was reported during the recovery period. As food consumption was not measured, it is not possible to determine if this minimal weight loss was a result of the animals avoiding their food.

None of the rats exhibited adverse signs u pon gross necropsy and no exposure

- induced signs of toxicity were noted in the 15,000 ppm

- group animals as compared to controls. It is notable that 2/5 control males exhibited minimal CPN, as did 1/5 males at 15,000 ppm. The incidence of CPN in the other groups, if any, is not reported because tissues from those animals were not evaluated microscopically.

Subacute (28

- day) Study

In a 28

- day whole body inhalation study (DeLorme 2014), male and female CD ® rats (20/ sex) were exposed to : 0; 1,000; 2,500; and 5,100 ppm of the study compound for 6 h ou rs per day, 5 days per week

, for 4 weeks (21 exposures). Blood samples were taken from 5 rats/sex/exposure group following the

fourth exposure and again at the end of the exposure period for analysis of micronucle i induction (discussed in the Genotoxicity section). Following the exposure period, 10 male and 10 female rats in each group were allowed a 14

- day recovery period to assess the reversibility of any observed adverse effects. Blood and urine samples were ta ken from the remaining 10 rats/sex in each exposure group for hematology, clinical chemistry and urinalysis assessment; the rats were then sacrificed for gross necropsy and organ analysis.Final

— July 2, 2015

15 The study followed harmonized guidelines and appropriate endpoints were measured. Exposure to

MPHE did not result in early mortality

, moribundity or adverse clinical signs. 7 Further, no adverse findings were noted in the measured ophthalmological or neurobehavioral endpoints, including forelimb and hindlimb grip streng th, motor activity assessment, and functional observational battery measurements. No changes were noted in any exposed groups in body weight gain, food consumption, or hematology. High

- concentration males did exhibit a slight (11.3%) but significant reduct ion in body weight following the final exposure compared to controls. Plasma fluoride was increased significantly in

mid

- and high

- concentration males and females and urinary fluoride was increased significantly in all exposed rats. Plasma fluoride levels returned to near control levels following the 14

- day recovery period; urinary fluoride levels had decreased, but not completely returned to pre

- exposure levels following recovery. Male rats at 5,100 ppm exhibited diuresis (increased urine volume and decr eased urine specific gravity), as well as increased serum albumin, globulin, and total protein levels, and decreased body weight. The study authors considered the increased serum protein load and the decreased body weight to be secondary to the dehydratio n resulting from fluoride

- induced increased urine output; ICF agrees with

this assessment. Diuretic effects were also noted in low

- and mid

- concentration males and in mid

- and high

- concentration females; slight increases in serum proteins in males at 1,00 0 and 2,500 ppm were also seen, but the changes were minimal and were not coincident with body weight decrements. Thus, although exposure related, the changes were not deemed adverse. Further, the observed changes in urinalysis and clinical chemistry par ameters were reversible following the recovery period.

Adaptive changes related to compound exposure were noted in the liver, as well as in the larynx :

• mild hepatocellular hypertrophy in all high

- concentration rats,

• minimal hypertrophy in

o 3/10 males at 1,000 ppm

o 10/10 males at 2,500 ppm, and

o 10/10 females at 5,100 ppm;

• minimal hyperplasia/squamous metaplasia of the larynx in

o 8/10, 6/10, and 10/10 exposed males in low

- , mid

- , and high

- concentration groups at

necropsy,

o 5/10, 8/10, and 10/10 exposed fem ales in low

- , mid

- , and high

- concentration groups at

necropsy,

o 3/10 low

- and 4/10 high

- concentration males at recovery, and

o one high

- concentration female at recovery;

• minimal goblet cell 8 hyperplasia in the anterior section of the nose at terminal and rec overy necropsy in

o 8/10, 8/10, and 8/10 low

- , mid

- , and high

- concentration males, and

o 5/10, 8/10, and 7/10 low

- , mid

- , and high

- concentration females.

Liver weights were slightly but significantly increased in all exposed male groups and in high

concent ration females, resulting from the hypertrophy. These increases were partially resolved after the

14

- day recovery period: males at 2,500 and 5,100 ppm and females at 5,100 ppm still exhibited increased liver weights compared to controls, but the values had decreased over the preceding 14 days. Interestingly, 2,500

- p p m recovery females had significantly (8%) increased liver weights compared to controls, but this value was unlikely to be biologically relevant as it was not present at the end of exposure. No other organ weights were affected by exposure.

7 One 1

, 000

- ppm male was sacrificed on day 27 due to poor health; based on necropsy findings, the animal's condition was attributed to urogenital tract inflammation that was not related to exposure.

8 Goblet cells are epithelial cells that produce mucins (components of mucus).Final

— July 2, 2015

16 A single male at 5,100 ppm exhibited degeneration/atrophy of ameloblastic epithelium 9 at recovery, believed to be due to fluoride exposure in the study compound. Very slight lamination of dentin was

noted in one male at 2,500 ppm and in 2/10 males at 5,100 ppm at recovery, and incomplete decalcification of enamel/dentin in 4/10 males at 2,500 ppm and 5/10 males at 5,100 ppm. No exposed females exhibited these endpoints. The incomplete decalcification is indi cative of exposure only and is an artifact of tissue processing. The slight lamination of dentin was not considered adverse and occurred in only one male at 2,500 ppm. The NOAEC was identified as 2,500 ppm by the study author, based on

diuresis

- related ef fects (increased serum proteins, dehydration and weight loss) and microscopic effects in

the enamel

- producing cells of the teeth in 1 male at 5,100 ppm.



### Oral Exposure

The remaining rodent toxicity studies all utilized the gavage ( oral ) exposure pathway b ecause, according to the submitter, significant repeated inhalation exposures were unlikely and it would be difficult to

achieve airborne concentrations of MPHE given its relatively low vapor pressure (DuPont 2013b). Four gavage studies were conducted: a limit dose (acute) study, two subacute ( 28

- day ) repeat exposure studies, one subchronic study, and a developmental study.

Acute exposure

An oral limit

- dose assay in young adult Sprague

- Dawley rats (5 females) was performed to determine the

limits of acute toxicity (Durando 2009). In this study, only female rats were used because the study authors claimed that females are "frequently more sensitive to the toxicity of test compounds than males." One female was initially given a single bolus dose of MPHE (ne at) via gavage at 5,000 mg/kg. When this rat did not die prematurely, 4 additional females were dosed in the same manner. The animals were watched cage

- side for mortality and clinical signs of toxicity within the first 30 minutes and during the

first seve ral hours after dosing

. N o behavioral challenges were performed as in the inhalation study, although it was noted that "particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma." Gross necropsies were perform ed after 14 days of recovery, but no histopathology was done to determine that tissues were not affected. No adverse effects were reported and the rats satisfactorily gained weight (body weights were only measured at days 7 and 14, so subtle changes in bo dy weight over 1

- 2 days would not have been evaluated in this study). Food consumption

was not measured. The LC 50 for females was determined to be >5000 mg/kg.

Subacute ( 28

- day ) Study

In the first 28

- day repeat exposure study (MacKenzie 2009), male and female young adult Sprague

Dawley rats (10/sex/dose) were exposed to the following doses of MPHE once daily, for 28 total days: 0 ; 250 ; 500 ; or 1,000 mg/kg. The exposure did not adversely affect mortality, clinical signs of toxicity, food consumption or efficiency, body weight gains, hematology or clinical chemistry parameters, or gross necropsy. Significant increases in absolute and relative liver weights were noted in all dosed male and female groups, with an associated, small increase (2/10) incidence of minimal centrilobular hypertrophy at 1,000 mg/kg. No histological effects were noted in any dosed females. Significantly increased

absol ute and relative kidney weights were also seen in dosed male rats, but not in females; however, there was no associated kidney histopathology in these male rats. The liver effects were considered by the study authors to be the result of an adaptive respons e to the presence of a xenobiotic; ICF agrees because of the lack of effects on liver cells (i.e., no adverse histopathology). There were incidental, small changes in some clinical chemistry parameters which were not considered adverse either because the c hanges were

9 Ameloblastic cells produce enamel in the tooth.Final

— July 2, 2015

17 not consistently dose

- dependent or they did not correspond with tissue damage: increased serum globulin and glucose in female rats at the top two doses, and decreases in select enzymes/compounds (sorbitol dehydrogenase, creatinine, inorganic ph osphorus). The NOAEL for this study is identified as 1,000 mg/kg.

In the second 28

- day repeat exposure study (Akahoshi 2010), 5 male and female Sprague

- Dawley rats

were administered doses of 0 ; 100 ; 250 ; and 1,000 mg/kg via gavage (oral) once daily for 28 consecutive days. Because certain parameters were not measured ( e.g., urinary analyses) this was not considered a guideline study. An additional 5 male and female control and high

- dose (1,000 mg/kg) rats were exposed identically to the main group animal s, and were then maintained post

- dosing for 14 days to assess recovery. Exposure to MPHE did not affect clinical signs, parameters measured in a functional observational battery, mortality, food consumption, body weights, hematology, most clinical chemistr y parameters, select urinalysis parameters, or gross necropsy findings.

In males at 1,000 mg/kg, significantly increased serum cholesterol and total phospholipids were noted at the end of exposure. This is most likely the result of stress to the liver a s a result of increased metabolic activity, which is noted in the increased absolute liver weights in these males and the presence of mild centrilobular hepatocellular hypertrophy in 1/5 males at 250 mg/kg and 3/5 males at 1,000 mg/kg. Significantly incre ased liver weight relative to body weight was noted at all three exposure doses in males, but in low

- and mid

- dose males, this is most likely the result of decreased mean body weights at the end of the study (compared to controls). Liver weights in exposed females were unaffected, but 1/5 and 2/5 females at 250 and 1,000 mg/kg respectively did exhibit mild centrilobular hypertrophy and 1/5 of the high

- dose females also exhibited fatty periportal hepatocyte degeneration with resultant

mononuclear cell infilt ration. Females and males at 250 mg/kg showed significantly increased absolute and relative kidney weights, respectively, but these changes were not considered related to compound exposure as no other dose groups were affected. One high

- dose male showed h istological evidence of accumulation of alpha 2

- mu globulin; this effect was not considered clinically relevant because it is male

rat

- specific and has no corollary in the human. In recovery animals, only 1,000

- mg/kg males still exhibited significantly in creased absolute and relative liver weights. Liver histopathology was resolved in high

- dose males after recovery. The NOAEL was identified by the study authors as 1,000 mg/kg as the adaptive effects were not considered adverse and were reversible; ICF agr ees that because the effects noted in this study were similar to those noted in the first 28

- day study, the effects are indicative of adaptive response to a xenobiotic (i.e., increased cell size due to increased production of metabolizing enzymes) and are considered to be reversible and not adverse.Final

— July 2, 2015

18 Subchronic ( 90

- day ) Study

In a subchronic oral study (Anand 2011), groups of male and female Sprague

- Dawley rats (15/group for controls and high

- dose animals, 10/group for intermediate groups) were given the fo llowing doses via gavage once/day, 5 days/week

, for 13 weeks: 0 ; 250 ; 500 ; and 1,000 mg/kg. At the end of the 90

- day exposure period, 5 rats per sex at 0 and 1,000 mg/kg were maintained for 30 days post

- dosing to determine the reversibility of any observed effects.

The exposure to MPHE did not affect the following measured parameters in any toxicologically significant way:

• mortality, 10

• clinical signs (including neurological parameters measured in a functional observation battery),

• ophthalmology,

• hematol ogy or

• gross necropsy.

Changes in liver and kidney weights and other measured parameters in exposed rats (main study) are provided below in Table 2. Mean terminal body weights of all male dosed groups were significantly lower than the controls (16%, 11% , and 9%, in the low

- , mid

- , and high

- dose groups respectively). Mean body weight values for the 250

- mg/kg

- day male group were consistently lower throughout the study (including prior to dosing at day 0); this may partly be the result of a significantly d ecreased food consumption (compared to controls) that occurred throughout the study except for days 42

- 56. Food consumption levels of the 500

- and 1,000

- mg/kg

- day males were comparable to controls throughout the exposure period. Overall mean body weight gains in the dosed groups were 76%, 83%, and 87%, respectively, of controls from day 0

- 91 (all values significantly decreased compared to controls). The study authors did not attribute decreased food consumption in the low

- dose males to exposure to MPHE

b ecause the behavior did not follow a dose

- related trend; no potential mechanism for the decreased terminal body weights or deficits in overall body weight gain in all dosed male groups was offered in the study report. These deficits suggest a problem relat ed either to the health of the male rats prior to the onset of exposure or to stress related to dosing methodology or treatment. Dosed females showed no changes in food consumption or efficiency compared to controls, and mean body weight gains were general ly higher in dosed females than in controls, which are reflected in the mean terminal body weights (shown in Table 2).

10 One control male in the recovery group was found dead after intubation on day 85.Final

— July 2, 2015

19 Table 2. Selected Organ Weights in Male and Female Rats Exposed to MPHE

Absolute and Relative Organ Weights (g) and Effects

Exposure Dose, mg/kg

0 250 500 1,000

Male, number of rats (10) (10) (10) (10)

Mean terminal body wt. 596.0 500.8* 528.1* 549.1

Liver

Absolute wt. 15.956 19.424* 20.553* 23.066*
Relative wt. (to body wt.) 2.668 3.882* 3.900* 4.196*
Hepatocellular hypertrophy

minimal 0 3 6 7

mild 0 0 0 1

Kidney

Absolute wt. 3.412 3.460 3.765 4.409*
Relative wt. (to body wt.) 0.573 0.694* 0.711* 0.801*

CPN, incidence 7 8 10 10

Severity, minimal 6 4 4 1

mild 1 4 6 9

Female, number of rats (10) (10) (10) (10)

Mean terminal body wt. 278.0 310.5* 288.4 291.1

Liver

Absolute wt. 7.314 9.127* 8.535* 8.833*
Relative wt. (to body wt.) 2.639 2.947* 2.953* 3.041*
Hepatocellular hypertrophy

minimal 0 0 1 4

mild 0 0 0 0

Kidney

Absolute wt. 1.828 2.190* 2.053* 2.017*

Relative wt. (to body wt.) 0.660 0.708 0.712 0.695

CPN, incidence 1 1 2 0

Severity, minimal 1 1 2 0

Source: Anand ( 2011 )

* S tatistically significant at p<0.05.Final

— July 2, 2015

20 Absolute and relative (to body weight) liver weights were significantly increased in all dosed male and female rats. In addition, minimal to mild hepatocellular hypertrophy

, "characterized by an increase in the size of cells due to an increase in cytoplasmic volume

, " was present in a dose

- dependent manner in all exposed male groups and in females at the top two doses ( Anand 2011 ) . Serum cholesterol was significantly increased in male rats at the top two doses (46% and 74% higher than controls), and in the recovery males, cholesterol levels were still statistically higher (26%) than controls. The difference in the recovery males was smaller than in the main study, indicating that the liver damage was reversible. Absolute liver weights in 1,000

- mg/kg recovery males and females were not significantly increased over controls, but relative (to body weight) liver weights in 1,000

- mg/kg males were still significantly increased (see Table 3 below ). These changes indicate that the increased metabolic burden posed by

MPHE was having some cellular effect on the liver, which had not fully resolved at 30 days past the termination of exposure.

Table 3. Organ Weights and Incidence and Severity of Hepatocellular Hypertrophy in Livers and CPN in Kidneys of Recovery Rats

Finding Dose, mg/kg

0 1,000

Liver W eights (incidence of hypertrophy)
Absolute, male 15.001 (0) 17.457 (0)
Absolute, female 7.534 (0) 8.466 (0) Relative to body weight, male 2.413 2.963* Relative to body weight, female 2.488 2.780

CPN (Male) 3 4

Minimal 3 3

Mild 0 1

Source: Anand ( 2011 ) *statistically significant at p<0.05.

The absolute and relative kidney weights in treated males were all significantly increased compared to

controls in a dose

- related fashion, although the increased relative kidney weights were affected by the lower terminal body weights of the dose d male rats. Absolute, but not relative, kidney weights of dosed female rats were also significantly increased compared to controls. CPN was noted in all male rats, and increased in severity in the dosed rats. CPN was also noted in female rats in the contr ol, low

- and mid

dose groups, although the severity was "milder" than that observed in the males. CPN was not noted in control or high

- dose recovery females, but it was noted in a smaller number of control males (3/4; minimal severity) and 1,000

- mg/kg

- day males (4/5; 3 with minimal severity, 1 with mild severity). Because of the decreased number of recovery animals compared to main study animals (5 rather than 10) it is not possible to determine if the incidence of CPN was decreased, but the severity of th e effect does appear to have decreased.

All dosed male rats exhibited significant increases in urinary micro

- total protein (83%, 186%, and 253%, respectively) compared to controls at the end of exposure, which corresponded to higher severity of CPN

in the se rats. There was also an increased incidence, not dose

- related, in granular casts in the urine

. M ean urine volume was increased and specific gravity decreased, in mid

- and high

- dose males (these last two endpoints were highly influence d by the values of one male rat in each group, and the values for the remaining rats in each group were within historical ranges). Mean urine volume and specific gravity wereFinal

— July 2, 2015

21 similar in control and high

- dose recovery males. Urinalysis parameters were not affected by treatmen t in

dosed females.

The study authors note that CPN is a common lesion in the aging rat, but can also be found in rodents as young as 2 months of age. The phenomenon is well

- known in 13

- week and 2

- year toxicity studies conducted by the National Toxicolog y Program (Travlos et al. 2007) and is associated with a high

- protein diet, NIH

- 07 (Seely and Hard 2008; Hard et al. 2009). It is noted that DuPont consistently uses in all its oral studies a diet with a protein content of 20%, which is intermediate betwe en the old diet used by the NTP(NIH

- 07; 23% protein) and the new diet adopted in the 1990s ( NTP 2000 ; 14% protein) ( Hard et al. 2009). It is possible that the diet used by DuPont has a high enough protein content to contribute to the development of CPN in its male and female rats. As noted previously, a few male rats in the acute inhalation study exhibited signs of CPN at the age of 2 months (2/5 control rats, with minimal severity; 1/5 rats at 15,000 ppm, with minimal severity; no other dose groups were evaluated histologically). CPN was observed in a significant number of control and dosed male rats in the 90

- day oral study; the presence of CPN in 2 control rats and 1 dosed rat in the inhalation study indicates that there may have been a predisposition for CPN in this particular strain of rat, or the potential for developing CPN in a very short period of time as a resul t of diet or other factors.

The study report argues that no NOAEL was identified for male rats due to the presence of CPN in all male rat groups, but identifies a NOAEL for females at 1,000 mg/kg due to the absence of test

- substance

related effects. Th e author indicates that CPN is a kidney pathology unique primarily to the male rat with no known relevance to humans; the study author did, however, state that the increase in CPN severity was

believed to be an adverse effect related to MPHE exposure. Som e scientists do believe that CPN has no relevance to human health risk assessment (Hard et al. 2009; Seely and Hard 2008), but others have disagreed with that viewpoint (Melnick et al. 2012). Nevertheless, the high incidence of CPN in control

rats makes a n assessment of the kidney as a target organ for MPHE impossible. As such, CPN is not considered a toxicologically relevant endpoint for humans, and it does not inform the AEL for this compound.

Of greater importance for the development of the AEL, howeve r, is the lack of relevance of oral exposure to an occupational worker. It is not believed that workers will be incidentally ingesting the study compound in any significant amounts. It is possible that like some perfluorinated alkanes which are also nephro toxins, MPHE may be metabolized by glutathione conjugation, followed by ß

- lyase dependent biotransformation to reactive intermediates (Iyer and Anders 1997; Anders 2008). However, even if

metabolic studies were to indicate MPHE were metabolized in this fas hion, the ß

- lyase metabolism pathway in humans is 10

- 30 fold less active than in rodents (Anders and Dekant 1998; Gentz and Malan 2001), suggesting that the effect in humans would be much less significant. As discussed previously, the inhalation pathway i s the most relevant, and the 28

- day inhalation study performed was used to determine

the AEL.

Developmental Study

In a developmental assay, 22 time

- mated female Sprague

- Dawley rats were administered MPHE via

gavage (oral) on gestation days (gd) 6

- 20 at d oses of 0 ; 250 ; 500 ; and 1,000 mg/kg (Munley 2010). The dams were euthanized on gd 21 and the recommended reproductive and developmental parameters were evaluated. Exposure to the study compound did not affect any measured endpoint including those

assess ing maternal health and fetal development (e.g., fetal number or weight, as well as external, visceral, or skeletal alterations). It was noted in the study that the percentage of male rat pups was statistically significantly increased at 500 and 1,000 mg/ kg. The study authors indicated that theFinal

— July 2, 2015

22 statistical significance was likely a result of the low ratio of males in the control group, and ICF agrees. Furthermore, ICF notes the following:

• no changes in pre

- or post

- implantation loss were observed across the exposed groups,

• pup gender was established at conception,

• the dams were purchased already mated and at gd 1, 2, or 3, and

• the dams were not exposed to the study chemical until gd 6.

Other than selective loss of female pups, which the aforementioned data disprove, there is no other mechanism by which exposure to the compound during this developmental period could increase the percentage of male pups. In addition, the ranges of male pu ps in this study are comparable to those found

in more wide

- ranging analyses (Stump et al. 2012). Therefore, ICF believes that the sex ratio in this study was unaffected by exposure to MPHE . The NOAEL was identified as 1,000 mg/kg by the study authors;

ICF agrees.



## V. Supporting Genotoxicity Studies

The genotoxicity data for this study compound consist of a bacterial reversion assay, an assay evaluating chromosomal aberration in Chinese hamster ovary cells, and two micronucleus assays in rat blood cells

foll owing repeated oral and inhalation exposures (Myhre 2009; Glover 2009; Myhre 2012; DeLorme 2014). All studies were determined to be negative, indicating that under the conditions used, MPHE and/or its metabolites are not believed to be mutagenic or clasto genic.Final

— July 2, 2015

23 

## VI. References

Akahoshi

, H. 2010. A 28

- day repeated dose oral toxicity study of MPHE in rats. Mitsubishi Chemical Medience Corporation for EI duPont de Nemours and Company, Wilmington, DE. 21 December 2010.

Anand

, S

. S. 2011. [ ] : Subchronic toxicity 90

- day gavage study in rats. E.I. du Pont de Nemours and Company, DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, DE. 2 June

2011.

Anders, M.W. 2008. Chemical toxicology of reactive intermediates formed by the glutathi one

- dependent bioactivation of halogen

- containing compounds. Chem. Res. Toxicol 21:145

- 159.

Anders, M.W., W. Dekant. 1998. Glutathione

- dependent bioactivation of haloalkanes. Ann Rev

Pharmacol Toxicol 38:501

- 537.

DeLorme

, M

. P. 2014. [ ] : Four

- week inhalation toxicity study with micronucleus evaluation in rats. E.I. du Pont de Nemours and Company, Newark, DE. 2 July 2014.

Durando

, J. 2009. [ ] : Acute oral toxicity

-- fixed dose procedure in rats. Eurofins Product Safety Laboratories Dayto n, NJ for EI duPont de Nemours and Company, Wilmington, DE. 12 March 2009.

E.I. du Pont de Nemours and Company. 2013a. Additional information provided to SNAP from DuPont. 27 May 2013.

E.I. du Pont de Nemours and Company. 2013b

. Additional information pr ovided to SNAP from DuPont. 11 February 2013.

Gentz, B.A. and T. P. Malan. 2001. Renal toxicity with sevoflurane: a storm in a teacup? Drugs 61:2155

- 62.

Glover

, K

. P. 2009. [ ] : In vitro mammalian chromosome aberration test in Chinese hamster ovary cells

. E.I. duPont de Nemours and Company, DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, DE. 26 June 2009.

Hard

, G

. C

. , J. K. Johnson, and S. M. Cohen. 2009. A comparison of rat chronic progressive nephropathy

with human renal dis ease

-- implications for human risk assessment. Crit Rev Toxicol 39:332

- 346.

Iyer

, R

. A . and M.W. Anders. 1997. Cysteine conjugate ß

- lyase

- dependent biotransformation of the cysteine S

- conjugates of the Sevoflurane degradation product 2

- (fluoromethoxy)

- 1,1, 3,3,3

- pentafluoro

- 1

- propene (Compound A). Chem Res Toxicol 10:811

- 819.

Kegelman

, T

. A. 2011. [ ] : Inhalation acute exposure with anatomic pathology evaluation in rats. E.I. duPont de Nemours and Company, DuPont Haskell Global Centers for Health & Environm ental Sciences, Newark, DE. 22 February 2011.

Mackay D

. , W. Y. Shiu

, and K. C. Ma. 1993. Illustrated Handbook of Physical

- Chemical Properties and Environmental Fate for Organic Chemicals. Vol. III. Volatile Organic Chemicals . Boca Raton: Lewis Publishers, 1993.Final

— July 2, 2015

24 MacKenzie

, S

. A. 2009. [ ] : Repeated

- dose oral toxicity 28

- day gavage study in rats. E.I. duPont de Nemours and Company, DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, DE. 16 July 2009.

Melnick

, R

. L

. , K. M. Burns, J. M. Ward, et al. 2012. Chemically exacerbated chronic progressive nephropathy not associated with renal tubular tumor induction in rats: an evaluation based on 60 carcinogenicity studies by the National Toxicology Program. Toxicol Sci 128:346

- 356.

Munley

, S

. M. 2010. [ ] : Developmental toxicity study in rats. E.I. duPont de Nemours and Company, DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, DE. 10 August 2010.

Myhre

, A. 2009. [ ] : Bacterial reverse mutation test. E.I. duPont de N emours and Company, DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, DE. 30 June 2009.

Myhre

, A. 2012. [ ] : Rat blood micronucleus test. E.I. duPont de Nemours and Company, DuPont Haskell

Global Centers for Health & Environmental Sciences, Newark, DE. 11 January 2012.

Seely, J. C. and G. C. Hard. 2008. Chronic progressive nephropathy (CPN) in the rat: review of pathology and relationship to renal tumorigenesis. J Toxicol Pathol 21:199

- 205.

Stump

, D

. G

. , M. D. Nemec , G. A. Parker

, et al. 2012. "Significance, reliability, and interpretation of developmental and reproductive toxicity" in Hood RD, ed: Developmental and Reproductive Toxicology, A Practical Approach, 3rd Edition. London: Informa Healthcare. 2012.

Travlos

, G

. S

. , L. Betz, and G. C. Hard. 2007. The influence of diet or route of exposure on chronic progressive nephropathy, kidney weight, blood urea nitrogen and creatinine concentrations in 13

- week toxicity studies for control F344/N male rats. Abstract. Toxicol Pathol 3 5:1.

United States Environmental Protection Agency (U.S. EPA). 1994. Methods for Derivation of Inhalation Reference Concentrations (RfCs) and Application of Inhalation Dosimetry. U.S. Environmental Protection Agency, Office of Research and Development, Of fice of Health and Environmental Assessment, Washington, DC, EPA/600/8

- 90/066F.