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Page 1 United States Office of Chemical
Environmental Protection Safety and Pollution Agency Prevention



# TSCA Workplan Chemical Risk Assessment for Trichloroethylene:

Degreaser and Arts/Crafts Uses

CASRN: 79-01-6

Ethene, 1,1,2

- trichloro December 2012

NOTICE

This document is an External Review Draft . This information is distributed solely for the purpose of pre

- dissemination peer review under applicable information quality guidelines. It
has not been formally disseminated by EPA. It does not represent and should not be construed to represent any Agency determination or policy. It is being circulated for review of its technical accuracy and science policy implications. 

# Cl H Cl

Cl

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## Table of Contents

AUTHORS / CONTRIBUTO RS / ACKNOWLEDGEMENT S / REVIEWERS

.................................................... 6

GLOSSARY OF TERMS AN D ABBREVIATIONS

....................................................................................... 7

EXECUTIVE SUMMARY

..................................................................................................................... 10

CHAPTER 1: BACKGROU ND AND SCOPE

........................................................................................... 13

B ACKGROUND

................................................................................................ .............................................................. 13
S COPE OF A SSESSMENT FOR TCE

................................................................................................ ..................................... 14

CHAPTER 2: SOURCES AND E NVIRONMENTAL FATE OF TCE

.............................................................. 16

A. P HYSICAL AND C HEMICAL P ROPERTIES OF TCE

............................................................................................................... 16
B. E NVIRONMENTAL F ATE

................................................................................................ .............................................. 17
C. P RODUCTION V OLUME AND G ENERAL I NFORMATION ON U SES

.......................................................................................... 21

CHAPTER 3: HUMAN HE ALTH RISK ASSESSMENT

.............................................................................. 22

A. E NVIRONMENTAL R ELEASES AND E XPOSURE S UMMARY

................................................................................................... 22
ENVIRONMENTAL RELEASES OF TCE

................................................................................................................... 22 Calculating Exposures used in this Risk Assessment

........................................................................................... 29
Con sumer Exposures – Degreaser and Arts/Crafts Uses of TCE

.......................................................................... 30
B. H AZARD S UMMARY

................................................................................................ .................................................. 33 Toxicokinetics (Absorption, Distribution, Metabolism, and Excretion)

............................................................... 34 Summary of Toxicity Information on TCE

............................................................................................................ 38 Hazard Data to be used in Risk Assessment for TCE

........................................................................................... 55
C. H UMAN H EALTH R ISK C HARACTERIZATION

.................................................................................................................... 57 Risk Estimation Approach for Acute and Repeated Exposures

........................................................................... 57 Risk Estimates for Acute (Short

- Term) and Chronic (Repeated) Exposures to TCE

............................................. 60 Summary

................................................................................................ ............................................................. 65
D. D ISCUSSION OF K EY S OURCES OF U NCERTAINTY AND D ATA L IMITATIONS

............................................................................ 69 Uncertainties in the Exposure Assessment

.......................................................................................................... 69 Uncertainties in the Hazard Assessment

............................................................................................................. 70 Uncertainties in the Risk Assessment

.................................................................................................................. 71
C ONCLUSIONS

................................................................................................ .............................................................. 72

REFERENCES

................................................................................................ .................................... 73

APPENDIX A: REGULAT ORY HISTORY OF TCE A T THE US EPA

............................................................. 86

APPENDIX B: 2006 IN VENTORY UPDATE RULE DATA FOR TCE

........................................................... 88

APPENDIX C: NAICS C ODES FOR TCE DEGREAS ING

............................................................................ 91

APPENDIX D: CALCULA TIONS FOR SMALL COMM ERCIAL WORKER DEGREA SER EXPOSURES

.............. 93

APPENDIX E: CONVERT ING E

- FAST ADRS TO CONCENT RATION IN AIR

............................................... 97

APPENDIX F: HAZARD VALUES IDENTIFIED FO R USE IN THIS RISK A SSESSMENT

................................ . 99

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## List of Tables

Table 1

- 1. Primary Uses of TCE and Determination of Inclusion in this Risk Assessment.

........................ 15

Table 2

- 1. Physical

- Chemical Properties of TCE a

. ....................................................................................... 16

Table 2

- 2. Environmental Fate Characteristics of TCE a

. ............................................................................. 20

Table 3

- 1. TCE Ambient Air Monitoring Data (μg/m 3 ) a

. ............................................................................. 23

Table 3

- 2. The Number of TCE

- Emitting Emission Points and Corresponding Total Annual Air Emissions of TCE as reported in the 2008 NEI (US EPA, 2008b).

............................................................ 25

Table 3

- 3. Total Annual Air Emissions of T CE as Reported in the 2008 TRI (TRI, 2012b).

.......................... 25

Table 3

- 4. Relevant TCE Releases from Solvent Cleaning in 2010.

............................................................ 26

Table 3

- 5. Breakdown of Degreasing Cleaning Machine Type for Point Source TCE Emissions

................ 27

Table 3

- 6. Estimate of 2010 TCE Releases for Small Industrial/Commercial Facilities (n = 1,483).

........... 28

Table 3

- 7. Potential Operating TCE Emission Factors from Degreasing (Calculated and Reported Values).

................................................................................................ ................................................ 29

Table 3

- 8. Summary of Potential Workplace TCE Inhalation Exposures: Small Commercial Degreaser.

.. 30

Table 3

- 9. TCE Products in Household Products Database Retrieval.

........................................................ 31

Table 3

- 10. Estimated TCE Potential Acute Dose Rates from Use of Two Hobbyist Products Indoors at Residences as Determined by E

- FAST.

................................................................................... 32

Table 3

- 11. Estimated TCE Inhalation Calculated Concentration in Air (Over the Course of a Day a ) from Use of Two Hobbyist Products Indoors at Residences.

.......................................................... 33

Table 3

- 12. Hazard/Risk Assessment Documents Consulted for this Report.

........................................... 33

Table 3

- 13. Common Metabolites of TCE and Related Compounds a

........................................................ 35

Table 3

- 14. TCE Metabolites Identified by Pathway a

. ................................................................................ 36

Table 3

- 15: Half

- Life Data For TCE in Rats and Humans a

. .......................................................................... 38

Table 3

- 16. Proposed AEGL Values for TCE (in ppm) a

. ............................................................................... 40

Table 3

- 17. Inhalation Stu dies Identified In US EPA (2011c) For Use In OPPT TCE Risk Assessment.

....... 53

Table 3

- 1 8. U.S. EPA IRIS PBPK

- Modeled Dose Metrics for TCE Dose

- Response Assessment.

.................. 56

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- 19. Range of TCE Candidate POD/HEC Values Derived by US EPA (2011c).

................................ . 57

Table 3

- 20. Us e Scenarios, Population of Concern, and Health Effects of Concern.

................................ . 59

Table 3

- 21 . TCE Noncancer Risk Estimates for Small Commercial Degreasers and Non

- users: Using the Lowest 99th Percentile HECs (Numbers are MOEs) 1,2

........................................................... 62

Table 3

- 22. TCE Cancer Risk Estimates for Small Commercial Degreasers and Non

- users (Numbers are Extra Lifetime Cancer Risk and Bolded Vales Represent Concern

........................................ 63

Table 3

- 23. TCE Non

- cancer Risk Estimates for Use of Two Hobbyist Products Indoors at Residences: Neurotoxicity as Endpoint of Concern and Using the Lowest 99 th Percentile HECs and 2 4- Hour Average Exposure Concentrations (Numbers are MOEs]) 1

. .......................................... 64

Table 3

- 24. TCE Non

- cancer Risk Estimates for Use of Two Hobbyis t Products Indoors at Residences: Developmental Toxicity as Endpoint of Concern Using the Lowest 99 th Percentile HECs and
24

- Hour Average Exposure Concentrations (Numbers are MOEs) 1

....................................... 65

Table 3

- 25. Summary of Overall Risk Assessment for TCE Using the Lowest 99 th Percentile HECs

........... 66

Table 3

- 26. Changes in the Non

- Cancer MOEs If Different HECs are Used a

............................................. 68

Table B

- 1. US EPA 2006 IUR Data for TCE.

................................................................................................ . 88

Table B

- 2. National Chemical Information.

................................................................................................ 89

Table B

- 3. Summary of TCE Uses.

.............................................................................................................. 89

Table B

- 4. TCE Use Category Summary.

..................................................................................................... 90

Table C

- 1. TCE Used as a Degreaser Primarily in These Industries (US Census, 2008).

............................. 91

Table D

- 1. Near

- Field/Far

- Field Model In puts.

.......................................................................................... 95

Table D

- 2. Potential Workplace TCE Inhalation Exposures and Number of Workers Exposed; No LEV.

... 95

Table D

- 3. Potential Workplace TCE Inhalation Exposures and Number of Workers Exposed; With LEV. 96

Table E

- 1. Estimated TCE Inhalation Calculated Concentration in Air (Over Course of Day) from Use of Two Hobbyist Products Indoors at Residences.

..................................................................... 98

Table F

- 1. Studies Identified In US EPA (2011c) For Use In Dose

- Response Assessment For TCE.

............ 99

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## List of Figures

Figure D

- 1. An Illustration of an Imperfectly Mixed Room; Near

- Field/Far

- Field Approximation of a Solvent Cleaning Facility; Potential Worker Exposures Depend on How Close a Worker is to the Emission (Volatile) Source.

.............................................................................................. 93

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## Authors / Contributors / Acknowledgements / **Reviewers**

This report was developed by the Office of Pollution Prevention and Toxics (OPPT), Office of Chemical Safety and Pollution Prevention (OCSPP). The 2012 workplan risk assessments were prepared based on existing data and any add itional information received up to June 15, 2012. Mention of trade names does not constitute endorsement by the US EPA.

EPA Assessment Team Lead: Louis S carano , OPPT/RAD

Team: David Lynch, OPPT/EETD Lead Marcus Aguilar, OPPT/CCD Rehan Choudhary, OPPT/EETD Lynn Delpire , OPPT/EETD (retired) Cathy Fehrenbacher, OPPT/EETD Kathy Hart, OPPT/EETD Laura Nielsen, OPPT/EETD Nhan Nguyen, OPPT/EETD
Justin Roberts , OPPT/EET D Yvette M. Selby – Mohamadu, OPPT/EETD David Tobias, OPPT/EETD

Acknowledgements Weihsueh Chiu, ORD/ NCEA for consultations on TCE IRIS assessment and PBPK modeling

Acknowledgements Portions of this document were developed with support from:

Contractor name (contract number) Task SRC, Inc. ( EP -W- 12

- 003) Environmental Fate

Internal Peer Review ers H. Kay Austin, OPPT/EETD Stan Barone Jr., OPPT/RAD Todd Stedeford, OPPT/RAD

External Peer Review - A peer review panel is being arranged for this influential workplan assessment product based upon need and following Agency peer review guidance. The format
will be a teleconference of an ad hoc panel meeting consisting of independent experts.

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## Glossary of Terms and Abbreviations

μg/m 3 

### Microgram(s) per cubic meter
ACGIH American Conference of Governmental Industrial Hygienists

ADR Acute dose rate
AEGL Acute E xposure G uideline L evel
ATSDR Agency for Toxic Substances and Disease Registry

BAF Bioaccumulation factor
BCF Bioconcentration factor

BMD Benchmark dose

BMDL Benchmark dose, lower confidence limit(s)
BOD Biochemical oxygen demand
CalEPA California Environmental Protection Agency
CASRN Chemical Abstract s Service Registry Number
CCD Chemical Control Division
CEM Consumer Exposure Module
CERCLA Comprehensive Environmental Response, Compensation, and Liability Act
CI Confidence interval
CNS Central nervous system
cRfC Candidate reference concentration
CYP Cytochrome P450
DCA Dichloroacetic acid
DCAC Dichloroacetyl chloride
DCVC S-D ichlorovinyl -L- cysteine (collectively, the 1,2 - and 2,2 - isomers)
DCVG S- Dichlorovinyl

- glutathione
DCVT Dichlorovinyl thiol

DIY Do

- it

- yourself

DNA Deoxyribonucleic acid
ECA Enforceable consent agreement
EEG Electroencephalogram

EETD Economics, Exposure and Technology Division

E- FAST Exposure and Fate Assessment Screening Tool

EFH Exposure Factors Handbook
EIS Emissions Inventory System
EU European Union

g Gram(s)
GGT P Gamma glutamyl transpeptidase
GSH Glutathione (reduced)

HAP Hazardous air pollutant
HC V Human cancer value
HEC Human equivalent concentration
HEC 50 

### “Typical” human equivalent concentration
HEC 99 

### “Sensitive” human equivalent concentration

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### HSIA Halogenated Solvents Industry Alliance, Inc.
lb Pound(s)
IARC International Agency for Research on Cancer
IRIS Integrated Risk Information System
IUR Inhalation unit risk kg Kil o gram(s)
LADC Lifetime average daily concentration

LADD Lifetime a verage d aily d ose LEV Local exhaust ventilation
LOAEL Lowest

- observed

- adverse

- effect level
MCL Maximum contaminant level
MCLG Maximum contaminant level goal mg/kg

- bw/day Milligram(s) per kil o gram body weight per day mg/L Milligram(s) per liter mg/m 3 

### Milligram (s) per cubic meter mg/mL Milligram(s) per milliliter

MITI Ministry of International Trade and Industry
MOE Margin of Exposure
MOE acute 

### Margin of Exposure (for acute exposure/hazard conce rns)
MOE chronic 

### Margin of Exposure (for chronic exposure/hazard concerns)

MOU Memorandum of understanding

N Ac DCVC N- Acetyl -S- (1,2

- dichl o rovinyl) -L- cysteine
NAICS North American Industry Classification System
NAS National Academy of Sciences
NCI National Cancer Institute

NEI National Emissions Inventory

NHL Non

- Hodgkins lymphoma

NIH National Institutes of Health
NOAEL No

- observed

- adverse

- effect level
NOES National Occupational Exposure Survey
NIOSH National Institute for Occupational Safety and Health

NPL National Priority List

NTP National Toxicology Program
OAR Office of Air and Radiation
OCSPP Office of Chemical Safety and Pollution Prevention
OECD Organisation for Economic Co

- operation and Development
OPPT Office of Pollution Preven tion and Toxics
OR Odds ratio
OSHA Occupational Safety and Health Administration
OSWER Office of Solid Waste and Emergency Response
OW O ffice of Water

PBPK Physiologically

- based pharmacokinetic

p- cRFCs PBPK model

- based candidate RfCs
PFC Plaque

- for ming cell

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### PND Postnatal day
POD Point of departure
POTW Publicly owned treatment works ppb Parts per billion

ppm Parts per million
PVC P olyvinyl chloride

RAD Risk Assessment Division
RCC Renal cell carcinoma
RCRA Resource Conservation and Recovery Act RfC Reference concentration
RfD Reference dose

RR Rate ratio
RRm Summary relative risk
SAB Science Advisory Board
SARA Superfund Amendments and Reauthorization Act
SCC Source Classification Code
TCA Trichloroacetic acid
TCE Trichloroethylene
TCOG Trichloroethanol

, glucuronide conjugate
TCOH Trichloroethanol

TRI Toxics Release Inventory
TTC Total trichloro compounds
TSCA Toxic Substances Control Act

TWA Time

- weighted average
UF Uncertainty factor
US United States
US EPA United States Environmental Protection Agency
VCCEP Voluntary Children’s Chemical Evaluation Program
VOC Volatile organic compound

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## Executive Summary

T richloroethylene (TCE) was identified for risk assessment as part of the United States (US)
Environmen tal Protection Agency’s (EPA)’s Existing Chemicals Management Program. The US EPA reviewed readily available information on TCE including uses, physical and chemistry properties , fate, exposure potential, and associated hazards to humans and the environment.

TCE was selected based on concerns for its human health hazard ( e.g., probable human carcinogen), and its exposure profile ( i.e., widely used in consumer products and detected in drinking water, indoor environments, surface water, ambient air, groundwater, and soil) using the recently adopted Office of Pollution Prevention and Toxics (OPPT) screening methodology ( US EPA, 2012c ) . TCE also was determined to have moderate persistence and low bioaccumulation potential. The potential for environmental effects was judged to be low because of TCE’s moderate persistence, low bioaccumul ation, and low hazard for aquatic toxicity. This risk assessment does not include a n assessment of environmental effects.

TCE is a volatile organic compound (VOC) that is produced or imported into the US in large quantities (>250 million lb s (lbs) per y ea r) and has multiple uses. The majority, roughly 84 percent
, of TCE is used as an intermediate chemical for manufacturing refrigerant chemicals,
but no emission information was available because it is processed in a closed system. Much of the remaining ~ 15 percent is used as a solvent for metals degreasing, leaving a relatively small percentage to account for all other uses, including its use in consumer products.

This assessment is focused on TCE’s use as a degreaser in small commercial settings 1 

### and b y

consumers in residential settings and its use as a clear protective coating spray by arts and crafts hobbyists. Due to TCE’s high volatility, all exposures were evaluated for the inhalation exposure pathway only . The US EPA recognizes that dermal exposu re can occur, but this exposure pathway is co nsidered less significant and was not considered with in the scope of this
risk assessment.

For the exposure assessment, OPPT reviewed available data from three separate sources ( i.e., National Emissions Inventory [NEI], Toxics Release Inventory [TRI], and the North American Industry Classification System [NAICS]) and developed estimates for exposures for the small commercial degreaser use. There were no reliable data regarding the hobbyist scenarios, so OPPT estimated hobbyist exposures using a standard exposure assessment modeling approach ( i.e., EPA’s Exposure and Fate Assessment Screening Tool [E

- FAST], Consumer Exposure Module [CEM]).

Modeling and evaluation were used to develop exposure estimates fo r the following exposure scenarios: small commercial degreaser worker; consumer/hobbyist degreaser user; and consumer/hobbyist clear protective coating spray user. For all three scenarios, exposure estimates also were developed for bystanders ( i.e., non

- users) defined as individuals not actually usi ng the TCE product, but who are physically nearby and thus, possibly exposed.

1 Small commercial settings represent small businesses that use degreaser products/equipment regularly, but not all day during the course of their job. An example would be a garage/car mechanic business.

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### For the hazard information, the US EPA relied on the Integrated Risk Information System’s (IRIS) published toxicological review of TCE ( US EPA, 2011c )

. This information was used to identify

non

- cancer hazard values for acute ( i .e., single or short

- term) and chronic ( i .e., repeated) exposure conditions. There were 27 different candidate studies identified that evaluated 32 endpoints, which encompassed a variety of effects following both acute ( i .e., developmental toxicity and neurotoxicity) and chronic ( i .e., liver, kidney, immunotoxicity, and male reproductive toxicity) exposures. From this pool of studies, OPPT chose 12 studies that used
inhalation as th e route of exposure. These 12 studies evaluated 17 different endpoints. H azard values were chosen to represent effects in each of the majo r target organs . By not limiting the analysis to a single, s ensitive endpoint or effect, this assessment allows both the exposure duration and the population exposed to help determine which hazard value may be the most appropriate or important.

The IRIS inhalation unit risk (IUR) value, based on concerns for human cancers of the kidney, liver, a nd non

- Hodgkin’s lymphoma (NHL), was used for OPPT’s TCE cancer risk assessment.

Adult male and female workers and bystanders in small commercial facilities were identified as a populat ion or life stage targeted for chronic or daily exposure scenarios in this assessment

. Because acute exposures also can occur during daily exposures, there may be a potential hazard for both neurotoxicity and developmental toxicity; thus, given the latter, women of
child

- bearing age were included as a life stage or populati on

.
For both the residential consumer and hobbyist user scenarios, the same populations identified for the small commercial worker and bystander scenarios ( i.e., males and females, including
women of child

- bearing age) were used. However, the non

- cancer evaluation was limited to acute exposures and to neurological effects to males and females, and developmental effects to women of chil d- bearing age . For the consumer, non

- user population, the US EPA identified all ages for evaluation because all

- age members of a household could be in the home during the use of the consumer product.

For all non

- cancer risk calculations, the Margin of Exposure (MOE) approach was used. In this approach, the hazard value is divided by the exposure value to derive a number that is compared to conventional benchmark values used to estimate or quantify risk. In this risk assessment, all of the hazard values were derived using a special mathematical model as
determined by US EPA (2011c ) . The modeling exercise used test data from both animals and humans to derive values called Human Equivalent C oncentrations (HEC). Although many HEC values were calculated by the IRIS program, in this assessment a more conservative value was used ( i .e., the lower bound 99 th 

### percentile HEC value) for each of the non

- cancer adverse effect
outcomes evaluated.

When the hazard value (HEC) is divided by the exposure value, the resulting number is calle d
the “ Margin of E xposure” or MOE . In this r isk assessment, if the value is determined as less than 30, there is a potentia l risk concern; if the value is found as greater than 30

, there is no risk

concern.
For the cancer risk assessment, a different metric was us ed to quantify risk. The method EPA
used calculated extra cancer risk from benchmarks of concern based on no more than one

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### excess cancer in a population of 100,000 workers ( i.e., 1 x 10 -5 

### ) or one excess cancer in a population of one million nonworkers ( i.e., 1 x 10 -6 

### ).

EPA relied on physiologically

- based pharmacokinetic (PBPK) modeling performed by the US EPA’s IRIS program, which resulted in a variety of hazard values to represent HECs. In choosing the values used, assumptions were made that could introduce some uncertainty into the risk assessment. However, using conservative measures ( i.e., the lower bound 99 th 

### percentile HEC)
and values from inhalation

- only studies for each of the six major target organs or adverse
effects associated wit h TCE, strengthens the degree of confidence that the risks were not
under

- estimated for the scenarios evaluated in this report.

As with any risk assessment, there are uncertainties that need to be considered when interpreting the results. Assumptions were used in estimating the exposure scenarios covered in this assessment. Examples include assumptions about the number and duration of use events ( i.e. , how often a consumer may use a degreaser or clear protective coating spray product) and the assumptions used to estimate inhalation exposures to small shop commercial degreaser workers. OPPT did not quantify these uncertainties and recognizes that they may under - or

over

- estimate actual exposure.

Finally, by focusing on six different target organs or effects for chronic and acute exposure durations, rather than on a single, sensitive value or endpoint, the robust hazard database on TCE is fully utilized. This provides important context that is both useful and informative to those interested in understanding the potential risks of concern from TCE exposures for the scenarios
evaluated in this risk assessment.

The results of the risk assessment show:

• For the commercial degreaser user and non

- user, non

- cancer MOEs were less than 30 for acute toxicity for dev elopmental toxicity and neurotoxicity effects, and chronic
effects for liver, kidney, and immune system effects

. This indicates potential risks of

concern.

• For the commercial degreaser user and non

- user, using the IRIS IUR the cancer risks
were all below the benchmark values. This indicates potential risks of concern.

• For the hobbyist degreaser user and non

- user and for the hobbyist clear protective

spray user s, the acute non

- cancer MOEs for developmental toxicity were less than 30. This indicates pot ential risks of concern.

• The hobbyist clear protective spray non

- user scenario resulted in an MOE of greater than 30 for both developmental toxicity and neurotoxicity

. This indicates no potential
risks of concern.

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## Chapter 1: Background and Scope

T richloroethylene (TCE) has been identified for assessment as part of the United States (US) Environmental Protection Agency ’s (EPA) Existing Chemicals Management Program. TCE was selected based on EPA ’ s concerns for human health hazard ( i.e., probable h uman carcinogen)

, and its exposure profile ( i.e., widely used in consumer products and detected in drinking water, indoor environments, surface water, ambient air

, groundwater

, and soil) using the recently adopted Office of Pollution Prevention and Toxics ( OPPT ) screening methodology ( US EPA,
2012c )

.

In this c hapter, a brief discussion is presented on the steps that EPA has taken to determine the focus and scope of this risk assessment.



## B ACKGROUND

TCE is a liquid, volatile organic compound with high vapor pressure, moderate water solubility, and high mobility in soil. The biodegradation of TCE in the environment is dependent on a variety of factors ( e.g., pH, resident microorganisms, moisture, etc. ) and so a wide range of degradati on rates are possible

, ranging from days to years. TCE also has moderate persistence and low bioaccumulation potential.

This substance is produced or imported into the US in large quantities ( i.e., > 250 million lbs/ yr) and has many uses. The majority, almost 84 percent, of TCE is used as an intermediate chemical for manufacturing refrigerant chemicals. Much of the remaining roughly 15 percent is used as a solvent for metals degreasing, leaving a relatively small percentage to account for all other uses, including

, its use in some consumer products. TCE can be found in consumer products including but not limited to those “do

- it

- yourself” [DIY] consumer uses such as a solvent for metal degreasing for use on cars, bikes, etc. , or as an ingredient in hobbyist products, including a clear protective coating spray for artwork, a film cleaner, a toner aide, and a mirror edge sealant.

Most reported environmental releases of TCE are to air with much fewer releases to landfills and very little releases to water (see Chapter 3, Section A, Environmental Release and Exposure Summary).

Due to its high production volume, physical

- chemical properties, uses, and environmental releases, TCE has been the subject of various regulations across many offices within the US EPA: the Office of Air and Radiation (OAR), the Office of Solid Waste and Emergency Response (OSWER), the Office of Water (OW), and OPPT. Appendix A provides a review of the US EPA

wide regulatory hi story of TCE.

The US EPA’s assessment of th e human health hazard of TCE is largely based on the US EPA’s toxicological review of TCE ( US EPA, 2011c ) . This comprehensive review compiled hazard

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### information and was reviewed by the US EPA’s Science Advisory Board (SAB) ( US EPA, 2011a )

. In addition, a literature search was conducted in March, 2012 for new information.



## S COPE OF 

## A SSESSMENT FOR 

## TCE

Given that the majority of TCE produced and used in the US is as a chemical intermediate that would not likely result in exposures to the general population, the US EPA assumed that virtually all of the TCE that is used as an intermediate for manufacturing refrigerant chemical is consumed in this process or released as fugitive air emissions. Large

- scale manufacturing occupational exposure scenarios were not addressed in this risk assessment. In general, exposures that result from large

- scale industrial operations are likely to be better controlled and monitored than those exposures from small commercial settings and consumer uses.

The US EPA focused the assessment on uses of TCE as a degreaser ( i.e., both in small commercial settings and by consumers or hobbyists) and on consumer use of TCE in products used by individuals in the arts and crafts field. Bystanders, those who are in the vicinity of the product use, also were addressed. Because of TCE’s high volatility, all exposures were evaluated only for the inhalation exposure pathway. The US EPA recognizes that dermal exposure can occur for both of these scenarios, but this exposure pathway is considered less significant and is not considered in thi s risk assessment.

Information from EPA’s toxicological review of TCE ( US EPA, 2011c ) was used as the basis for develop ing an assessment of the human health hazard of TCE in targeted use by workers in small commercial degreasing applications and by consumer/hobbyists using T CE as a degreaser and an art spray fixative. EPA identified non

- cancer hazard values for acute ( i .e., single or short

term) and chronic ( i .e., repe ated) exposure conditions for a variety of effects including both acute ( i .e., developmental toxicity and ne urotoxicity) and chronic ( i .e., liver, kidney, immunotoxicity, and neurotoxicity ) endpoints.

EPA did not evaluate environmental effects in this risk assessment from the manufacture and use of TCE. Available information reviewed in the European Union (EU) risk assessment for TCE ( EC, 2004 ) concluded there were no concerns for environmental effects on aquatic organisms, including benthic organisms, terrestrial orga nisms , and the atmosphere. The EU risk conclusions were based on the production and use of TCE ( i.e., including releases to wastewater treatment plants, to air from all uses, and from dichloroacetic acid [DCA; photodegradation product of TCE]). The hazar d information EPA reviewed

, particul arly the aquatic toxicity data, suggest there is no immediate concern for potential environmental effects.

Table 1- 1 shows the use and exposure scenarios considered and the rationale for inclusion or
exclusion in this assessment. The primary criteria for inclusion were whether there was a high TCE concentration in the product and the frequency of use of the product. EPA focused its

assessment on s mall commercial operators where workers such as garage mechanics may use a solvent degreaser at some point as a part of their daily activities. It is assumed that these
individuals are all adults (> 16 and older) . Furthermore, exposures were estimated and risks

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Page 15 

### were calculated for workers in t he vicinity of the degreasing use , but not actually performing
the operation ( i.e. , bystanders).

Table 1 -1 . Primary Uses of TCE and Determination of Inclusion in this Risk Assessment

.

Use Category Typical
Percent

TCE
Content Population Exposed To Be Considered in this Assessment?

Intermediate in the manufacturing of refrigerant >99 Workers in the refrigerant manufacturing

process No – US EPA is assuming that most of the TCE is consumed in producing the refrigerant

Solvent
d egreaser >90 Large commercial/ industrial settings (adults) No – Such exposure scenarios are more likely to be monitored/controlled in the workplace and by OSHA

Solvent
d egreaser >90 Small commercial shop employees and

non

- users (all adults) Yes – high content, possible frequent use ( i.e. , chronic exposures )

Solvent
d egreaser >90 Consumer users (adults >16 years old), non

- users (all ages) Yes – high content, assumed low frequent use ( i.e. , acute exposures)

Plastic clear protective coating spray (h obbyists; arts/crafts) 20

- 30 Yes – low content, but likely most frequent use of consumer products evaluated ( i.e.

, acute exposures)

Film c leaner (h obbyists) >90 No

– although high content, use of negatives/ cameras with film is thought to be low and so frequency of use is assumed to be negligible ; t here is the potential for frequent use by small population ( i.e. , film developers)

Toner aide (h ome office) 15

- 20 No

– low content, assumed less frequent use

Mirror edge
sealant (h obbyist/ home maintenance) 20

- 30 No – low content, assumed less frequent use



### Consumers are individuals using the products listed in Table 1

- 1 in and around their home.
Non

- users are individuals physically close to the use activity as it occurs and/or living in the user’s residence. The consumer/hobbyist users are assumed to be adults (16 years or older),
and the non

- users could be any age.

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## Chapter 2: **Sources and Environmental Fate of TCE**

In this c hapt er, information on the physical and chemical properties and environmental fate of TCE is presented. There also is a brief su mmary of the production volume and general
information on the uses of TCE in the US

. All of these factors are important to understa nding the potential risks of TCE to workers in this assessment.



## A. P HYSICAL AND 

## C HEMICAL 

## P ROPERTIES OF 

## TCE

TCE is a colorless liquid with a pleasant, sweet odor resembling that of chloroform. It is
considered a VOC because of its moderate boiling point, 87.2 °C, and high vapor pressure, 73.46 mm Hg at 25 °C. TCE is moderately water soluble (1.280 g/L at 25 °C), and has a log octanol:water partition coefficient (K ow 

### ) of 2.42. The density of TCE, 1.46 g/cm 3 

### at 20 °C, is greater than that of water. Table 2- 1 lists the chemical/physical properties of TCE.

Table 2 -1. Physical

- Chemical Properties of TCE a

. Property Value

CASRN 79

- 01 -6

Molecular w eight 131.39

Molecular f ormula C 2 HCl 3 Physical s tate Colorless liquid

Odor Sweet, pleasant, resembles chloroform

Density 1.46 g/cm 3 @ 20 ° C b

Flash p oint 90 °C (closed cup) b

Auto f lammability 410 °C a

Viscosity 0.53 mPa·s @ 25 °C c

Refractive i ndex 1. 4775 e

Dielectric c onstant 3.4 ε 0 @ 16 °C c
Melting p oint

- 84.7 °C (measured)
Boiling p oint 87.2 °C (measured)

Vapor pressure 73.46 mm Hg at 25 °C (measured) d

Dissociation c onstant (pK
a ) Not applicable
Henry’s l aw c onstant 9.85×10 - 3 atm

- m 3 /mole (measured)

Water s olubility 1,280 mg/L at 25 °C (measured)

Log K ow 2.42 (measured)

a SRC (2012 ).

b EC (2000 ).

c Weast and Selby (1966 ). d Daubert and Danner (1989 )

. e O'Neil et al. (2001 ).

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## B. E NVIRONMENTAL 

## F ATE

The environmental fate of a compound is important to understanding potential exposures to its impact on specific environmental media ( e.g., water, sediment, soil, and plants) and target organisms of concern. TCE is a volatile liquid with high vapor pressure, moderate w ater solubility, and high mobility in soil. Most reported environmental rel eases of TCE are to air with much fewer releases to landfills and very little released to water (see Chapter 3, Section A, Environmental Release and Exposure Summary). If released to air, degradation by sunlight and reactants in the atmosphere is slow. If released to water, sediment

, or soil, the fate of TCE is influenced by volatilization from the water surface or from moist soil and by microbial biodegradation under some conditions. The biodegradation of TCE in the environment is dependent on a variet y of factors and so a wide range of degradation rates are possible ( i.e., ranging from days to years). Finally, TCE is not expected to bioconcentrate in aquatic organisms.

Fate in Air
T CE does not absorb light greater than 290 nm very well; therefore, degradation of TCE by
direct exposure to light

, if it is released to the atmosphere

, is not expected to be an important fate process ( US EPA, 1979a )

. TCE is expected to undergo relatively slow atmospheric hydroxy radical oxidation with an estimated atmospheric half

- life of about 13 days (using Version 4.10 of EpiSuite

, US EPA 2012a ) . Phosgene, dichloroacetyl chloride (DCAC) , chloroform

, and formyl
chloride can be formed from the reaction of TCE with hydroxyl radicals ( Kao, 1994 ; Gay et al.

, 1976 ; US EPA, 1980 ).

Fate in Water Volatilization from water surfaces will be an important fate process based upon TCE’s measured Henry's l aw constant. However, its density may cause it to sink in the water column, potentially increasing the aquatic residence time of TCE. Volatilization half

- lives in an experimental field mesocosm consisting of seawater, planktonic

, and microbial communities ranged from 10.7 to 28 days ( Wakeham et al. , 1983 ) . TCE achieved only 19 percent of its theoretical biochemical oxygen demand (BOD) over the c ourse of a 28

- day incubation period using the closed bottle ( Organisation for Economic Co

- operation and Development [ OECD ] 301D) test, and thus is not considered readily biodegradable. It achieved 2.4 percent of its theoretical BOD using an
activated slud ge inoculum in the modified Ministry of International Trade and Industry ( MITI

, OECD 301C) test over the course of a 14

- day incubation period. It was not inherently biodegradable in a Zahn

- Wellens (OECD 302B) test. These studies suggest that TCE will biodegrade slowly in surface waters. However, slow photooxidation in water has been reported (half

- life of 10.7 months) ( Dilling et al. , 1975 )

. Based on these studies, biodegradation and hydrolysis in surface waters are not expected to be important environmental fate processes.

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### Fate in Soil, Sediment , and Groundwater TCE is expected to have high mobility in soil based on measured soil organic carbon partition coefficients ranging from 72 to 148. Volatilization of TCE from moist soil surfaces is expected to be an important fate process given its relatively high Henry's l aw constant. TCE is expected to volatilize from dry soil surfaces based upon its high vapor pressure.

Both laboratory tests and field studies in the environment show wide variation in TCE biodegrad at ion rates. In some cases, laboratory studies have s hown rapid biodegradation. TCE has been shown to biodegrade under aerobic conditions by methanotrophic microbes in the presence of other substrates and under anaerobic conditions (in suitable reducing environments) in the presence of other organic matter. Without competent microorganisms that can degrade TCE and favorable environmental conditions, TCE can persist in the environment on the order of years.

Aerobic biodegradation of TCE by specialized communities of microorganisms has been reported ( Wackett et al. , 1989 )

. B iodegradation of TCE has also been shown to occur under
conditions where additional substrates have been added to the medium ( Mu and Scow, 1994 ; Kao and Prosser, 1999 ; Wilson and Wilson, 1985 )

. Mixed microbial cultures of m ethane

utilizing bacteria have been shown to degrade TCE in two days under aerobic conditions ( Fo gel
et al. , 1986 ) . However, there are several factors that can limit the aerobic biodegradation of TCE, including TCE concentration, pH

, and temperature. Toxicity of the degradation products ( e.g. , dichloroethylene , vinyl chloride, chloromethane) to the degrading microorganisms may also reduce the rates of biodegradation of TCE in aerobic soils.

Biodegradation of TCE also occurs under anaerobic conditions. Under these conditions, as might be seen in flooded soils, sediment , or aquifer environments, TCE is biodegraded via reductive dechlorination; the extent and rate of degradation are dependent upon the strength of the reducing environment and other factors ( McCarty, 1996 )

. TCE half

- lives in the field for aquifer studies range from 35 days to over six years. Major products of biodegradation of TCE in groundwater include dichloroethylene, chloromethane, and vinyl chloride ( HSDB, 2012 )

.

TCE contamination exists in the subsurface en vironment as a result of spills and leaking transfer lines/ storage tanks. Because of its density and low Koc, TCE will ultimately move downward in the soil until an impermeable barrier is reached. This may occur when a TCE spill is of sufficient magnitude or deep enough in soil for volatilization to be restricted. Once in soil, TCE can become associated with soil pore water, enter the gas phase because of its Henry’s Law constant, or exist as a nonaqueous phase liquid (NAPL). It is possible that u pward or downward movement of TCE can occur in each of these three phases, thereby increasing the areal extent of the original spill. Nonaqueous phase concentrations of TCE which are large enough to overcome capillary forces will move downward into the aquifer. Once the water table is penetrated, lateral flow may be mediated by the regional ground

- water flow. Due to its high density, the movement of free

- phase TCE is still directed vertically until lower permeability features are encountered. Once an imperm eable layer is encountered, horizontal movement

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Page 19 

### will occur. Such movement may even be directed against the natural ground

- water flow by the effects of gravity. Since permeability is a function of the liquid as well as the medium, the
vertical movement of T CE through an aquifer is determined by geological properties of the aquifer material; i.e., granular size of sand or clay lenses. T CE will tend to pool near these impermeable features. Water passing over and around these pools may solubilize TCE so that it can be spread throughout the aquifer. This pattern of release and distribution in aquifers and TCE persistence have led to the widespread detection of TCE in groundwater and drinking water supplies derived from the contaminated groundwater ( US EPA

, 1992)

.

Bioconcentration TCE is not expected to bioconcentrate in fish, with measured bioconcentration factors (BCFs) in carp ranging from four to 17. TCE’s low measured BCF value suggests that bioconcentration in aquatic organisms is low ( NITE, 2012 )

. The estimated upper trophic level bioaccumulation
factor (BAF) for TCE is 24 ( using Version 4.10 of EpiSuite, US EPA, 2012a ).

Table 2

- 2 provides a summary of the environmental fate information for TCE.

Conclusions on Environmental Fate TCE is a volatile liquid and if released to air, will be slowly degraded by atmospheric hydroxy radicals. If released to water, volatilization t o the atmosphere will be an important fate process and biodegradation will be slow. In soil, TCE does not bind strongly to soil organic matter and if not biodegraded at an appreciable rate, TCE can migrate through soil to groundwater. Based on the experim ental evidence and environmental fate data available, TCE is expected to have low bioaccumulation potential and moderate persistence.

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Page 20 Table 2

- 2. Environmental Fate Characteristics of TCE a

. Property Value

CASRN 79

- 01

- 6
Photodegradation h alf

- life 13.2 days (estimated)
Hydrolysis h alf

- life Does not hydrolyze under environmental conditions b

Biodegradation 19% after 28 days (not readily biodegradable) b ; 4% after 28 days (not inherently biodegradable) b ; 100% after 2 days (anaerobic conditions using mixed march cultures) b ; 2.4% after 14 days (not readily biodegradable) c

Bioconcentration BCF = 4.3

- 17 (measured in carp at 0.070 mg/L) c ; BCF = 4

- 16 (measured in carp at 0.007 mg/L) c ; BCF = 17 (measured in freshwater fish at 0.0087 mg/L) c ; BAF = 23.7 (estimated) a

Log K oc 2.17 (measured in silty clay Nebraska loam) c ; 1.94 (measured in silty clay Nevada loam) c ; 1.86 (measured in a forest soil) c ; 1.8 (estimated)

Fugacity (Level III Model) b Air (%) Water (%) Soil (%) Sediment (%) 35.4
54.2
10.1

0.3

Persistence d P2 (moderate)

Bioaccumulation d B1 (low)

a US EPA (2012a ).

b EC (2000 ).

c NITE (2012 ).

c US EPA (1999 ).

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## C. P RODUCTION 

## V OLUME AND 

## G ENERAL 

## I NFORMATION ON 

## U SES

In 2011 , global consumption of TCE was 945 million lb s with expected growth at about 1.5 percent annually over the next five years. The corresponding US consumption was 255 million
lb s ( Glauser and Funda, 2012 ) . The re were two US producers for TCE as of 2011 : The Dow Chemical Company in Freeport, TX and PPG Industries, Inc

. in Lake Charles, LA ( Glauser and Funda, 2012 ) 2



### .

TCE production volumes of 100 to 500 million lb s were reported to EPA in 2006 under the Inventory Update Rule (IUR) . In 2005

, there were four known importers of TCE (Chemcentral Corporation; Ineos Chlor Americas, Inc.; JSL Chemical Corporation; and TR International, Inc.) reported in the IUR ( US EPA, 2006b ). Exports of TCE from the US have increased along with similar increases for all chlorinated solvents (80 percent in 2011 , 72 percent in 2010 ) ( ICIS,
2010 , 2012 ) . More information can be found in Appendix B.

TCE has historically had a wide ra nge of uses drawn from various markets, including intermediate chemicals (for refrigerant and polyvinyl chloride [ PVC ] manufacture), industrial and commercial solvents, pharmaceuticals, insecticides, fumigant, textiles (processing and flame retardants), adhesives, and paints (as diluent) ( Ash and Ash, 2009 )

. However, as of 2011

, most US consumption is attributable to two specific uses: 83.6 percent of total TCE production
volume is used as an intermediate for manufacturing the refrigerant, HFC

- 134a (a major
alternative to CFC

- 12), and 14.7 percent is used as a solvent for metals degreasing, with 1.7
percent attributed to “other uses” ( Glauser and Funda, 2012 ) 3



### .

2 This material includes data or information derived from IHS Products provided to the US EPA. IHS products have been provided to the US EPA for its internal use and in the context of a license agreement. By receiving and accessing this material, you agree that IHS is not liable to you or any third party for your use of and/or reliance on the IHS data and information contained in this document, and any such use shall be at your own risk.

3 Ibid

.

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## Chapter 3: Human Health Risk Assessment

This chapter has five major sections: (1) Environmental Releases and Exposure Summary; (2) Hazard Summary; (3) Risk Characterization; (4) Discussion of Uncertainties and Data Gaps;
and (5) Conclusions.



## A. E NVIRONMENTAL 

## R ELEASES AND 

## E XPOSURE 

## S UMMARY

TCE has been detected in air, water

, and humans ( US EPA, 2011c )

. In identifying exposure pathways for TCE, its volatility plays a major role

, and the inhalation route of exposure is of primary importance and concern. This section characterizes the environmental releases of

, and workplace and consumer/hobbyist exposures to

, TCE.

ENVIRONMENTAL RELEASES OF TCE

General There is potential for release of TCE to air, water, sediment

, and soil from manufacture, processing

, and use . As noted previously, the large st percentage of TCE production and importation is used as an intermediate in the manufacture of refrigerants (~84 percent). Because most of the TCE associated with this use is expected to be reacted to form another chemical, potential releases to the environment from the refrigerant use is unlikely to contribute to the TCE found in ambient air/water/human bio monitoring as descr ibed below. It is expected that a small percentage of TCE may be released as fugitive air emissions ( i.e.

, material lost during use) . This consistent with the Toxic s Release Inventory (TRI) data which
indicates some of the highest fugitive and point sour ce air releases reported for TCE come from the degreaser use ( i.e., roughly 15 percent of the production/importation volume in the US). Thus, while there is some potential for fugitive emissions, fugitive TCE releases from manufacture of refrigerants will not be considered in this risk assessment.

The US EPA developed a summary of ambient air monitoring ( i.e., measured) data for TCE in the
US from 1999 to 2006 ( as reported in US EPA, 2011c ) that is provided in Table 3

- 1. These data suggest that TCE levels have remained fairly constant in the US since 1999 , with a n approximate mean value of 0.3 μg/m 3 

### ( i.e., which is equivalent to 5.6 x 10 -5 

### ppm).

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Page 23 Table 3 -1. TCE Ambient Air Monitoring Data (μg/m 3 ) a

.

Y ea r Number of

M onitors Number of
S tates Mean Standard

D eviation Median Range

1999 162 20 0.30 0.53 0.16 0.01

- 4.38

2000 187 28 0.34 0.75 0.16 0.01

- 7.39

2001 204 31 0.25 0.92 0.13 0.01

- 12.90

2002 259 41 0.37 1.26 0.13 0.01

- 18.44

2003 248 41 0.35 0.64 0.16 0.02

- 6.92

2004 256 37 0.32 0.75 0.13 0.00

- 5.78

2005 313 38 0.43 1.05 0.14 0.00

- 6.64

2006 258 37 0.23 0.55 0.13 0.03

- 7.73

a The US EPA’s Air Quality System database at the AirData Web site: http://www.epa.gov/airdata/ ( as summarized in US EPA, 2011c ). Note that t he data are not from a statistically based survey and cannot be assumed to provide nationally representative values.



### Other releases of TCE may occur, such as TCE entering publicly owned treatment works (POTWs)

, which will likely result in releases to surface waters and air. Disposal of TCE wastes to Resource Conservation and Recovery Act (RCRA) Subtitle C landfills also occurs and is of potential concern because TCE has moderate persistence under certain environmental
conditions

, and it is volatile, water soluble, mobile in soil and groundwater, and present in landfills. Under the Comprehensive Environmental Response, C ompensation, and Liability Act (CERCLA) and the Superfund Amendments and Reauthorization Act (SARA), the US EPA and the Agency for Toxic Substances and Disease Registry (ATSDR) have established a prioritized list of substances most commonly found at facilities on the National Priority List (NPL) ( ATSDR, 2011 )

. The listing is based on the frequency of occurrence, toxicity, and potential for human exposure.
TCE was ranked 16 th 

### out of 847 candidate substances f or the 2011 ranking; only the top 275 a re considered to be on the list

.

Releases of TCE from Consumer Uses
TCE can be released to indoor air from the use of consumer products that contain it, as well as
from vapor intrusion and volatilization from contaminated water suppl ies ( US EPA, 2011c )

. Where indoor air sources are present, it is likely that indoor levels will be higher than outdoor
levels ( US EPA, 2011c )

. US EPA (2011c ) discussed several studies that measured indoor levels of TCE, but did not include any monitoring data for use of consumer products containing TCE.
Recent literature sources report a few TCE air and personal monitoring studies that were not
included in US EPA (2011c ) ; however, no monitoring data for use of consumer products containing TCE were found. Specifically, the literature searc h did not find any studies that measured emissions of TCE from the six consumer products identified for consideration in this risk assessment (see below).

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### Releases of TCE from Small Commercial Degreasing Operat i ons Halogenated solvent cleaning (degreasing) is widely used to remove grease, oils, waxes, carbon deposits, fluxes, and tars from metal, glass, or plastic surfaces ( US EPA, 2006a , 2007b ) . The degreasing process is used in many industries

, both large and small

. An analysis of the North American Industry Classification System (NAICS) iden tified 78 different industries (NAICS codes are listed in Appendix C; data not shown, but available in US EPA (2008b ).

There are two general types of degreasing machines: batch and in

- line. Batch cleaning machines are the most common type

, while in

- line cleaners are typically used in large

- scale industrial operations ( US EPA, 2006a )

. The size of a degreasing machine is defined by the area
of its s olvent

- to -a ir interface. Emissions from degreasing machines typically result from : (1) evaporation of the solvent from the s olvent

- to -a ir interface ; (2) “carry out” of excess solvent on
clean ed parts ; and (3) evaporative losses of the solvent during filling and draining of the degreasing machine ( US EPA, 2006a ).

Use of TCE as a degreaser in an occupational/commercial setting w ill result in its releases primarily to air due to its volatility. The US EPA has developed an analysis of available
information from the 2008 National Emissions Inventory (NEI), the 2010 TRI, and the NAICS to estimate TCE releases and occupational exposures from this use. These release estimates were used to estimate TCE exposures to workers in small commercial degreaser operations. Though
these releases also could result in TCE exposure to the general population , such an analysis is
outside the s cope of this risk assessment.

The NEI is a comprehensive and detailed estimate of air emissions of both c riteria and
h azardous air pollutants (HAPs) from all air emissions sources; the NEI is prepared every three years by the US EPA (2008b ) 4



### . As background, p oint sources are stationary sources ( i.e.

, sources that remain in one place); a large facility that houses an industrial process is an example of a point source ( US EPA, 2004a ) . Nonpoint sources refer to smaller

, more diffuse sources; a variety of sources are categorized as nonpoint sources, including small industrial/commercial operations ( US EPA, 2004a ).

Data from the most recent NEI ( US EPA, 2008b ) were considered. Based on the 78 NAICS codes (identified in Appendix C ), and in conjunction with Source Classification Codes (SCC), the Pollutant Name, and Unit Type descriptions from the NEI, it is possible to identify the reported number of TCE emission points from 2008 (see Table 3 -2 ); 66 percent of TCE emissions in 2008

4 For those interested, here are the specific data sources/files used: ftp://ftp.epa.gov/EmisInventory/2008v2/nei2008v2_national_county_level_sector.zip ; ft p://ftp.epa.gov/EmisInventory/2008v2/2008neiv2_facility.zip ; http://www.epa.gov/ttn/chief/net/neip/appendix_6.mdb At the following website: http://www.epa.gov/ttn/chief/net/2008inventory.html

, under “SCC Data Files”, there is an option to download data by pressing the “Download” button. The following data sets are relevant: 1) Point and 2) Nonpoint

.

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Page 25 

### were from nonpoint sources (NPS) , while approximately 34 percent were from point sources PS)

. Thus, approximately two

- thirds of the estimated emission points for TCE come from nonpoint sources.

Table 3-2. The Nu mber of TCE -E mitting E mission P oints and C orresponding Total Annual Air Emissions of TCE as reported in the 2008 NEI ( 

### US EPA, 2008b ).

Type of Emission Point Reported Number of Emission
Points Total Annual Air Emissions ( Lb s/ Yr )

Point s ource (PS) 186 1,480,000
Nonpoint s ource (NPS) 1, 779 2,860,000



### The US EPA’s TRI is a database that contains detailed information on environmental releases
and transfers of certain listed toxic chemicals from industrial facilities; the TRI is maintained by the US EPA and is updated annually ( TRI, 2012 a) . Based on the NAICS codes, the 2008 TRI can be queried to identify stack and fugitive air emissions of TCE (see Table 3-3 ). Thus

, the NEI and TRI data from the same year ( 2008 ) can be compared.

Table 3 -3

. Total Annual Air Emissions of TCE as R eported in the 2008 TRI ( TRI, 2012 b).
Type of Emission Total Annual Air Emissions ( Lb s / Yr )

Stack a ir e missions 1,320,000
Fugitive a ir e missions 1,230,000



### In 2008

, based on the NAICS codes listed in Appendix C, total NEI TCE air emissions were approximately 1.7 times greater than those reported in the 2008 TRI 5 

### . Whereas the NEI is the
US EPA’s primary emissions inventory for HAPs and criteria pollutants, the TRI is another inventory that may be considered . The TRI provides releases to other environmental media ( e.g. , land and water) besides air; however, the TRI may exclude releases from small

- scale operations, the intended focus of this risk assessment ( US EPA, 2004a , 2011e ). In l ight of this,
release values from the 2010 TRI will be referenced, but the TCE air emissions will be estimated/adjusted based on the comparison between the 2008 NEI and TRI data ( 1.7 times the TRI reported value ).

Point sources include large industrial facilities; they can also include small industrial/ commercial facilities, which have traditionally been classified as nonpoint sources ( US EPA, 2008b ) . However, the choice of whether small industrial/commercial facilities are classified as point or nonpoint sources is determined by the appropriate State, Local, or Tribal air agency ( US EPA, 2008b )

. Thus, EPA assumed that point sources are representative of large industrial
facilities , while nonpoint sources are assumed to be representative of small/commercial
facilities.

5 Derived by adding the total 2008 NEI emissions (1,480,000 + 2,860,000 = 4,340,000) and dividing this by the total 2008 TRI emissions (1,320,000 + 1,230,000 = 2,550,000)

, which results in 4,340,000/2,550,000 = 1.7.

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Page 26 

### For point source emissions, based on the Emiss ions Inventory System (EIS) Identifier and EIS Unit Identifier from NEI, it is possible to identify the number of unique facilities (154) and degreasing units (machines; 180) reporting TCE emissions in 2008 ( or about 1.2 degreasing units/facility ) . These 154 facilities would be considered large industrial facilities rather than
small commercial operations.

Assuming each reported nonpoint source represents a unique facility, and by applying the estimate of 1.2 degreasing units per facility to nonpoint sources, the number of facilities corresponding to the nonpoint sources in Table 3 -2 can be approximated to be 1, 483 ( i.e., 1, 779 divided by 1.2 de greasing unit per facility)

, making the total number of degreasing
facilities 1, 637 ( i.e., 154 unique, large Industrial facilities, plus the 1, 483 s mall
i ndustrial/ c ommercial f acilities ).

Based on the NAICS codes listed in Appendix C and information reported in the 2010 TRI, EPA identified relevant releases of TCE from solvent cleaning/degreasing operations (see Table 3

- 4).

Table 3

- 4. Relevant TCE Releases from Solvent Cleaning in 2010.

Release Type Total Annual Release ( lb s/ Yr ) Percentage of Air

- Emitting Facilities also Reporting this Type of Release (Percent) Fugitive air emissions 780,000 100
Stack air emissions 750,000 100
Surface water releases 70 5.5
Release to RCRA Subtitle C landfill 1,711 1.1
Release to other landfill 8,308 2.2

Source: US EPA (2011e ).



### By examining the SCC from the NEI, the cleaning machine type could be identified (see Table 3- 5). Large industrial facilities are not typically classified as nonpoint sources ( US EPA, 2008b )

. Based on this, in

- line degreasing units also are not classified as nonpoint sources. For this
assessment, EPA classified n onpoint sources as either b atch v apor or b atch c old units. Table 3

- 5 shows a total of 129 ( i.e., 116 b atch v apor plus 13 b atch c old units) of this cleaning/degreasing machine type. Thus

, EPA determined that approximately 90 percent ( i.e., 116 out of 129) of the 1, 779 nonpoint sources would be expected to be b atch v apor degreasing
units

, while 10 percent would be expected to be b atch c old degreasing units. General
d egreasing u nits were ignored in this calculation bec ause they cannot be categorized; their type
is unknown.

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Page 27 Table 3

- 5

. Breakdown of Degreasing Cleaning Machine Type for Point Source TCE E missions

Cleaning Machine Type Number of
Units Percentage of
Units Total Annual Air Emissions ( lb s/ Yr ) a

Open t op v apor d egreasing ( b atch v apor) 116 64 890,000
Conveyorized v apor d egreasing ( i n

- line) 11 6 120,000

Cold s olvent c leaning (b atch c old) 13 7 140,000

General d egreasing u nits (u nknown) 40 22 330,000

a The total is equal to 1,480,000 lb s as reported for point sources in Table 3

- 2.
Source: US EPA (2008 c ).



### All the information described above and presented in Tables 3

- 2 through 3

- 5 was used to develop an estimate of TCE releases to air from small commercial degreasing operations (Table
3- 6). An explanation of how these estimates were derived follows:

Air Releases As indicated earlier, TCE air emissions from degreasing were estimated to be 1.7 times the 2010 TRI reported value. Also, based on the 2008 NEI, point sources (large industrial facilities)
accounted for 34 percent of all air releases

, while nonpoint sources (small industrial/ commercial facilities) accounted for a higher number, 66 percent

. Thus, for small industrial/ commercial facilities, the “Annual Release” was calculated as follows: 1.7 × 0.66 × “Total 2010 TRI TCE Air Releases” ; or 780,000 + 750,000 = 1,530,000

. Thus, the final estimate for small commercial degreasing facilities emissions to air is:

1.7 × 0.66 × 1,530,000 = 1,720,00 0 lb s

All Other Releases The percentage values from Table 3 -4 were applied to the number of facilities ( 1, 483 s mall
i ndustrial/ c ommercial f acilities) to develop estimates for TCE release to other environmental
media as presented in Table 3 -6 6



### .

6 Thus, as an example, the value for “Release per Facility” in Table 3

- 6 for releases to surface water was calculated as follows: “Annual release” (3

, 426 lb s) divided by the product of “Number of Facilities” (1

, 483 small commercial degreaser operations) x “Percentage of Air

- Emitting Facilities Expected to also have t his Type of Release” (0.055) = 3, 426/82 = 42 lb s released to surface water per facility.

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Page 28 Table 3 -6

. Estimate of 2010 TCE R eleases for Small Industrial/Commercial Facilities ( n = 1, 483).

Media of Release Annual Release ( Lb s/ Yr ) Release per Facility ( Lb s/ Yr ) Percentage of Air

- Emitting Facilities Expected to also have this Type of Release (P ercent )

Air 1,720,000 1, 160 100

Surface w ater 3

, 426 42 5.5

RCRA Subtitle C l andfill 150,000 8

, 308 1.2

Other l andfill 55

, 823 1, 711 2.2

POTWs 245 5 3.3



### To estimate worker exposure in small degreaser operations using environmental release data required some additional assumptions about working operations in small commercial degreasing operation. For the purposes of this assessment, small industrial / commercial degreasing processes are expected to operate 260 days per year for 2 hours per day ( US EPA,
2001a ) . Thus, combining the inf ormation from environmental releases and assumptions for operations, the potential operating emission factors (amount of TCE released) were calculated
as follows:

“Annual Air Release per Facility” × “1 / Number of operating days per year” × “1 / Operating hours per day” × “1 hour / 60 minutes”, OR (providing all units and conversion values)

1, 160 lbs/ yr × 454 grams/lb. × 1/260 days × 1 / 2 hours × 1 hour/60 minutes = 16.8 grams of TCE/minute

Depending on workplace controls ( e.g. , local exhaust ventilation), average TCE emissions escaping into the workplace from Ope n Top degreasers ( i.e., the kind noted above in Table 3

- 5 as representative of nonpoint, or small commercial operations) can range from 2.57 to 27.29 grams of TCE per minute ( Wadden et al. , 1989 )

. For this assessment, EPA a ssu med that TCE emissions occur only during the hours of operation, and that the calculated and reported pote ntial operating emission factors are of the same order of magnitude (see Table 3

- 7).

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Page 29 Table 3

- 7. Potential Operating TCE Emission Factors from Degreasing (Calculated and Reported Values).

Type of Facility Calculated Potential Operating TCE
Emissions Esc aping into the Workplace (g TCE/Minute) Reported Potential Operating TCE Emissions Escaping into the Workplace (g TCE/Minute)
Large industrial 27.47 1 27.29 ( Wadden et al. , 1989 )
24.9 ( US EPA, 2001a )
Small industrial/commercial 16.73 27.29 ( Wad den et al. , 1989 )
9.72 ( US EPA, 2001a )

1 Data/calculation not shown; information provided because it represents an 8

- hour work shift and so is most comparable to the Wadden et al. data.



### Calculating Exposures used in this Risk Assessment

This section characterizes exposures for the two scenarios that are the focus of this assessment: small industrial/commercial facilities, where TCE is used as a cleaning solvent (degreaser), and the hobbyist at home who may use TCE either as a degreaser o r in an arts and crafts use scenario. For these scenarios, EPA also provided estimates for individuals who may be in the same building as the user, but are not physically near the user or use of the TCE product. These individuals are called bystanders or non

- users.

Calculating Occupational/ Worker Exposures to TCE from Degreasing The National Occupational Exposure Survey (NOES), conducted by the National Institute for Occupational Safety and Health (NIOSH) from 1981 to 1983 , estimated that 401,000 workers employed at 23,225 plant sites were potentially exposed to TCE in the U S ; about 17 workers
were estimated per facility ( ATSDR, 1997 ) . This estimate is understood to include both workers
who are and are not (occupational non

- use rs) directly involved with solvent cleaning operations. EPA estimated t he average number of workers directly involved with solvent cleaning operations as five workers per facility ( US EPA, 2001a ).

Appendix D presents the rationale and calculations for estimating inhalation exposure s for workers and bystanders in small commercial/industrial degreasing facilities

. Exposure estimates were calculated for bystanders ( i.e., those non

- users, likely all adults, who may be in the building/room, but not physically close to the degreasing ope ration )

. Typical and worst

- case values represent the range of room ventilation volumes ( i.e., 3, 000 cubic fee t per minute (min -1 ) 

### and 500 cubic feet per min -1 

### , respectively). Finally, the use of local exhaust ventilation ( LEV) is important because it offers some control of TCE emissions and exposures. Results are shown in
Table 3 -8

. These values were used to determine the range of exposures for the small commercial degreaser scenario in the risk assessment.

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Page 30 Table 3

- 8. Summary of Potential Workplace TCE Inhalation Exposures: Small Commercial Degreaser

. Typical Worst

- Case Number
of
Workers With
LEV 4 No
LEV With
LEV No
LEV

Worker 1 Inhalation e xposure (8 -h ou r TWA 3 , ppm) 2 17 6 63 7, 415
Occupational
b ystander/ n on -user 2 Inhalation e xposure (8

- h ou r TWA, ppm) 1 9 5 55 17

, 79 6

1 Workers are directly involved with degreasing operations.

2 Occupational Bystanders have the potential to be exposed to TCE but they are not directly involved with degreasing operations

3 TWA = Time Weighted Average

4 LEV = local exhaust ventilation



### Consumer Exposures – Degreaser and Arts/Crafts Uses of TCE

TCE has been used in many different formulations and in many commercial and consumer products over the years. In March 2012 , 12 consumer products from three manufacturers were
found in the National Institutes of Health ’s (NIH) ’ Household Products Database that contained TCE. Further research confirmed that six of these products contained TCE (Table 3 -9) 7



### . The other six products w ere absent from the former product manufacturer’s website or were determined not to contain TCE. T hree of the six non

- TCE containing products were reformulated ( i.e., using tetrachloroethylene, hydrotreated light distillate, dipropylene glycol n

propyl ether, dipropylene glycol methyl ether acetate, aliphatic petroleum solvent, or acetone instead of TCE) ; the other three products were discontinued. There may be other consumer and hobbyist products that contai n TCE that EPA did not identify 8



### .

The six p roducts highlighted in bold in Table 3 -9 are auto products and arts and crafts aerosol spray products that may be used at home by hobbyists, as well as in commercial settings. Use of these products by hobbyists indoors, at home, may lead to inhalation exp osure to users and other residents of the home. Dermal exposure to users may also occur, although there is a low concern for this exposure due to TCE’s high vapor pressure. Ingestion exposure from the use of these products appears to be unlikely given th e way they are used ( i.e. , sprayed onto artwork).

7 See attached document entitled: “Supplemental Product Information for the TSCA Workplan Chemical Risk Assessment of TCE (External Review Draft) .pdf ” for further details o n the results of the Household Products Database

ret rieval and for the Material Safety Data Sheets and other information retrieved from company websites.

8 T hough the search was not exhaustive, there were several spot cleaners for fabrics marketed to consumers , but none contained TCE; lists of ingredients were not available for a few of the spot cleaners.

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Page 31 Table 3 -9 . TCE Products in Household Products Database Retrieval

. Product Percent TCE (as of March 2012 ) a

Lectra Clean 0 2018 heavy duty electrical parts degreaser N one

Lectra Clean 0 2120 Lectra Clean II non

- chlorinated heavy duty electrical parts degreaser N one

Sprayway C

- 60 063 solvent degreaser >90
Sprayway C

- 60 064 solvent degreaser >90
Sprayway 073 brake parts cleaner N one
Sprayway 201 clear protective coating spray 20

- 30
Sprayway 205 film cleaner >90
Sprayway 208 toner aide 15

- 20
Sprayway 209 mirror edge sealant 20

- 30
Sprayway 669 gravel guard Product not found on m anu fa cturer product list
Sprayway 732 industrial cleanup dry cleaner Product not found on manu fa cturer product list

TrakAuto Trouble Free Rust Buster Company no longer in business

a Percent TCE according to Material Safety Data Sheets retrieved from company websites in March, 2012 ( See attached document titled “Supplemental Product Information for the TSCA Workplan Chemical Risk Assessment of TCE (External Review Draft).pdf ” ).



### In the absence of available emissions and monitoring data for use of consumer products containing TCE, EPA used a screening level modeling approach to assess consumer exposure. Of the six products confirmed (Table 3 -9 ) to contain TCE, two hobbyist products, a clear protective coating spray and an aerosol solvent degreaser, were selected for exposure modeling.

The Exposure and Fate Assessment Screening Tool Version 2 (E

- FAST2) Consumer Exposure Module (CEM) 9 

### was selected for the consumer/hobbyist exposure modeling because it generates inhalation exposure estimates for aerosol spray products such as the two TCE

containing products identified above. E- FAST 2 /CEM requires fewer inputs than do higher tier ( more complex ) indoor air models. For example, higher tier indoor air models r equire inputs for measured emission values (generally based on chamber studies), which usually are not available for the consumer prod ucts that are the subject of this exposure assessment.

The E

- FAST 2 /CEM modeling for TCE include d a combination of upper percentile, mean, and assumed (hypothetical) input values in the calculation of potential exposures. The resulting exposure estimates are characterized as hypothetical exposures. As explained more fully in the

9 For further information on the E

- FAST/CEM defaults or underlying equations, see the E

- FAST documentation
manual ( US EPA, 2007a )

.

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Page 32 

### Supplemental Informa tion

, 10

, 11 

### these hypothetical exposures are more likely to be high

- end exposures than they are to be central tendency exposures ; thus they represent conservative exposure values 12



### .

OPPT did not locate consumer product survey data for hobbyist use patterns for the two hobbyist products, including mass of product used per event, duration of event, and events per year, so these values are hypothetical. Specific information and assumptions are provided in the Supplemental Information (notes 10 and 11) ; however , the general assumptions we re:

• For the consumer degreaser scenario: 1 hour/event, two events/month

• For the consumer clear protective coating spray scenario: 0.5 hour/event, one event per
week

It was assumed that these exposures represent unique and separate acute exposure events for
b oth users and non

- users. This was based primarily on the information mentioned in the Hazard section below in which a high end estimate for the half

- life in humans is 51 hours. This suggests that from week to week there would be some residual TCE (or metabolite[s]) left over from the previous week, but EPA did not assume that the residual would be substantial or build up.

Exposure factors for age groupings , inhalation rates, body weights, and life expectancy are
derived from the 2011 Exposure Factors Handbook ( EFH; US EPA, 2011d ) and replace the E

FAST 2 defa ults derived from the 1997 EFH ( US EPA, 1997 ) . The E

- FAST 2 /CEM exposure estimates are potential dose rates that do not include any assumptions about absorption through the lung. Selected modeling results appear in Table 3 -10 . Details on modeling results appear in the attached Supplemental Information (notes 10 and 11)

.

Table 3

- 10. Estimated TCE Potential Acute Dose Rates from Use of Two Hobbyist Products Indoors at Residences as Determined by E

- FAST.

Age ( Yr s) Clear Protective Coating Spray User ADR pot (mg/kg

- bw/day) Clear Protective Coating Spray Non

- user ADR pot (mg/kg

- bw/day) Solvent Degreaser
User ADR pot (mg/kg

bw/day) Solvent Degreaser
Non

- user ADR pot (mg/kg

- bw/day)

<1 NA 0.5 NA 3

1

- 2 NA 0.4 NA 3

3-5 NA 0.4 NA 2

6- 10 NA 0.3 NA 2

11

- 15 NA 0.2 NA 1

10 See attached document titled “Supplemental Information on E

- FAST2 CEM Outputs (Degreaser Use) TSCA Workplan Chemical Risk Assessment of TCE (External Review Draft). pdf ”).

11 See attached document titled “Supplemental Information on E

- FAST2 CEM Outputs (Cl ear Protective Coating Spray) TSCA Workplan Chemical Risk Assessment of TCE (External Review Draft). pdf ”

12 High

- end exposures represent values above a mean or median and may include the high end of an exposure distribution. A central tendency value repre sents some measure of the center of a distribution, such a s an average or mean or median.

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- 20 0.5 0.2 3 1

21

- 78 0.4 0.1 3 0.8

ADR pot = potential acute dose rate; NA = not applicable



### These values were converted to concentrations in air in ppm following the methodology presented in Appendix E

. Table 3 -11 presents the hobbyist exposure values that will be used in
the risk assessment.

Table 3 -11

. Estimated TCE Inhalation Calculated Concentration in Air ( O ver the C ourse of a D ay a ) from Use of Two Hobbyist Products Indoors at Residences

.

Age (yrs) Clear P rotective
C oating S pray U ser ADR pot (ppm) Clear P rotective C oating
S pray N on
- user ADR pot (ppm) Solvent D egreaser U ser ADR pot (ppm) Solvent D egreaser N on
- user ADR pot (ppm)

<1 NA 0. 1 NA 0.8

1-2 NA 0. 1 NA 0.8

3-5 NA 0. 1 NA 0.8

6- 10 NA 0. 1 NA 0.8

11

- 15 NA 0. 1 NA 0.8

16

- 20 0.4 0.1 2 0.8

>21 0.4 0.1 2 0.8

a See Appendix E for method.



## B. H AZARD 

## S UMMARY

In this section, a brief summary of the hazard information on TCE is presented and is followed by a discussion of the hazard data that were used in this risk assessment.

EPA identified a number of published hazard and/or risk assessments on TCE that have been conducted by numerous governmental bodies, review panels and others. Table 3

- 12 shows some of the major documents reviewed and used in this assessment.

Table 3 -1 2. Hazard/Risk Assessment Documents Consulted for this Report

. US Government Reports US NRC Reports International Reports

US EPA IRIS Toxicological Review and RfD/RfC summary for TCE ( US EPA, 2011c ) Gulf War and h ealth, Vol. 2: Insecticides and

s olvents ( IOM, 2003 ) EU Risk Assessment ( EC,
2004 )

OPPT/AEGL for TCE ( US EPA,
2008a ) Human h ealth r isks of TCE: Key s cientific i ssues ( NAS, 2006 ) Australia ( NICNAS, 2000 )

ATSDR Toxicological Profile for
TCE ( ATSDR, 1997 ) Contaminated w ater s upplies at Camp Lejeune: Assessing p otential h ealth e ffects ( NAS, 2009 ) OECD/SIDS (1996 )

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Page 34 Review of s tudies of p ossible t oxic e ffects from

p ast e nvironmental c ontamination at Fort
Detrick: A l etter Report ( NAS, 2010 )
AEGL = Acute Exposure Guideline Level; RfC = reference concentration; RfD = reference dose



### Toxicokinetics (Absorption, Distribution, Metabolism
, and Excretion)

Absorption TCE is fat soluble (lipophilic) and easily crosses biological membranes. Though there are quantitative differences across species and routes, TCE is readily absorbed into the body following oral, dermal

, or inhalation exposure. Because of its lipophilicity, TCE can cross the placenta and also passes into breast milk.

Absorption following inhalation of TCE is rapid an d depends upon exposure concentration, duration of exposure

, and lung ventilation rate. Mammalian lungs have the capacity to metabolize TCE, but uptake and distribution is based largely on the blood:air partition coefficient, which ranges between 8.1 and 11.7 in humans and between 13.3 and 25.8 in
rodents ( US EPA, 2011c ) 13



### .

Although this assessment focuses on inhalation exposure only, it is worth noting that following oral ingestion, TCE is rapidly absorbed from the gastrointestinal tract into the systemic circulation ( i.e., blood). Absorbed TCE is first transported to the liver where it is metabolized for eventual elimination ( i.e., “first

- pass effect”). Also, US EPA (2011c ) summarized several volunteer studies in which both TCE liquid and vapors were shown to be absorbed in humans
via the dermal route. Following exposures of between 20 and 30 minutes, absorption was rapid

, with peak TCE levels in expired air occurring within 15 minutes (liquid) and 30 minutes (vapor).

Distribution Regardless of the route of exposure, TCE is widely distributed throughout the body. The major determining factor in its distribution is the blood: tissue partition coefficient 14 

### . Other important factors include age

- dependencies ( i.e., largely based on anatomical and physiological parameters such as metabolic and ventilation rates) and TCE binding to tissues/cellular
components. Human d ata and data from animals indicate TCE levels can be found in many different tissues including: brain, muscle, heart, kidney, lung, liver

, and adipose tissues. Human data also document levels of TCE in maternal and fetal blood and in the breast milk of lactating

women. It is difficult to interpret the available human data given the lack of accurate information on source and extent of exposures.

US EPA (2011c ) summarize d many expe riments in animals that quantify TCE levels in various tissues in rodents following oral and inhalation exposures

, some of which provide key

13 For ease in reading, “the IRIS program” will be used often to refer to this reference.

14 Th is represents the ratio of the concentration of TCE in blood to the concentration of TCE in tissue. When the ratio is much less than 1, more TCE would be found in tissue rather than in the circulating blood.

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### data/parameters for the physiological ly

- based pharmacokinetic (PBPK) model used to derive
the EPA’s reference concentration (RfC) and reference dose (RfD) 15



### .

Metabolism The metabolism of TCE has been extensively studied ; the resulting metabolites play a key role in the toxicity of T CE. Of additional importance are the many TCE metabolites that also are known metabolites of other, similar compounds to which people may be exposed (see Table 3

- 13 ). This may be important in determining exposures because people may be co

- exposed to many of thes e solvents at the same time ( e.g. , DCA as disinfection by

- products of chlorination of drinking water supplies ) ( Johnson et al

., 1998 ).

Table 3 -1 3. Common Metabolites of TCE and Related Compounds a

Parent →
Metabolites ↓ Tetrachloro

ethylene 1,1,2,2,

- T etrachlor oethane TCE 1,1,1

- Trichloro

ethane 1,2,

- Dichloro

ethylene 1,1

- Dichloro

ethane

Oxalic acid X X X

Chloral X X
Chloral hydrate X X

Monochloroacetic acid X X X X X X

Dichloroacetic acid (DCA) X X X X

Trichloroacetic acid X X X X

Trichloroethanol X X X X

Trichloroethanol

- glucuronide X X X X

a Adapted from Table 2

- 1 in US EPA (2011c ).



### A comprehensive review of the metabolism of TCE in humans and rodents was provided in the
IRIS document ( US EPA 20 11c ) . Animals and humans extensively metabolize TCE. The two major metabolic pathways are oxidative metabolism via the cytochrome P450 (CYP) mixed function oxidase system and glutathione (GSH) conjugation

, the latter followed by further
transformation s with other enzymes. Both pathways are saturable, and above the saturable concentration/dose

, TCE is excreted unchanged in expired air. According to US EPA (2011c )

, there was no metabolic saturation achieved in the human studies reviewed. However, in
animal studies when metabolic saturation was achieved, 43 to 78 percent of TCE was exhaled as unchanged TCE in rats with a lower amount (from 10 to 18 percent) observed in mice.

15 The RfC/RfD as defined by the IRIS program ( http://www.epa.gov/iris/help_ques.htm#rfd ): “ RfD (expressed in units of mg of substance/kg body weight

- day) is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure t o the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. An RfD can be derived from a no

- observed

adverse

- effect level (NOAEL), lowest

- observed

- adverse

- effect level (L OAEL), or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used. The inhalation RfC (expressed in units of mg of substance/m 3 air) is analogous to the oral RfD but provides a continuous inhalation exposure estimate.”

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### Table 3 -14 presents the important metabolites formed following both the CYP (oxidation) and
GSH ( conjugation ) pathways. The amount and types of metabolites formed are important for understanding the toxicity of TCE in both animals and humans.

Table 3 -1 4. TCE Metabolites Identified by Pathway a

. Oxidative Metabolites b GSH Conjugation Metabolites c

Chloral ; metabolized to TCOH DCVG; metabolized to DCVC isomers (t here are different theories as to how the presumed toxic
metabolite intermediate [DCVT] is formed; see text) TCE oxide; re

- arranged to DCAC
TCOH; metabolized to TCOG

TCA; may lead to DCA

a In humans and animals.

b In vitro data suggest that rodents have a greater capacity to metabolize TCE via this pathway.

c There are sex and species differences in this metabolic pathway (see text).
DCVC = either S

- (1,2

- dichlorovinyl cysteine) [1,2

- DCVC] or S

- (2,2

- dichlorovinyl cysteine) [2,2

- DCVC];
DCVG = S- dichlorovinyl

- glutathione; DCVT = dichlorovinyl thiol ; TCOG = trichloroethanol

, glucuronide conjugate;
TCOH = trichloroethanol



### A review of in vitro data suggests that rodents ( i.e., especially mice) have greater capacity to
metabolize TCE via the oxidation pathway ( US EPA, 2011c ). In addition, although there doesn’t appear to be large sex - or age

- dependent differences in TCE oxidative metabolism, there may
be subst antial differences in humans based on the existence of CYP isoforms and/or genetic polymorphisms.

Normally, conjugation is a process that leads to detoxification; however, this is not the case for many halogenated alkanes and alkenes, including TCE. For TCE, the eventual metabolite(s) of concern are formed several steps from the initial GSH conjugate formed in the liver , which ultimately results in toxicity or carcinogenicity in the kidney. The key GSH metabolite is one of two cysteine conjugate isomers; either S

- (1,2

- dichlorovinyl cysteine) [1,2

- DCVC] or S

- (2,2

- dichlorovinyl cysteine) [2,2

- DCVC ], which can be further metabolized via N- acetylation to N

acetyl -S- (1,2

- dichlrovinyl) -L- cysteine (or the 2,2

- dichlorovinyl one)

— NAcDCVC.

There are various theories about how DCVC is toxic to the kidney and, to a lesser extent, the
liver. One theory states that a β

- lyase enzyme catalyzes the breakdown of 1,2

- DCVC to
S- dichlorovinyl thiol (DCVT)

, an unstable intermediate that rearranges to o ther metabolites (enethiols) that form covalent bonds with cellular nucleophiles and results in toxicity. Another theory is that there is a kidney enzyme (L

- alpha

- hydroxy [L- amino ] acid oxidase ) that can form intermediates and keto acid analogues that dec ompose to DCVT. In rat kidney homogenates, this enzyme appeared to be responsible for up to 35 percent of the GSH pathway. However, this enzyme is not found in humans. A third theory suggests involvement of sulfoxidation of either the cy s teine (DCVC) or mercapturic acid (NAcDCVC) conjugates by flavin

- containing monooxygenase and CYP3A enzymes, respectively.

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Page 37 

### In contrast to the CYP oxidation pathway, there appear to be sex and species differences in TCE
metabolism via the GSH pathway ( US EPA, 2011c ) . Animal data show that rates of TCE GSH conjugation in male rats/mice are higher than females. According to some in vitro data, the rates of DCVG production in liver/kidney cytosol are highest in humans, followed by mice

, and
then rats. In vitro data a lso suggest that γ -g lutamyl transpeptidase ( i.e., GGT P

, an enzyme involved in DCVC production) activity in kidneys seems to be highest in rats, then humans, and
then mice.

Thus, the key in evaluating the TCE metabolism data is to determine the relative roles of CYP and GSH pathways. It appears that

, in rodents

, the oxidation pathway is clearly more dominant than the GSH pathway. US EPA (2011c ) suggests that the GSH pathway may play a larger role in
humans than it does in rodents

, but there is substantial uncer tainty about this given the
available data. In fact, Jollow et al. (2009 ) , using essentially the same data, suggest ed that rodents have a higher capacity to conjugate TCE with GSH and are thus more susceptible to kidney toxicity/cancer compared with humans.

US EPA (2011c ) concluded the following regarding the metabolism of TCE:

“In summary, TCE oxidation is likely to be greater quantitatively than conjugation with GSH in mice, rats, and humans. Some evidence suggests that the flux through the GSH pathway, particularly in humans, may be greater by an order of magnitude or more th an the <0.1% typically excreted of NAcDCVC in urine...However, these data are not consistent with studies in other laboratories using different analytical methods, which report 2

- 5 orders of magnitude lower estimates of GSH conjugation. Because the

reasons for these differences have not been fully determined, substantial uncertainty remains in the degree of GSH conjugation, particularly in humans.” ( US EPA, 2011c, p. 3

- 51 )

.

Excretion As noted earlier, the major routes of excretion are urinar y ( i.e., predominantly with oxidative metabolites such as TCA and TCOH, with minor GSH metabolites), followed by exhalation of unchanged TCE; e limination ( i.e., as metabolized TCE) via feces and via exhalation are minor pathways. Table 3

- 15 provides elimination half

- li f e values in humans and rodents from different conditions for total trichloro compounds (TTC ) following TCE exposures.

Half

- lives are useful indicators for bioaccumulation potential. Assuming first

- order kinetics,
>90 perce nt is eliminated after four half

- lives and about 99 percent after seven half

- lives ( Shen,
2008 ) . Thus, assuming a half

- life of about 51 hours ( e.g., the longest valu e listed in Table 3

- 15), TCE would be mostly cleared by approximately 200 hours ( i.e., about eight days) with nearly complete clearance by approximately 350 hours ( i.e.

, a little over two weeks).

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Page 38 Table 3 -15 : Half

- Life Data For TCE in Rats and Humans a

.

Elimination
Route Rats Humans

Exposure Conditions Elim ination Half

- life Exposure C ond itions Elim ination Half

- life

Exhaled a ir – – Inhalation : 100 ppm/4 h ou rs b

6- 38 ppm/0.5 -1 h ou r c 1 ppm/6 h ou rs d 0.04, 0.67, 5.6 h ou rs 8- 44 h ou rs 14

- 23 h ou rs

Urine Inhalation: 50, 100, and 200 ppm/
8 h ou rs 4

Oral (gavage)

D ose not given f 14.3

- 15.6 hours (f emales );
15.5

- 16.6 h ou rs (m ales )

“complete” within
1-2 days Assumed Inhalation:
Measured various metabolites
for three post

- exposure days in four exposure groups (no concentrations provided) e

Experimental exposures in groups of two to five adults (no concentrations provided) g

Inhalation: Occupational setting, six males
and six females ; m ales exposed to 200 ppm, females exposed to 50 ppm (duration not reported) h Males: TTC (50.7 h ou rs)
Females: TTC (26

- 48.8 h ou rs)

TTC (31

- 50 h ou rs)

Males: TTC (26.1 h ou rs)
Females: TTC (50.7 h ou rs)

a All data taken from information presented in pp. 3

- 53 to 3

- 56 in US EPA (2011c ).

b Sato et al. (1977 ) .

c Opdam (1989 ).

d Chiu et al. (2007 ) .

e Ikeda and Imamura (1973 ) .

f Green and Prout (1985 ) ; Prout et al. (1985 ) ; Dekant et al. (1984 ) .

g Nomiyama and Nomiyama (1971 ) ; Ogata et al. (1971 ) ; Stewart et al. (1970 ) ; Bartonicek (1962 ) .

h Ikeda (1977 ) .



### Summary of Toxicity Information on TCE

A very brief overview of the TCE hazard database is presented. Based primarily on the IRIS Toxicological Review ( US EPA, 2011c ) , the multiple studies identified for evaluation as points of departure (PODs) 16 

### for candidate RfCs ( i.e., specifically p

- cRfCs values derived using PBPK modeling instead of an applied dose/concentration) for non

- cancer endpoints are specifically identified below as they are used in evaluating the hazard for this risk assessment. These
i nclude three studies for liver toxicity; four studies on immunotoxicity; five studies each for the

16 POD represents the derived value from the animal or human study. It can be the actual dose or concentration at which an effect was observed or a benchmark dose (BMD) calculated for a pre

- defined response rate for that
effect.

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Page 39 

### kidney and the nervous system; seven studies for developmental toxicity; and nine studies for reproductive toxicity. Because there was some overlap ( i.e. , o ne study may be used for several endpoints), the total of number of different studies is 29. P ODs were identified for each of the
studies and are based on the identified route of exposure/units. All values were converted to concentrations in air by the US EPA (201 1c ) and are presented in later sections of this report

.

TOXICITY FOLLOWING ACUTE (SHORT

- TERM) EXPOSURE

This summary is taken from the Interim Acute Exposure Guideline Level (AEGL) document ( US EPA, 2008a ) . AEGLs represent threshold exposure limits to which the general public may be exposed under emergency conditions ( e.g., an evacuation) for a short time ( i.e., acute) period from 10 minutes to eight hours ( i.e., five values for each AEGL level are established at 10 minutes, 30 minutes, and one , four , and eight hours). The deve lopment of these values
involved a rigorous scientific review of acute toxicity data

, first by a Federal Advisory
Committee an d then by a Nationa l Academy of Sciences (NAS) panel ( see US EPA, 2012b for
more information )

.

In humans, TCE odors can be detected at concentrations of ≥ 50 ppm

, although the Level of Distinct Odor Awareness determined by the AEGL program is 337 ppm. Information on the toxicity of TCE in humans comes from either volunteer studies or case reports in the medica l/ occupational literature. As mentioned previously , in the early part of the 20 th 

### century
, TCE was used as a medical anesthetic. According to the AEGL program, the concentrations applied for this particular use ranged from 5

, 000 to 15

, 00 0 ppm for anesthetic use and from 3, 500 to 5, 000 ppm for use as an analgesic.

V olunteer studies have shown that acute exposure to TCE results in central nervous system (CNS) effects and irritation in humans. The AEGL document summarizes 14 different hu man volunteer studies conducted between 1969 and 1982 . Most of these studies had limitations ( i.e. , no control group, reporting of effects were subjective). However, EPA used two of the
studies as the basis for the AEGL values reported below. Researcher s ( Vernon and Ferguson,
1969 ; Ferguson and Vernon, 1970 ; as reported in US EPA, 2008a ) exposed eight male volunteers to 0, 100, 300, or 1, 000 ppm TCE for a two

- hour period ( via a breathing tube) in two
separate s tudies. In both cases, subjects performed six different tests to assess visual

- motor function. The 1, 000 ppm concentration in this study was the highest concentration used in any
of the 14 volunteer studies. There were clear effects at that concentration in both studies ( i.e.

, subjective symptoms such as CNS

- depression, dizziness, and lethargy as well as reductions in performance of visual perception, steadiness

, and a pegboard test 17 

### ). Some subjects had
similar effects at the middle concentr ation (300 ppm), with no such effects observed at the 100 ppm concentration.

17 A pegboard test evaluates the ability of the subject to place pegs into holes. It is an indicator of hand eye
coordination and motor effects.

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### The AEGL process proposed the values shown in Table 3

- 16. These values are considered interim and not yet final. Only three of the five AEGL values are presented because these
coincide with the time frames of interest for this risk assessment 18



### .

Table 3 -1 6. Proposed AEGL Values for TCE (in ppm) a

. Classification 30

- Minute
Value 1

- Hour Value 8

- Hour Value Endpoint

AEGL

- 1 (non

- disabling effects) 180 130 77 CNS (humans) Marginal CNS effects ( not specified in original study, according to 

### US EPA, 2008a ), in 1/8 volunteers exposed to 300 ppm for 2 hours

AEGL

- 2 (disabling effects) 620 450 240 CNS (humans) Light

- headedness, dizziness, or lethargy in combination with reduced performance in neurobehavioral test in volunteers exposed to 1000 ppm for 2 hours

AEGL

- 3 (lethal) 6, 100 3, 800 970 Mortality in mice (4600 ppm for 4 hours)

a Only the 30

- minute, 1- hour

, and 8- hour values are presented (representing the three time frames of interest in this assessment)

.



### TOXICITY FOLLOWING REPEATED EXPOSURES (INCLUDING CANCER)

There are many studies in animals and humans that report effects in a variety of organ systems following exposure to TCE. The summary presented below is very brief and touches on the major points for each type of toxicity/cancer. For the purposes of this risk assessment, there
was no attempt to re

- review the majority of the original studies/literature

, because a very thorough review was most recently published by the US EPA (2011c )

. A number of key studies were reviewed, and other assessment/reviews are referenced where appropriate.

Liver Toxicity (Including Cancer)
Animals and humans exposed to TCE consistently experience liver toxicity. Specific effects include the following structural changes: increased liver weight, increase in deoxyribonucleic acid ( DNA ) synthesis ( transient ) , enlarged hepatocytes, enlarged nuclei

, and peroxisome proliferation. In addition, US EPA concluded that TCE exposure causes liver tumors in mice but not rats and there is “...minimal support for association between TCE exposure and liver and gallbladder/biliary cancer” ( US EPA, 2011c, p. 4

- 238 ).

18 The clear protective coating spray use assumes a 30

- minute exposure, the hobb yist degreaser use assumes one hour and the small commercial degreaser, although assuming only two hours of degreaser use, is reported as an eight

- hour TWA

.

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### Human Data The US EPA (2011c ) reviewed 21 non

- cancer and 24 cancer studies in humans that evaluated
effects on the liver. In the non

- cancer studies, 13 were epidemiology studies evaluating the role of TCE exposure and liver cirrhosis. The US EPA concluded that the role of TCE exposure on
liver cirrhosis could not be ruled out.

Five of the 21 human non

- cancer reports were occupational studies

, four of which were specifically TCE degreaser operations ( Nagaya et al. , 1993 ; Rasmussen et al. , 1993 ; Xu et al.

, 2009 ; Neghab et al. , 1997 ; as cited in US EPA, 2011c )

. Overall, the US EPA (2011c ) concluded that “...these observations are suggestive of liver disorders as associated with potential TCE exposure, but whether TCE caused the se conditions is not possible to determine given the study’s limitations” ( US EPA, 2011c, p. 4

- 221 ).

The human cancer studies evaluated included cohort, case

- control

, and community (geographic) studies that evaluated the following cancer types in humans: liver and biliary tract cancer, primary liver cancer

, and gallbladder and extra

- hepatic bile duct cancer ( see Table 4

- 57 in US EPA, 2011c, for a summary of the 24 studies ). Not all studies were used in the US EPA ’s

meta

- analysis, but the overall conclusions suggested a small, statistically significant sum mary relative risk (RRm) for liver and gallbladder/biliary cancer and TCE exposure.

Animal Data The IRIS program 

### devotes Appendix E , of its document, to evaluation of liver toxicity (primarily)
to animals. The discussion revolves around two main issues: (1) understanding the events leading to liver tumors in rodents

, and (2) determining the role of the various metabolites in that process (termed “co

- exposure” by the IRIS program). In terms of the latter, many investigators have dosed animals with TCE

, as well as with many of its metabolites to determine
th e role and potency of each in terms of target organ toxicity. It appears that the oxidation pathway is important for the development of liver toxicity

, but the specific role of each metabolite ( i.e.

, that of TCA, DCA, and chloral hydrate ), as well as the parent TCE , is unclear

.

For non

- cancer effects, many oral/inhalation studies in rats and mice were reviewed ; US EPA (2011c ) concluded that TCE exposure in animal studies does result in increased liver weight, a small, transient increase in DNA synthesis, enlarged hepatocytes, increased size of nuclei of liver cells, and proliferation of peroxisomes.

Liver effects (increase in liver/body weight ratio) observed in three animal studies ( Kjellstrand
et al. , 1983 ; Woolhiser et al. , 2006 ; Buben and O'Flaherty, 1985 ; as cited in US EPA, 2011c ) were chosen by the IRIS program for use in the non

- cancer dose

- response assessment. NMRI mice were exposed to up to nine different TCE concentrations (ranging from 3 7 to 3,600 ppm) for various durations (1, 2, 4, 8, 16

, or 24 hours/day) and for different time frames (from 30 to 120 days) ( Kjellstrand et al. , 1983 ; as cited in US EPA, 2011c )

. The IRIS program calculated a benchmark dose, lower confidence limit ( BMDL ) of 21.6 ppm as a POD for an increase in the liver/body weight ratio from this experiment. In Woolhiser et al. (2006 ) ( as cited in US EPA,
2011c ) , Sprague

- Dawley rats were exposed to TCE via inhalation at concentrations of 0, 100,

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### 300

, or 1, 000 ppm for six hours/day, five days/w ee k for four weeks. As with the Kjellstrand et al. (1983 ) data, a BMDL of 25.2 ppm for increased liver/body weight ratio. Finally, the Buben and O'Flaherty (1985 ) data came from an oral study with Swiss

- Cox mice (gavage, seven doses ranging from 100 to 3

, 200 mg/kg

- bw /day plus control, five days/w ee k for six weeks) and a BMDL of 81.5 mg/kg

- bw /day was calculated as a POD for increased liver/body weight ratio.

In the cancer bioassays, B6C3F 1 

### mice ( via inhalation and gavage routes) and Swiss mice ( via inhalation) have consistently shown to have increased liver tumors following exposure to TCE. Gene marker studies cited by the IRIS program have shown specific mutation frequencies associated with tumors following exposure to TCE, TCA, DCA

, and chloral hydrate . There is some overlap among the groups, but it is not clear what may be the predominant metabolite. Studies with rats do not report statistically significant increases in liver tumors.

Summary for Liver Toxicity/Cancer
For both cancer and non

- cancer effects on the liver, the role of metabolites is important but not
well understood

. The oxidation pathway seems necessary for TCE

- induced liver toxicity. Thus, IRIS concluded that multiple TCE metabolites ( i.e., and thus pathways) likely contribute to TCE

induced liver tumors.

Kidney Toxicity (Including Cancer)
Studies in both humans and animals have shown changes in the proximate tubules of the kidney following exposure to TCE. As with liver toxicity, TCE metabolites appear to be the causative agent s that induce renal toxicity

, including cancer. DCVC formation appears critical,
bec ause animals treated with DCVC alone show the same type of kidney damage as those
treated with TCE.

Human Data
E ight human studies were reviewed by the IRIS program that evaluated kidney toxicity and over
35 epidemiological studies examining the possible relationship of kidney cancer and TCE exposure in humans.

All eight non

- cancer studies evaluated workers ( i.e., for all degreasing operations) exposed to some level of TCE, and several followed renal cell carcinoma (RCC; or kidney cancer) or end
stage renal disease cases. These studies showed increased levels of kidney damage (proximal tubules) exposed to “high” levels of TCE. Determining the level of TCE exposure was somewhat complicated and was expressed as one or more of the following descriptors: “intensity” × duration; job title; “ever exposed ; ” “high ; ” and “very high”.

The more than 30 cancer studies with humans include evaluation of possible association of TCE exposure with cancer of the kidney and renal pelvis as well as RCC (the most common type of kidney cancer). US EPA (2011c ) performed a meta

- analysis of 15 cohort and case

- control studies to evaluate the relationship between kidney cancer and TCE exposure, resulting in a summary relative risk (RRm) of 1.27 (95 percent confidence interval [CI] of 1.13 to 1.43). A

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### similar metric was determined for the 13 studies with higher TCE exposures (RRm of 1.64;
95 percent CI of 1.31 to 2.04).

There appears to be greater susceptibility to TCE exposure/kidney cancer in individuals with an active polymorphism in a gene associated with the GST metabolic pathway

, which is associated
with the β

- lyase gene region ( i.e., which is responsible for converting DCVC to the presumed unstable intermediate DCVT). Also, there are some human studies suggesting a role for mutations to the tumor suppressor gene

, von Hippel Lindau. US EPA (2011c ) suggests that this tumor suppressor gene is inactivated in certain TCE

- induced kidney cancers.

The US EPA concluded that TCE is “carcinogenic to humans” based on convincing evidence of a causal relationship between TCE exposure in humans and kidney cancer

.

Animal Data In the animal studies, renal toxicity was evident in both rats and mice following either inhalation or gavage exposures. The toxicity includes damage to the renal tubules ( e.g., both cytomegaly and karyomegaly). Under chronic gavage exposure scenarios, rodents exhibit
almost 100 percent kidney toxicity induction. Under inhalation exposure scenarios, male rats are more susceptible than female rats or mice to kidney toxicity. As noted earlier, this toxicity is likely caused by DCVC formation, with possible roles for TCOH and TCA. Kidney effects
observed in five animal studies were chosen by the IRIS program for use in the non

- cancer dose

- response assessment: three studies for histological changes in the kidney ( Maltoni and
Cotti

, 1986 ; ( NCI, 1976 ; NTP, 1988 ; as cited in US EPA, 2011c ) and two studies for increases in the kidney/body weight ratio ( Kjellstrand et al. , 1983 ; Woolhiser et al. , 2006 ; as cited in US EPA,
2011c ).

The three studies that reported histological changes in the kidney of exposed animals included
one inhalation and two oral exposure studies. The Maltoni and Cotti ( 1986 ) study ( as cited in US EPA, 2011c ) exposed Sprague

- Dawley rats to TCE via inhalation (0, 100, 300

, or 600 ppm)

seven h ou rs/day, five days/w ee k for 104 weeks (and allowed all rats to continue unexposed until they died). A BMDL of 40.2 ppm was derived for renal tubular pathological changes (meganucleocytosis). The National Cancer Institute ( NCI, 1976 ; as cited in US EPA, 2011c ) reported an oral (gavage) 90

- week study with B6C3F 1 

### mi ce ( i.e., dosed five days/week for 78 weeks, the final 12 weeks with no exposure) at doses ranging from 0 to 2,339 mg/kg

- bw /day; a
lowest

- observed

- adverse

- effect level ( LOAEL ) was identified as the POD for toxic nephrosis.
The National Toxicology Program ( NTP, 1988 ) study ( as cited in US EPA, 2011c ) report ed toxic nephropathy in Marshall rats exposed to TCE via gavage at doses of 0, 500

, or 1, 000 mg/kg

bw /day, five days/w ee k for 104 weeks. The derived POD for this study was a BMDL of 9.45 mg/kg

- bw /d ay

.

The two studies that reported increases in kidney/body weight ratio that were used to develop

PODs /p

- cRfCs were both inhalation studies and were also used for the observed effects in the
liver ( Kjellstrand et al. , 1983 ; Woolhiser et al. , 2006 ; as cited in US EPA, 2011c )

. The PODs

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### developed were BMDL values for 34.7 ppm ( Kjellstrand et al. , 1983 ) and 15.7 ppm ( Woolhiser
et al. , 2006 )

.

Cancer bioassays with TCE in animals ( i.e., both gavage and inhalation exposure routes) did not show increased kidney tumors in mice, hamsters

, or female rats

, but did show a slight increase
in male rats. K idney tumors in rats a re relatively rare (US EPA, 2011c)

.

Summary of Kidney Toxicity/Cancer From a mechanistic standpoint, it is suggest ed that DCVC (and to a lesser extent other metabolites) is responsible for kidney damage and kidney cancer following TCE exposure (US EPA, 2011c) . There are data that demonstrate that DCVC is delivered to the kidney following TCE exposure. A lso , the genotoxicity of DCVC (see genotoxicity section below) further suggests
that a mutagenic mode of action is involved

, although cytotoxicity followed by compensatory cellular proliferation cannot be ruled out. There are possible roles for both genetic polymorphism (GST pathway) and mutations to tumor suppressor genes in the develop ment of kidney cancers in humans following exposure to TCE.

Neurotoxicity Neurotoxicity has been demonstrated in animal studies under both acute and chronic exposure conditions, and has been observed in human studies under acute conditions (chamber studie s)

, as well as under chronic, occupational exposure conditions. The effects observed include alterations in nerve function, cognitive effects, sensory effects, and changes in psychomotor function, mood

, and sleep behaviors. As already noted, d ue to thes e effects on the nervous system, TCE was initially synthesized for use as an anesthetic in humans in the early part of the
20 th 

### century.

Human Data The available human studies that evaluated neurotoxicity fall into three general categories: (1) evaluation of residents exposed to TCE (and sometimes other solvents) near Superfund
sites ; (2) occupationally exposed individuals (generally degreasers and generally studies already discussed above under either liver or kidney toxicity); and (3) short

- term controll ed experiments/ studies with volunteers. Many different endpoints have been evaluated, and a brief review is presented below.

Thirteen studies were reviewed by the IRIS program, which concluded there was evidence of changes in trigeminal nerve function/m orphology in humans following exposure to TCE . One of
these studies was used in the dose

- response assessment for neurotoxicity ( i.e., increased latency in the jaw muscle reflex [masseter reflex] ) ( Ruijten et al. , 1991 ; as cited in US EPA,
2011c ) . In that study, human mail printing workers (31 exposed and 28 controls) were evaluated for possible health effects from TCE exposure, defined as “cumulative exposure” (concentration × time). Using historical monitoring data mean exposures were calculated as 704 ppm × number of years worked

, where the mean number of years was 16. The POD derived from the dataset was a LOAEL of 14 ppm (US EPA, 2011c)

.

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### Four studies evaluated effects on auditory function in humans ; all reported effects from TCE exposure. All five studies that evaluated effects of TCE exposure on vision reported effects

, one of which was the basis for one of the AEGL values discussed above ( Ferguson and Vernon, 1970 ; Vernon and Ferguson, 1969 ; as reported in US EPA, 2008a )

. Ten studies evaluated cognitive functions such as learning and memory ; the US EPA concluded that the se studies “...collectively suggest cognitive function impairment” ( US EPA, 2011c, p. 4

- 110 ).

There were nine human studies that specifically evaluated developmental neurotoxicity and exposure to TCE; four looked at birth defects (CNS defects and neural tube defects) and the remainder evaluated postnatal effects (delayed newborn reflex, impaired learning and memory, aggressive behavior, speech and hearing impairments, encephalopathy, impaired executive function, impaired motor function, attention deficits

, and autism spectrum disorder). US EPA concluded t hat “... (W)hile there are broad developmental neurotoxic effects that have been associated with the TCE exposure, there are many limitations in the studies” ( US EPA, 2011c, p.
4- 568 ).

Animal Data
Dozens of animal studies were reviewed in US EPA (2011c ) that evaluated many endpoints under a variety of exposure conditions; however, only the following four studies were used in
the dose

- response assessment to evaluate neurotoxicity.

Isaacson et al. (1990 ) ( as cited in US EPA, 2011c ) dosed weanling Sprague

- Dawley rats via the oral route (drinking water) in an experimental protocol for an eight

- week period. Animals were given no TCE for eight weeks (control group), 47 mg/kg

- bw /d ay TCE for four week s and then no TCE for four weeks (“5.5 mg/kg

- bw /d ay group”), or 47 mg/kg

- bw /d ay TCE for four weeks, no
TCE for two weeks

, and then 24 mg/kg

- bw /d ay TCE for two weeks (“8.5 mg/kg

- bw /d ay group ” ). From this study, a LOAEL of 47 mg/kg

- bw /d ay for demyelination in the hippocampus was identified as the POD

.

Male Wistar rats were exposed to TCE via inhalation to concentrations of 0, 50, 100

, or 300 ppm for eight h ou rs/day, five days/week for six weeks ( Arito et al. , 1994 ; as cited in US EPA, 2011c )

. Electroencephalo gram (EEG) responses were used to measure the number of wakeful hours versus sleep hours. A significant decrease in wakefulness was identified as the neurological effect ; a POD of 14 ppm ( i.e., LOAEL, adjusted for continuous exposure) was identified.

Gash et al. (2008 ) ( as cited in US EPA, 2011c ) evaluated the effects of TCE ( i.e., oral gavage experiments with F344 male rats at doses of 0 or 1, 000 mg/kg

- bw /d ay , five days/week for six weeks) on dopamine

- containing neurons in the CNS

. The POD of 710 mg/kg

- bw /d ay represents a LOAEL (adjusted for time) for loss of dopamine containing neurons.

The final animal neurotoxicity study used in the dose

- response assessment for this endpoint is Kjellstrand et al. (1987 ) ( as cited in US EPA, 2011c )

. In this study, the effect of TCE on regeneration of the sciatic nerve after a crush lesion was evaluated in mice (NMRI strain, males

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### only) and rats (Sprague

- Dawley, females only). Animals were pre

- exposed to TCE (0 or 300 ppm in rats and 0, 150

, or 300 ppm in mice

, both via inhalation and for 24 hours/day) for 20 days, the lesion was induced, and exposure continued for an additional fo ur days prior to evaluation. The POD for this effect was a LOAEL of 300 ppm (rats) and 150 ppm (mice).

Summary of Neurotoxicity Like kidney and liver toxicity, neurotoxicity is a well

- documented effect in both humans and animals following exposure to TCE . The following effects were concluded to be a result of exposure to TCE by US EPA (2011c ) : alterations in trigeminal nerve function (humans); auditory effects (humans and animals); alterations in nystagmus (humans and animals); changes in vision (humans and animals); changes in cognitive function (humans and animals); changes in psychomotor effects (humans and animals); mood disturbance (humans and animals); sleep disturbance (animals); and developmental neurotoxicity (primarily animals).

Immunotoxicity (Includi ng Cancer)

Immune

- related effects following TCE exposures have been observed in both animal and
human studies . In general, these effects were associated with inducing enhanced immune responses as opposed to immunosuppressive effects. Of concern are the indirect effects of immune hypersensitivity ( i.e. , development of cancer via faulty tumor surveillance by a compromised immune system, and atherosclerosis).

Two of the three key studies used to derive the US EPA’s RfD

, one of which was also used to derive the RfC, were immunotoxicity studies in mice ( Keil et al. , 2009 ; Peden

- Adams et al.

, 2006 ) ; because the latter is a developmental study, it is discussed in the Developmental Toxicity section below). In a ll, four animal studies evaluating immunotoxicity were used in the non

cancer IRIS dose

- response assessment. Also, one of the three cancers for which the US EPA (2011c ) based its cancer findings was non

- Hodgkin ’ s l ymphoma (NHL) (the other two being kidney and liver cancer).

Human Studies US EPA (2011c ) found only limited evidence of immunosup p ression, asthma

, and allergies in the
three studies reviewed. However, Arif and Shah (2007 ) did not find an association between
TCE 19 

### exposure (as measured with passive monitors in NHANES participants over a 48 - to
72

- hour period; geometric mean reported levels were 0.03 μ g/ m 3 

### [95 percent CI of 0.02 to 0.04]) and asthma in 550 individuals in that study.

The re is evidence for high TCE exposures in the workplace leading to a generalized hypersensitivity skin disease. As summarized in US EPA (2011c ) , a number of studies published
since 1995

— largely from Asian countries reflecting recent industrialization in those areas

— report a skin disorder (not contact dermatitis) that includes systemic effects (hepatitis, lymph

19 In their paper, Arif and Shah (2007 ) use the abbreviation TCE for perchloroethylene and trichloroethylene is
identified as trichloroethene. In this assessment, the acronym TCE means the trichloroethene results from the Arif and Shah (2007 ) paper.

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### nodes

, and other organs). These were seen in workers exposed to high levels of TCE in air (from ~9 to >700 ppm). The US EPA (2011c ) performed a meta

- analysis o f a number of human studies evaluating a possible connection between scleroderma i.e., (an autoimmune disease) and TCE exposure. Results indicated a significant odds ratio (OR) in men with a lower (not significant) increase in women. These results may no t reflect a true gender difference in response because the incidence of this disease is very low in men (approximately one per 100,000 per yr ) and somewhat higher in women (approximately one per 10,000 per yr).

Finally, in a study of degreasers, there was an increase in human inflammatory cytokine levels following TCE exposure ( Iavicoli et al. , 2005 ; as cited in US EPA, 2011c ) . These findings are supported by studies in auto

- immune prone mice (described below) in which short ex posures to TCE result in increased levels of inflammatory cytokines. What does this mean then?

Animal Data
The f ollowing is a short description and identification of the PODs for the four immunotoxicity
studies identified for consideration in the dose

- res ponse analysis for immunotoxicity.

Keil et al. (2009 ) exposed two strains of mice (NZBWF 1 

### mice

, genetically prone to develop autoimmune disease, and B6C3F 1 

### mice

, a standard test strain not genetically prone to develop autoimmune disease) to TCE via drinkin g water for 27 or 30 weeks at concentrations in water of 0, 1.4

, or 14 ppm. A variety of immune system markers were measured. TCE did not affect

some markers (natural killer cell activity or T - and B

- cell proliferation) in either strain. However, other findings showed an increase in renal pathology scores (low concentration only; not observed at the high concentration), a significant decrease in thymus weight concentrations (both concentrations), and increased anti

- dsDNA (at several time points, at both concentrations) in the B6C3F 1 

### strain. Two PODs were identified in this study

, both at the same
level ( LOAEL of 0.35 mg/kg

- bw /d ay for two different effects : decreased thymus weight and an
increase in anti

- dsDNA ).

In an inhalation study, Kaneko et al. (2000 ) ( as cited in US EPA, 2011c ) exposed auto

- immune prone mice to TCE at concentrations of 0, 500, 1, 000

, or 2, 000 ppm for four hours/day, six days/w ee k, for eight weeks

. There were changes in organs associated with immune response (liver inflammation, splenomegaly

, and hyperplasia of lymphatic follicles) ; a LOAEL of 70 ppm
was used as the POD for these effects.

There were two studies that evaluated immunosuppression in rodents. In Sanders et al. (1982 ) ( as cited in US EPA, 2011c ) , male and female CD

- 1 mice were given TCE in drinking water concentrations of 0, 0.1, 1.0, 2.5

, or 5.0 mg/mL for four or six months. Immunity was

s uppressed in females only ; a POD of 18 mg/kg

- bw /d ay was identified as a LOAEL for inhibition
of cell

- mediated immunity and bone marrow stem cell activity. Another study that has already been discussed for evaluating both liver and kidney effects ( Woolhiser et al. , 2006 ; as cited in US EPA, 2011c ) also reported immunosuppressive effects (decreased plaque

- forming cell [PFC] assay response) in rats exposed to TCE via inhalation for four weeks. In that study, a BMDL of 24.9 ppm was identified as a POD for this immunosuppressive effect.

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### Summary of Immunotoxicity US EPA (2011c ) concludes that “...the human and animal studies of TCE and immune

- related effects provide strong evidence for a role of TCE in autoimmune disease and in a specific type of generalized hypersensitivity syndrome, while there are less data pertaining to immunosuppressive effects” ( US EPA, 2011c, p. 4

- 627 )

.

Reproductive Toxicity
Available hum an and animal data suggest possible reproductive effects in males, but not in females following exposure to TCE. Nine reproductive studies were used by the IRIS program in their dose

- response assessment for this endpoint, including one human study.

Huma n Studies
Twelve human studies were evaluated; and most looked at potential effects in both males and
females. One of the 12 studies was carried forward in US EPA (2011c ) for the dose

- response
assessment. In that study ( Chia et al. , 1996 ; as cited in US EPA, 2011c ), a cohort of 85 workers in an electronics factory was selected, and 12/85 were monitored to assess exposure . The mean TCE exposure ( via inhalation) after an eight

- hour shift of these 12 workers was 29.6 ppm (range of nine to 131 ppm). There were no controls in the study

. Males experienced decreased normal sperm morphology and other sperm effects (hyperzoospermia) ; a BMDL of 1.4 ppm was
identified as the POD for these effects.

Overall, US EPA concluded that the TCE studies in humans showed a decreased incidence of
fecun dability (time

- to

- pregnancy) and menstrual cycle disturbances in women and the following effects in males: altered sperm morphology, hyperzoospermia, altered endocrine function, decreased sexual drive and function

, and altered fertility.

Animal Data
S even inhalation (all with males only) and eleven oral (both males and females evaluated)
studies were evaluated to assessed reproductive effects in animal studies. Eight of these
studies were carried into the dose

- response evaluation and are briefly described below. Overall, the data support findings seen in humans in that females appear to be less affected
than males.

There were five inhalation animal studies that evaluated reproductive toxicity and were used in
the IRIS dose

- response assessment; all of the se studies focused on effects on the male. Xu et al. (2004 ) ( as cited in US EPA, 2011c ) exposed male CD

- 1 mice to TCE at concentration of 0 or 1, 000 ppm for six h ou rs/day, five days/w ee k for six weeks. Sperm from treated animal s resulted in decreased in vitro sperm

- oocyte binding and in vivo fertilization; a POD of 180 ppm (LOAEL) was identified for this effect. In two separate experiments ( Kumar et al. , 2000 ; Kumar et al. , 2001 ; as cited in US EPA, 20 11c ) , male Wistar rats were exposed to TCE via inhalation at concentrations of 0 or 376 ppm. Both study protocols reported exposures of four h ou rs/day,
five days/w ee k, but in the 2000 report
, exposures were from two to 10 weeks

, followed by an unexposed time frame of between two and eight weeks. In the 2001 report, exposures were

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### for either 12 or 24 weeks. Effects on sperm and reproductive tract effects (decreased testes weight, smaller, nec rotic spermatogenic tubules, and other effects) were observed and PODs for these two types of effects were derived ; LOAELs of 45 ppm.

Importantly

, there was an increase severity in the effects when exposure duration went from
12 to 24 weeks. The final two inhalation studies evaluated effects on the male reproductive
tract of CD

- 1 male mice exposed to 0 or 1, 000 ppm TCE for six h ou rs/day, five days/w ee k for either 19 days over a four

- week period ( Forkert et al. , 2002 ; as c ited in US EPA, 2011c ) or for
one to four weeks ( Kan et al. , 2007 ; as cited in US EPA, 2011c ) . Sloughing of epididymal epithelial cells were observed in treated mice, and increased in severity with duration of exposures. A LOAEL of 180 ppm was identified as a POD for this effect.

The three oral animal studies selected for dose

- response assessment for reproductive toxicity
evaluated effects on males ( DuTeaux et al. , 2004 ; as cited in US EPA, 2011c ) , female reproductive outcomes ( Narotsky et al. , 1995 ; as cited in US EPA, 2011c ) , and reproductive behavior in both genders ( NTP, 1986 ; as cited in US EPA, 2011c )

.

DuTeaux et al. (20 04 ) ( as cited in US EPA, 2011c ) treated two strains of male rats (Sprague

Dawley or Simonson albino) by TCE exposure via the drinking water (0, 0.2

, or 0.4 percent, resulting in doses of 0, 143

, or 270 mg/kg

- bw /d ay for 14 days). Results showed decreased fertilization (as measured by in vitro fertilization of oocytes from untreated female rats) at both concentrations in both rats strains, with a LOAEL of 141 mg/kg

- bw /d ay identified as a POD. Narotsky et al. (1995 ) ( as cited in US EPA, 2011c ) treated F344 rats via gavage during gestation (nine days) to TCE at doses of 0, 475, 633, 844, or 1, 125 mg/kg

- bw /d ay

. The study was a prequel to a complicated protocol with other chemicals in a mixture study; however, delayed parturition was seen at all dose levels and was used as a POD (LOAEL = 475 mg/kg

- bw /d ay ). In

an NTP (1986 ) study ( as cited in US EPA, 2011c ) , F344 rats were exposed to TCE via the diet (TCE placed in microcapsules and incorporated into feed) at estimated intern al doses of 0, 72, 186

, or 389 mg/kg

- bw /d ay

. Male and female animals were treated for one week pre

- mating, then
for 13 weeks

, and then pregnant females were continued on treated diet throughout gestation. Results showed a decrease in mating and the LOAEL of 389 mg/kg

- bw /d ay was used as the POD
for consideration in the dose

- response assessment.

Summary of Reproductive Toxicity Overall, the US EPA concluded: “...the human and laboratory animal data together support the conclusion that TCE exposure poses a potential hazard to the male reproductive system” ( US EPA, 2011c, p. 4

- 629 ).

Developmental Toxicity
Because the US EPA RfC is based primarily on a developmental endpoint ( I.e., congenital cardiac
defects or heart malformations), considerable attention has been given to this issue in the
literature. US EPA (2011c ) evaluated many different developmental outcomes in both human and animal studies, including prenatal ( i.e., death, decreased growth, and congenital
malf ormations) and postnatal ( i.e., growth, survival, developmental neurotoxicity,

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### developmental immunotoxicity

, and childhood cancers) effects. There are seven animal studies used to develop PODs for eight different endpoints; all briefly described below.

H uman Studies
The US EPA evaluated numerous studies

— both occupational and geographic ally

- based

— in humans to examine the possible association of TCE with various developmental outcomes. Most of these studies have been mentioned earlier and represent workpla ce exposures ( Finnish
studies of Taskinen et al. , 1989 ; Taskinen et al. , 1994 ; both as cited in US EPA, 2011c ) ; the geographic studies in Arizona, C O (Rocky Mountain Arsenal) and Woburn, MA. Some have focused on reproductive/developmental outcomes (ATSDR studies in Endicott, NY and the Camp Lejeune studies, the latter of which was the subject of an NAS inves tigation ) ( NAS, 2009 )

.

US EPA (2011c ) concluded that there are positive associations between TCE exposures and the following developmental effects in humans: spontaneous abortions, miscarriage, pre - and/or
post

- implantation l oss, perinatal death, reduction in live births, decreased birth weight, small for gestational age, postnatal growth, cardiac defects, eye/ear birth anomalies, oral cleft defects, kidney/urinary tract disorders, musculoskeletal birth anomalies, anemia/blood disorders, and lung/respiratory tract disorders.

Since the publication of the IRIS Toxicological Review in 2011 , one recent update for the Endicott, NY community was published by the NY State Health Department that eval uated maternal exposure to TCE and other VOCs and pregnancy outcome (Forand et al

., 2012 ). The study evaluated all births recorded in Endicott, NY from either 1978 to 2002 (to assess low birth weight, pre

- term and fetal growth) or from 1983 to 2000 (birth defects). The comparison group

wa s the rest of NY State except for the city of New York. A large chemical spill occurred in the
town in 1979 , and monitoring of the contaminant plume occurred for years. Residents obtain their drinking water from an uncontaminated water source; however, TCE and other VOCs have been measured in groundwater, soil

, and inside buildings, the latter due largely to vapor intrusion. The study authors reported significant adjusted rate ratios (RRs) for the TCE

contaminated area for, among others, the following e ndpoints: low birth weight (RR of 1.36;
95 percent CI of 1.07 to 1.73), small for gestational age (RR of 1.23; 95 percent CI of 1.03 to 1.48), and cardiac defects (RR of 2.15; 95 percent CI of 1.27 to 3.62)

.

Animal Data There were five inhalation and 17 oral developmental toxicity studies with TCE in animals
reviewed in US EPA (2011c ) ; however, only five were considered in the dose

- response
assessment and only one was an inhalation study ( Healy et al. , 1982 ; as cited in US EPA, 2011c )
and the other four were oral studies.

Two developmental studies reported mortality ( pre - and postnatal mortalities as resorptions). Healy et al. (1982 ) ( as cited in US EPA, 2011c ) exposed female Wistar rats to TCE via inhalation at concentrations of 0 or 100 ppm for four h ou rs/day, for 13 days (gestation days eight to 21). There was an increase in resorptions at the only concentration tested and a LOAEL of 17 ppm
was identified as a POD. The other study in which a POD was identified for mortality in the

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### developing fetus was the Narotsky et al. (1995 ) study ( as cited in US EPA, 2011c ) mentioned above in the reproductive toxicity section (gavage study with rats treated during gestation); resulting in a BMDL of 32.2 mg/kg

- bw /d ay for resorptions as a POD. The Healy et al. (1982 ) study ( as cited in US EPA, 2011c ) was also used to derive a POD for reduced fetal weight (as a LOAEL of 17 ppm).

Johnson et al. (2003 ) report ed data from different experiments over a several

- year period in
which pregnant Sprague

- Dawley rats were exposed ( via drinking water) to TCE at four different concentrations (0, 0.0025 ppm

, 0. 250 pp m , 1.5 ppm, and 1, 100 ppm) for the duration of their pregnancies (22 days). The authors concluded that there was a statistically and biologically significant increase in the formation of heart defects at the 0.250 ppm dose level at both the
individual fetus level and the litter level. There was no statistical increase at the 1.5 ppm dose level (at either the individual fetus or li tter level), but there was an increase at the highest concentration ( 1, 100 ppm). 20 

### A BMDL of 0.0207 mg/kg

- bw /d ay as a POD for heart
malformations was identified (US EPA, 2011c)

.

There were two oral studies that evaluated developmental neurotoxicity and were used in the
dose

- response evaluation for developmental toxicity. Fredriksson et al. (1993 ) ( as cited in US EPA, 2011c ) treated male NMRI mouse pups with TCE via gavage (0, 50

, or 290 mg/kg

- bw /d ay )
for si x days (postnatal days [PND s ] 10 to 16) and then measured spontaneous activity in several ways on PND s 17 and 60. Treated animals showed decreased rearing activity at both dose levels on PND 60 (but not PND 17), resulting in a LOAEL of 50 mg/kg

- bw /d ay as a POD. In a rat study ( Taylor et al. , 1985 ; as cited in US EPA, 2011c ) , pregnant female Sprague

- Dawley rats were given TCE in their in their drinking water until 21 days post par tum at concentrations of 0, 312, 625

, or 1, 250 mg/L. Male offspring from treated animals in the mid and high exposure groups showed increased exploratory behavior on PND s 60 and 90, resulting in a derived LOAEL of 45 mg/kg

- bw /d ay as a POD.

Finally, there was a developmental immunotoxicity study that was used as a critical study for developing the RfD (for oral exposure). Although not used for the RfC, it is described here because it is the only other critical study not otherwise mentioned. Peden

- Adams et al. (2006 ) also exposed B6C3F1 mice to TCE via drinking water. Mice were exposed during mating and through gestation to TCE levels of 0, 1.4

, or 14 ppm in drinking water. After delivery, pups were further exposed for either three or eight more weeks at the same concentration levels in drinking water. Suppressed PFC response was seen in male pups (after three and eight weeks of exposure) and female pups (only at eight weeks) at 1.4 ppm. Delayed hypersensitivity response was increased in the females exposed for eight weeks at this concentration. At the higher concentration (14 ppm), both of these effects were observed again, but were seen in both males and females at both time points (suppressed PFC response) or in both males and females only at eight weeks (increase in delayed hypersensitivity response). A LOAEL of 0.37

20 The EPA Science Advisory Board ( US EPA, 2011a ) reviewed these da ta and suggested that the IRIS program use
the Johnson et al. (2003 ) study as one of the critical/principal studies for RfD/RfC derivation.

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### mg/kg

- bw /d ay served as a POD for the decreased PFC and increased delayed hypersensitivity

responses (US EPA, 2011c ).

Summary of Developmental Toxicity
The US EPA (2011c ) concluded the following regarding developmental toxicity and TCE

exposure:

“Overall, based on weakly suggestive epidemiologic data and fairly consistent laboratory animal data, it can be concluded that TCE exposure poses a potential hazard for prenatal losses and decreased growth or birth weight of offspring ... Epidemiological data provide some support for the possible relationship between maternal TCE exposure and birth defects in offspring, particularly card iac defects ” ( US EPA, 2011c, p. 4

- 629 ).

Regarding studies of birth defects in animal s , the US EPA concluded that there is potential for disruption of the development of the eye (from exposure to TCE and its oxidative metabolites) ( US EPA, 2011c, p. 4

- 630 ), and although the cardiac defect studies have some limitations, their findings cannot be dismissed and are based on some mechanistic grounds (predominantly findings in developmental studies with chick embryo, and concordance in the stages of heart
formation between mammals and birds ) ( US EPA, 2011c, p. 4

- 631 ).

Genetic Toxicity TCE, and many of its metabolites, have been shown to be genotoxic. TCE, however, does not appear to be a direct

- acting mutagen, but it does affect both DNA and chromosomes. In bacterial test systems, TCE does not induce mutations unless there is metabolic activation ( i.e.

, the presence of metabolizing enzymes). TCA, an oxidative metabolite of TCE, also does not induce mutations in bacterial test systems unless metabolic activation systems are present. However, other TCE metabolites (DCA, chloral hydrate , DC VG, and DCVC) all induce mutations
without metabolic activation.

US EPA (2011c ) evaluated data on TCE and the afore mentioned metabolites in a variety of in
vitro and in vivo test systems. Though it is thought that these metabolites may be responsible for TCE genotoxicity, US EPA (2011 c ) did not draw any conclusions on this matter

, largely because there were not sufficient genotoxicity data with standard tests for all of the
metabolites. However, the IRIS program did state that DCVC appears to have “predominantly resulted in positiv e data

, ” supporting the conclusion that it is genotoxic (particularly in the kidney).

Hazard Summary
Table 3

- 17 provides a list of the 12 inhalation studies from which hazard values will be used in
this risk assessment. There are at least two studies for each major target organ. Multiple species have been evaluated ( i.e., humans, mice, rats). Because some of the studies report more than one adverse outcome, 17 PODs (and therefore modeled human equivalent concentrations; explained more fully in the next section) were identified.

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- 17. Inhalation Studies Identified In US EPA (2011c ) For Use In OPPT TCE Risk Assessment.

T arget Organ Species Range of Doses or
Concentrations a Duration POD Type b Effect HEC 50 (ppm) HEC 99 (ppm) Reference

Liver Mouse 37

- 3,600 ppm 30

- 120 days BMDL = 21.6 ppm Increased liver weight/ body weight
ratio 25 9.1 1

Rat 100

- 1,000 ppm 28 days BMDL = 25 ppm 53 19 2

Kidney Rat 100

- 600 ppm 104 weeks BMDL = 40.2 ppm Pathology changes in
renal tubule 0.28 0.038 3

Mouse 37

- 3,600 ppm 30

- 120 days BMDL = 34.7 ppm Increased kidney weight/body weight

ratio 0.88 0.12 1

Rat 100

- 1,000 ppm 28 days BMDL = 15.7 ppm 0.099 0.013 2

Neuro

toxicity Human Mean exposure of
CxT Mean of 16 years LOAEL = 14 ppm Trigeminal nerve
effects 14 5.3 4

Rat 50

- 300 ppm 6 weeks LOAEL = 12 ppm Changes in
wakefulness 13 4.8 5

Rat 300 ppm 24 days LOAEL = 300 ppm Decreased regeneration of sciatic

nerve 274 93 6

Mouse 150

- 300 ppm 24 days LOAEL = 150 ppm 378 120

Immuno

toxicity Mouse (auto

immune

prone strain) 500

- 2,000 ppm 8 weeks LOAEL = 70 ppm Changes in
immunoreactive

organs 97 37 7

Rat 100

- 1,000 ppm 28 days BMDL = 24.9 ppm Immunosuppression 29 11 2
Reproduct

ive toxicity Human (male) Mean exposure =
29.6 ppm Measured values after an
8- hour work shift; mean years on job was 5.1 BMDL = 1.4 ppm Sperm effects 1.4 0.5 8

Mouse (male) 1,000 ppm 6 weeks LOAEL = 180 ppm Sperm effects 190 67 9

Rat (male) 376 ppm 2- 10 weeks, 12 weeks, 24 weeks LOAEL = 45 ppm Sperm effects and male reproductive
tract effects 32 13 10

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- 17. Inhalation Studies Identified In US EPA (2011c ) For Use In OPPT TCE Risk Assessment.

T arget Organ Species Range of Doses or
Concentrations a Duration POD Type b Effect HEC 50 (ppm) HEC 99 (ppm) Reference

Mouse (male) 1,000 ppm 19 days over 4 weeks,
1-4 weeks LOAEL = 180 ppm Effects on epididymis epithelium 190 67 11

Develop

mental toxicity Rat (female) 100 ppm 13 days (during gestation) LOAEL =17 ppm Increased resorptions 16 6.2 12

Rat (female) 100 ppm 13 days (during gestation) LOAEL = 17 ppm Decreased fetal weight 16 6.2 12

a Controls (or zero dose/concentration) are not presented, so a sense of the lowest and highest values is understood.

b POD type can be NOAEL, LOAEL, or BMDL; the IRIS program adjusted all values to continuous exposure.
Reference List ( all as cited in US EPA, 2011c ):
1 = Kjellstrand et al. (1983 )
2 = Woolhiser et al. (2006 ) 3 = Maltoni and Cotti (1986)
4 = Ruijten et al. (1991 )
5 = Arito et al. (1994 )
6 = Kjellstrand et al. (1987 )

7 = Kaneko et al. (2000 )
8 = Chia et al. (1996 )
9 = Xu et al. (2004 )
10 = Kumar et al. (2000 ); Kumar et al. (2001 )
11 = Forkert et al. (2002 ); Kan et al. (2007 )
12 = Healy et al. (1982 )

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### Hazard Data to be used in Risk Assessment for TCE

The US EPA ’ s IRIS program evaluates hazard and dose

- response information on effects that may result from exposure to environmental contaminants. The results of their analyses are hazard values; a n RfD or RfC to be used for non

- cancer risk estimates and an oral slope factor or inhalation unit risk (IUR) factor for cancer risk estimates. In this risk assessment, the inhalation route of exposure was evaluated ; therefore , cancer risks were a ssessed based on the IUR

, and

non

- cancer risk s were assess ed based on the identified PODs from studies used to develop the
US EPA’s RfC.

Rather than use a single, point estimate value for the non

- cancer risk assessment, a range of
risk estimates are pres ented, thereby providing a range of data

. This allows flexibility in evaluating or estimating risk based on exposure duration. Gi ven the different exposure scenarios considered (both acute and chronic for small commercial degreasers, and just acute
for the two consumer exposure scenarios), different endpoints were used based on the expected exposure duration s. For non

- cancer effects, both neurotoxicity and developmental toxicity could occur following acute (short

- term) exposures

, whereas other effects ( toxicity to the liver, kidney, immune system, and the reproductive system) could occur following repeated exposure to TCE. Cancer risk estimates were only derived for chronic exposure scenarios.

The US EPA (2011c ) non

- cancer hazard PODs were derived using PBP K modeling. This model was reviewed by the SAB ( US EPA, 2011a ) and found to be both useful and sophisticated. The PODs for each endpoint to be used in this risk assessment are those for which a human equivalent concentration (HEC ) was derived using this model developed by IRIS for TCE.

PBPK Modeling of TCE and its Metabolites
Given the com plicated metabolic profile of TCE, understanding the relationship between the external dose/concentration ( i.e. , exposure) and internal dose at the target organ of interest is critical to quantifying potential risk (s)

. US EPA ( US EPA, 2011c ) developed a detailed PBPK
model for TCE and its metabolites designed to make such predictions of PODs . As part of building the model, the IRIS Toxicological Review provides a detailed summary of the history of TCE PBPK models that have been built over the years, resulting in an updated model reported in
both Evans et al. (2009 ) and Chiu et al. (2009 ) . This model was used to predict 14 different
dose

- metrics as measures of potential TCE toxicity (each dose

- metric was developed to
evaluate a different metabolic pathway/target organ effect based on the dose

- response analysis and understanding of metabolism) (Table 3

- 18).

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- 18

. U.S. EPA IRIS PBPK

- Modeled Dose Metrics for TCE Dose

- Response Assessment.



### Dose

- Metric Identifier Explanation of What the Dose

- Metric Identifier Represents

ABioactDCVCBW 3 / 4 

### Amount of DCVC bioactivated in the kidney per unit body weight a



### ABioactDCVCKid Amount of DCVC bioactivated in the kidney per unit kidney mass

AMetGSHBBW 3 / 4 

### Amount of TCE conjugated with GSH b



### AMetLiv1B W 3 / 4 

### Amount of TCE oxidized in liver c



### AMetLivOtherBW 3 / 4 

### Amount of TCE oxidized to metabolites other than TCA or TCOH (per unit body weight)
AMetLivOtherLiv Amount of TCE oxidized to metabolites other than TCA or TCOH (per unit liver weight) AMetLngBW 3 / 4 

### Amount of TCE oxidized in respiratory tract (per unit body weight) AMetLngResp Amount of TCE oxidized in respiratory tract (per unit respiratory tract tissue)
AUCCBld Area under the curve of venous blood concentration of TCE d



### AUCCTCOH Area under the curve of blood concentration of TCOH

AUCLivTCA Area under the curve of the liver concentration of TCA
TotMetabBW 3 / 4 

### Total amount of TCE metabolized (per unit body weight) e



### TotOxMetabBW 3 / 4 

### Total amount of TCE oxidized (per unit body weight) f



### TotTCAInBW Total amount of TCA produced

a This was the dose

- metric used to derive the IUR for kidney cancer and some non

- cancer kidney effects.

b This was the dose

- metric used for some non

- cancer kidney effects.

c This was the dose

- metric used to derive the IUR for liver cancer and the non

- cancer liver effects.

d This was the dose

- metric used to derive a reproductive toxicity endpoint ( effects on male reproductive outcomes from one study; DuTeaux et al. , 2004 ; as cited in US EPA, 2011c ).

e This was the dose

- metric used to derive the cRfC for the immunological effect endpoint, some reproductive toxicity endpoints, some developmental toxicity endpoints, and neurotoxic ity. It was also used to derive the IUR
for NHL.

f This is the dose

- metric used to derive the cRfC for the cardiac malformations (developmental) endpoint.



### These dose

- metrics were converted to daily or weekly average concentrations based on simulations lasting 10 weeks for rats/mice and 100 weeks for humans. The predicted values were compared across species, compared to in vivo data

, and were also subjected to sensitiv ity analyses ( all summarized in Section 3.5.6 in US EPA, 2011c )

.

The 32 different candidate PODs/HECs that were identified and developed by the IRIS program to inform the development of the RfC (primarily) were used to identify the range of hazard
values that could be used in the current risk assessment. Appendix F contains a detailed table that presents all of the values. Table 3 -19 provides a list of the values that will be used in this risk assessment by endpoint and exposure duration.

The data in Tab le 3 -19 are from the 12 inhalation studies summarized in Appendix F

. In this risk assessment, the lower

- end of the range of hazard values for the “sensitive” human (the 99 th 

### percentile, or HEC 99 

### ) for each target organ/endpoint was used. These values are bolded in
Table 3 -19 . To provide an indication of the variability in the HEC predictions, the range of

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### hazard values for the “typical ” human (the 50 th 

### percentile or HEC 50 

### ) is also presented. In both instances, the terms “low

- end” and “high

- end” represent the minimum and maximum values within the data presented in Table 3

- 17 for the 12 inhalation studies used herein. Also, the third column in the table presents the original POD ( i.e. , a benchmark dose value or LOAEL) prior to the use of the PBPK model to develop the HEC. Importantly, for five of the six target organs, the HEC value is reasonably close to the original POD (within a factor of ~2). The exception is the kidney, for which the HEC is between 100 - and 1000

- fold lower than the original POD.

Ta ble 3

- 1 9 . Range of TCE Candidate POD/HEC Values Derived by US EPA (2011c )

.

Exposure
Duration Target Organ Original POD (Prior

to PBPK Model ) Range (Minimum and Maximum) of HEC values (All Values in ppm)

By Target

Organ (HEC 50 ) a By Target Organ (HEC 99 ) b By Exposure
Duration (HEC 50 ) By Exposure
Duration (HEC 99 )

Chronic Liver 21.6 c – 25 c 25

- 53 9.1

- 19
0.28 – 190 0.013 - 67 Kidney 40.2 c – 34.7 c 0.28 – 0.88 0.013 – 0.12

Immune system 24.9 c – 70 d 29 - 97 11

- 37
Reproductive system 1.4 c – 180 d 1.4

- 190 0.5

- 67

Acute Nervous system 12 d

– 150 d 13

- 378 4.8

- 120 16

- 378 4.8

- 120
Developing organism 17 d 16 6.2

a HEC 50 is the 50 th percentile for the continuous concentration that leads to an internal dose in a human equivalent
to the rodent internal dose POD.

b HEC 99 is the lower 99 th percentile for the continuous concentration that leads to an internal dose in humans equivalent to the rodent internal dose POD.

c BMDL, in ppm.

d LOAEL, in ppm. Bolded values will be used in the risk assessment



## C. H UMAN 

## H EALTH 

## R ISK 

## C HARACTERIZATION

Risk Estimation Approach for Acute and Repeated Exposures

For the current risk assessment ( i.e., targe ted at the use of TCE as a degreaser in a small commercial shop and by a consumer and the spray fixative use by a hobbyist) , a range of PODs identified in the US EPA (2011c ) for TCE w ere used for non

- cancer endpoints (Table 3 -19 ). The
IRIS IUR value for cancer also developed by US EPA (2011c ) w as used for cancer risk estimates for the chronic exposure scenarios.

The exposure scenarios evaluated in this risk assessment are shown in Table 3

- 20 . For the worker scenario, non

- cancer (acute and chroni c) and cancer effects was evaluated. EPA assumed that chronic ( i.e. , working lifetime) conditions apply . It is further assumed that only

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### adults ( i.e., greater than 16 years old) would be working with the degreaser

, and adults ( i.e., greater than 16 years old) would be in the vicinity as bystanders or non

- users in the workplace

. Becaus e there are both acute and chronic effects following exposure to TCE, endpoints encompassing both exposure durations w ere evaluated for the non

- cancer r isk assessment. The acute endpoints include two that are known to occur following short exposures , including neurotoxicity and developmental effects. Neurotoxicity is the basis for the identified AEGL and
also is the basis for the development of occupati onal guidelines by OSHA and the American Conference of Governmental Industrial Hygienists (ACGIH) 21 

### . The developmental endpoint s of
concern in the inhalation stud ies are both increased resorptions and decrease d fetal body weight. Thus, the populations of concern include both adult male (neurotoxicity) and females (neurotoxicity for non

- pregnant women and developmental toxicity for women of child

- bearing age). For chronic exposure concerns, the following target organs/systems have been shown to
be affected in animals and/or humans following exposure to TCE : liver, kidney, immune system, male reproductive system, and cancer ( i.e., primarily kidney and liver, but also NHL).

Fo r the two consumer exposure scenarios , acute exposure/effects were identified as concerns
because the half

- life data for TCE in humans ( i.e., range of values for elimination in urine after inhalation exposures is ~15 to 51 hours; see Table 3

- 15 and associated text) suggests that the
residual TCE /metabolites from week to week for the cle ar protective coating spray use or for the degreaser use over two events/month, would be relatively small. Furthermore, based on the hazard endpoint, the population of concern for users of the two consumer products are adults ( i.e., >1 6 years old) and include females who are

, or could possibly be

, pregnant, or are of child

- bearing age, and both males and females for possible neurotoxicity effects . This also means that the populations of concern for the non

- user scenario also would have to be women
of child

- bearing age (developmental effects) and all gender/ages (neurotoxicity).

21 The curren t OSHA PEL is 100 ppm and the ACGIH TLV is 25 ppm for TCE.

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- 20 . Use Scenarios, Population of Concern, and Health Effects of Concern.

Use Scenario Assumptions For Exposure Duration Population of
Interest Ha zard Value
Used Comments

Small commercial degreaser Chronic exposure (2 hours per 8- hour workday, 5 days/week) Adults (>16 years old), including
women of child

bearing age Non

- cancer :

r ange of hazard
values for both
acute and
chronic effects
Cancer : IRIS IUR Footnotes a, b, c

Bystander to small
commercial degreaser In the same building, no direct exposure

Hobbyist – c lear protective coating

spray Acute exposure (0.5 hour/event, one event per week) Adults (> 16 years old), including

women of child

bearing age

Non

- cancer :

r ange of hazard
values for acute effects only Footnotes a, d

Bystander to hobbyist – c lear protective coating

spray In the same building, no direct exposure All ages Footnotes a ,d ,e

Hobbyist – degreaser use Acute ( 1 hour/event, two events/month) Adults (> 16 years old), including
women of child

bearing age Footnotes a, d

Bystander to hobbyist – degreaser use In the same building, no direct exposure All ages Footnotes a, d ,e

a Acute exposure concern is for women of child

- bearing age (possible developmental effects) as well as all adults for possible neurotoxicity

. b Possible chronic exposure concern due to effects on the liver, kidney, immune system and reproductive (male)
effects

. c Possible cancer concern from chronic exposure (kidney, liver, NHL).

d Half

- life in humans suggests that there would be minimal carryover exposure from week to week; thus, there is no chronic exposure concern.

e Acute exposure concern is for women of child -b earing age (possible developmental effects) as well as all ages for possible neurotoxicity. The neurotoxicity endpoints used were based on adult animals or humans; thus, there is some uncertainty about their applicability to younger ages which are included in the consumer bystander
scenario.



### Acute or chronic MOEs (MOE acute 

### or MOE chronic 

### ) are used in this assessment to estimate non

cancer risks:

MOE acute or chronic 

### = Hazard value (POD) Exposure value

MOE = margin of exposure (unitless) Hazard value (POD) = point of departure for hazard endpoint (ppm)

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### Exposure value = Exposure (in ppm)

Benchmark MOE values generally range between 10 and 100, depending on the endpoint, the population being evaluated, and a number of other factors generally associated with uncertainty. Generally, each order of magnitude ( i.e. , factor of 10) is used to represent som e uncertainty, such as in extrapolating data from animal studies to humans, from one route of exposure to another, for intraspecies differences within the human population, or extrapolation based on exposure duration of the study ( i.e. , from short - to long er

- term). In this case, all of the PODs were derived using a PBPK model to extrapolate an internal dose in the animal to an internal dose in humans (HEC). In addition, the HECs derived were presented both in terms of median (HEC 50 

### ) and 99 th 

### percentile (H EC 99 

### ) predictions.

If MOEs are less than the benchmark MOE value, there could be a cause for concern, depending upon the frequency of such exposures and the ir magnitude. Thus, in this assessment, because
the HEC 99 

### is more conservative, a benchmark MOE will be 30 ( i.e., based on a factor of 10 for intraspecies variability and uncertainty and a factor of 3 for the pharmacodynamic portion of
the interspecies extrapolation factor ; the latter being reduced based on the kinetic modeling performed to arrive at an HEC).

The equation for cancer risk estimation is presented below. Estimates of cancer risks should be interpreted as the incremental probability of an individual developing cancer over a lifetime as a result of exposure to the potential carcinogen ( i.e. , incremental or excess individual lifetime cancer risk).

Risk = Human Exposure × IUR

Risk = c ancer risk (unitless)

Human e xposure = h uman exposure estimate (μg/m 3 

### )

IUR = i nhalation unit risk (4.1 × 10 -6 

### per μ g/m 3 

### ) 22



### Risk Estimates for Acute (Short

- Term) and Chronic ( Repeated ) Exposures to TCE

Small Commercial Degreaser Scenario
Table 3 -21 presents the results of calculating the non

- cancer risk estimate for the small commercial degreaser exposed to TCE using the MOE method. Calculations were made for different exposure scenarios ( i.e., acute and chronic, user and bystander, with and withou t
LEV ). Six different hazard endpoints were evaluated and for each one the lowest HEC 99 

### was used from among the available inhalation studies (see Table 3

- 17)

.

22 The IUR is 4.1 × 10 -6 per μ g /m 3 ; which converts to 4.1 × 10 -6 per 0.2 ppb (or 0.0002 ppm)

, which in turn is (4.1 × 10 -6 )(5

, 000) [conversion factor to make the unit risk per ppm for ease in calculation) = 2 × 10 - 2 per ppm.

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### The results show that there are potential non

- cancer risk concerns for all endpoints and for both acute and chronic exposure conditions when the lowest HEC 99 

### POD is used. Table 3 -19 also presents a higher HEC 99 

### POD value as well as a range of H EC 50 

### values. If these valu e s are used, there would be changes in some scenarios ( i.e., see summary at t he end of this section
and Table 3-26 ). Though there is a wide range of POD values for different inhalation endpoints

, the results suggest an important point about the relative sensitivity of different organ systems

. F or TCE, the most sensitive endpoints appear to be developmental toxicity and toxicity to the kidney and immune system; neurotoxicity and reproductive toxicity are estimated to be 10
times less sensitive , whereas liver toxicity is approximately 100 times le ss sensitive than those endpoints.

Table 3 -22 presents the excess lifetime cancer risk to TCE using the exposure assumptions identified previously and the US EPA (2011c ) IRIS IUR value for cancer potency for the small commercial degreaser/bystander exposure scenarios. The values indicate that all estimated cancer risks are above concern levels for either the occupational setting (1 × 10 -5 

### ) or the general population (1 × 10 -6 

### ). Again, the non

- users represent individuals who are nearby where the actual work is being done, but are not directly involved in use of product

.

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Page 62 Table 3 -21 . TCE Noncancer Risk Estimates for Small Commercial Degreasers and Non

- users: Using the Lowest 99th Percentile HECs (Numbers are MOEs) 1,2

Expo

sure Dura

tion Hazard
Value 2 Degreaser Worker Degreaser Bystander
With LEV 3 Without LEV With LEV Without LEV Typical Worst

- Case Typical Worst

- Case Typcial Worst

- Case Typical Worst

- Case Exposure Values 4 ↓ → Endpoint of
Concern 2 ppm 6 ppm 17 ppm 63 ppm 1 ppm 5 ppm 9 ppm 55 ppm

Acute 4.8 Neurotoxicity 2.4 0.8 0.3 0.08 4.8 1.0 0.5 0.09

6.2 Developmental Toxicity 3.1 1.0 0.4 0.1 6.2 1.2 0.7 0.1

Chronic 9.1 Liver 4.6 1.5 0.5 0.1 9.1 1.8 1.0 0.2

0.013 Kidney 0.007 0.002 0.0008 0.0002 0.013 0.003 0.001 0.0002

11 Immune System 5.5 1.8 0.6 0.2 11 2.2 1.2 0.2

0.5 Male Reproductive System 0.3 0.08 0.03 0.008 0.5 0.1 0.06 0.009

1 All values are rounded for simplicity. See text for further explanation about MOEs; all bolded values are considered to represent potential risk concern

. 2 All values are in ppm and represent the lowest HEC 99 from an inhalation study for the endpoint listed.
3 LEV = loca l exhaust ventilation

4 The two numbers represent typical and worst case as 8 hour TWA in ppm. See text under Exposure Assessment for details

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Page 63 Table 3 -22. TCE Cancer Risk Estimates for Small Commercial Degreasers and Non

- users (Numbers are Extra Lifetime Cancer Risk and Bolded Vales Represent Concern
Typical Exposure Values a Worst

- Case Exposure Values a

Degreaser (I nhalation ) Degreaser Bystander (I nhalation ) Degreaser (I nhalation ) Degreaser Bystander (I nhalation )

With LEV Without
LEV With LEV Without
LEV With LEV Without
LEV With LEV Without
LEV

Estimated

e xposure l evels (concentration in air in ppm) 2 17 1 9 6 63 5 55

Cancer r isk b 1.3 × 10 - 3 >10 - 2 6.6 × 10 - 4 5.9 × 10 - 3 4.0 × 10 - 3 >10 - 2 3.3 × 10 - 3 >10 - 2

a The two numbers represent typical and worst case as 8

- hour TWA in ppm. See text under Exposure Assessment for details.

b Excess l ifetime c ancer risk calculated as follows u sing California Environmental Protection Agency methodology ( CalEPA, 2007 ) : Excess Lifetime Risk = ( c onc entration in μ g/ m 3 )(2 h ou rs /24 h ou rs )(5 d ays /7 d ays )(50 w ee ks /52 w ee ks )(40 y ea rs /

70 y ea rs )( IUR per μ g/ m 3 ). The IUR value from US EPA (2011c ) IRIS is 4.1 × 10

P -6

P per μ g/m

P 3

P , which converts to
4.1 × 10

P -6

P per 0.2 ppb (or 0.0002 ppm) and in turn is (4.1 × 10

P -6

P )(5

, 000) ( conversion factor to make the unit risk per ppm for ease in calculation) = 2 × 10

P - 2

P per ppm. Thus, for each exposure value above, the excess lifetime cancer risk = (exposure concentration in ppm)(0.033)(2 × 10

P -2

P per ppm)

, where the 0.033 is the product of (2 h ou rs /

24 h ours )(5 d ays /7 days) (50 weeks/52 week) (40 years/70 years). A cell’s notation that the excess lifetime cancer
risk is “>10

P -2

P ” indicate s that the average daily lifetime exposure is larger than the value at which the linear approximation ceases to apply (the threshold value is 15.2 ppm

, which is (1 × 10

P -2

P )(IUR)).



### Consumer (Hobbyist Degreaser and Arts and Crafts Clear P rotective C oating S pray User) No chronic risk concerns were identified for these scenarios, based on the following assumptions : 1) the half

- life data in humans , and 2) the duration of 0.5 or one hour per event,
which occurs once per week for the arts/crafts user two times p er month for the consumer hobbyist degreaser use

. Because only acute exposure scenarios are expected , the two endpoints of concern are neurotoxicity (both genders and all ages) and developmental toxicity (women of child

- bearing age).

Table 3 -23 presents the results of calculating the acute, non

- cancer risk estimate for the hobbyist degreaser, arts/crafts user, and non

- users exposed to TCE using the MOE method and neurotoxicity as an endpoint of concern. Results show no risk concern for non

- users of the clear protective coating spray; all other scenarios show risk concerns (clear protective spray users and degreaser user and non

- user).

Because the neurotoxicity endpoint of concern used to derive the POD was observed in adult animals (change in wakefulness), it is likely that the younger ages in Table 3 -23 may respond differently (in terms of dose, magnitude or response, or different response). Thus, the MOEs presented in Table 3 -23 may under

- estimate risk to these age groups for this endpoint.

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Page 64 Table 3 -23 . TCE Non

- cancer Risk Estimates for Use of Two Hobbyist Products Indoors at Residences: Neurotoxicity as Endpoint of Concern and Using the Lowest 99 th Percentile
HECs and 24

- Hour Average Exposure Concentrations (Numbers are MOEs]) 1

. Ages
of Ind. (yrs) Clear protective
coating spray

User Clear protective
coating spray non

user Solvent degreaser

user Solvent degreaser

non

- user

4.8 2 4.8 4.8 4.8

<1 NA 3 48 5 NA 6 7

1-2 NA 48 NA 6

3-5 NA 48 NA 6

6- 10 NA 48 NA 6

11

- 15 NA 48 NA 6

16

- 20 12 4 48 2 6 6

> 21 12 48 2 6

1 All values are rounded for simplicity. See text for further explanation about acceptable MOEs; all bolded values are considered to represent risk concerns

. 2 The lowest HEC 99 for neurotoxicity from an inhalation study is presented (in ppm).

3 NA = not applicable. Individuals less than 16 years old are assumed to not use either TCE

- containing product.

4 The exposure value used was 0.4 ppm

5 The exposure value used was 0.1 ppm

6 T he exposure value used was 2 ppm

7 The exposure value used was 0.8 ppm



### Table 3 -24 presents the results of calculating the acute, non

- cancer risk estimate for the hobbyist degreaser, arts/crafts user, and non

- users exposed to TCE using the MOE method and developmental toxicity as an endpoint of concern. For these scenarios, only women of child

bearing age are considered the population of concern

. As with the neurotoxicity endpoint,
results show no risk concern for non

- users of the clear protective coating spray; all other
scenarios show risk concern s (clear protective spray users and degreaser user and non

- user.

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Page 65 Table 3 -24

. TCE Non

- cancer Risk Estimates for Use of Two Hobbyist Products Indoors at
Residences: Developmental Toxicity as Endpoint of Concern Using the Lowest 99 th Percentile HECs
and 24

- Hour Average Exposure Concentrations (Numbers are MOEs) 1

Population of
Concern Clear Protective Coating Spray
User Clear Protective Coating Spray Non

user Solvent Degreaser
User Solvent Degreaser
Non

- user

6.2 2 6.2 6.2 6.2

Women of child

bearing age 16 3 62 4 2 5 8 6

1 All values are rounded for simplicity. See text for further explanation about acceptable MOEs ; all bolded values are considered to represent risk concerns

. 2 The lowest HEC 99 for developmental toxicity from an inhalation study is presented (in ppm).

3 The exposure value used was 0.4 ppm

4 The exposure value used was 0.1 ppm

5 The exposure value used was 2 ppm

6 The exposure value used was 0.8 ppm



### Summary

T his risk assessment focused on three exposure scenarios for TCE: small commercial degreasing operations; consumer use of an aerosol degreaser; and the consumer use of a clear protective coating spray in an arts/crafts home setting. Assumptions and estimations on the exposur e values used have been presented, and the associated uncertainties are described below. Only the inhalation route of exposure was considered in this risk assessment.

On the hazard side of the risk equation, OPPT used the literature review and analyses

pe rformed by the US EPA ’s IRIS program to identify 12 inhalation studies considered relevant for this particular assessment. Relevancy was primarily based on the route of exposure (inhalation). In addition, the TCE database is robust

, and there is evidence for a variety of
adverse effects in animals

, and potentially, humans. For inhalation studies, these include effects that may be elicited following a single, or short

- term exposure ( e.g., neurotoxicity and developmental toxicity)

, as well as effects associa ted with long

- term or chronic exposures ( e.g., immunotoxicity, kidney toxicity, liver toxicity, reproductive effects in males and cancer [kidney, liver, and NHL).

This risk assessment, using MOEs for all non

- cancer effects and the IRIS IUR for cancer effe cts
, identified risk s for virtually all scenarios (see Table 3 -25 ).

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Page 66 Table 3 -25 . Summary of Overall Risk Assessment for TCE Using the
Lowest 99 th Percentil e HECs

Exposure Category Chronic Non

Cancer Risk? Acute Non

Cancer Risk? Cancer Risk?

Small Commercial Degreaser operator (user) YES YES YES

Small Commercial Degreaser operator (non

- user) YES YES YES

Consumer Degreaser (user) Not Applicable YES Not Applicable
Consumer Degreaser (non

- user) Not Applicable YES Not Applicable

Consumer Clear Protective Coating Spray (user) Not Applicable YES Not Applicable

Consumer Clear Protective Coating Spray (non

- user) Not Applicable NO Not Applicable



### The range of estimated exposure values for the worker and consumer scenarios are:

• Small commercial degreaser worker user: from 2

- 63 ppm (30 × difference)

• Small commercial degreaser non

- user: from 1

- 55 ppm (55 × difference)

• Consumer degreaser user/non

- user: from 0.8 - 2 ppm (~2 × difference)

• Consumer clear protective coating spray user/non

- user: from 0.1 - 0.4 ppm (4 × difference)

T he range of hazard values used in the risk assessment (using the lowest HEC 99 

### value in the

range reported for each major target organ/endpoint ) was < 2 for the acute toxicity endpoints

a nd almost 1,000 for the chronic toxicity endpoints:

• Acute toxicity: 4.8 – 6.2 ppm (neurotoxicity and developmental toxicity, respectively)

• Chronic toxicity: 0.013 – 9.1 ppm (for kidney and liver toxicity, respectively).

Although there may be some differences in the risk outcome if alternate exposure values were available, given the ranges seen ( i.e., 55x being the highest), this difference is only slightly higher than an order of magnitude. However, there are many different hazard values that could
also be used and , if used, would likely present a different risk profile for the scenarios that are
the focus of this assessment.

Although not presented quantitatively, Table 3 -26 presents the results of the risk assessment if
different HEC values were used . In Table 3 -19 , in order to provide an indication of the variability in the HEC predictions, the range of hazard values for the “typical” human (the 50 th 

### percentile
or HEC 50 

### ) is also presented. As explained earlier, the terms “low

- end” and “high

- end” represent
the minimum and maximum values for the data sets within each major target organ/endpoint. Thus, if one were to take three other sets of hazard values (the high

- end HEC 99 

### , the low

- end

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Page 67 

### HEC 50 

### , and the high

- end HEC 50 

### ), the qualitative results are presented in Table 3 -26 . Examples
for each “alterna te” hazard value used are presented below:

• T he high

- end HEC 99 

### value in the range reported in Table 3 -19 for each target organ/endpoint ( i.e., the 99 th 

### percentile represents a “sensitive” human HEC; an example value is 19 ppm for the liver [the low

- end H EC 99 

### used in Tables 3

- 20 was 9.1 ppm]).

• T he low

- end HEC 50 

### value in the range reported in Table 3 -19 for each target organ/endpoint ( i.e., the 50 th 

### percentile represents a “typical” human HEC; an example
value is 25 ppm for the liver).

• The high

- end HEC 50 

### value in the range reported in Table 3 -19 for each target organ/endpoint ( i.e., the 50 th 

### percentile represents a “typical” human HEC; an example value is 53 ppm for the liver).

Though complicated given all the permutations 23



### , EPA draws some generalizations

, including :

• If evaluated by “typical” or “sensitive” HEC:

o T he lower

- end HEC 50 

### shows risk for all scenarios/endpoints except for the acute clear protective coating spray user and non

- user scenarios;

o The higher

- end HEC 50 

### and higher

- end HEC 99 

### values show no risk concern fo r some scenarios (see Table 3 -26 ) and some endpoints (reproductive toxicity, immunotoxicity, and liver toxicity)

• If evaluated by user/non

- user scenario:

o If any of the three alternate HEC value s listed above is used (except for development al toxicity for the higher

- end HEC 99 

### value) for the clear protective coating spray user/non

- user scenario, there is no risk concern

• If evaluated by acute effect endpoint:

o Risk concern for neurotoxicity does change from “risk” to “no risk” for all
scenarios except for the worker and co nsumer degreaser when the lower

- end
HEC 50 

### is used

• If evaluated by chronic effect endpoint:

o There is no change in risk estimates for kidney effects regardless of the HEC
value used

o Some risk concerns are alleviated depending on the HEC value used for reproductive toxicity and immunotoxicity, and, to a lesser extent, liver toxicity

Even with these alternative analyses , the results suggest concern for most scenarios that were
the foc us of this risk assessment except perhaps for the clear protective coating spray in the
case of non

- user s. In terms of acute effects, neurotoxicity seems less of a concern than

23 Four different hazard values (the lowest HEC 99 ; the primary value used in this risk assessment) plus three other
measures as shown in Table 3

- 19 . Especially for the worker scenario: typical vs. worst

- case, with and without LEV,
user and non

- user, two acute endpoints and four chronic endpoints. For the consumer scenarios it is less complicated (user and non

- user).

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Page 68 

### developmental toxicity. For the chronic effect endpoints, the kidney hazard val ue appears to be the predominant concern regardless of HEC value chosen ( i.e. , kidney toxicity seems to be the most sensitive chronic endpoint).

In terms of cancer risk assessment, use of the IRIS IUR suggests risk to workers/non

- users regardless of their potential exposure ( i.e., from a low of 1 ppm up to the highest exposure estimate of 63 ppm).

Table 3 -26 . Changes in the Non

- Cancer MOEs If Different HECs are Used a

Exposure Category Change in Chronic Risk With... Change in Acute Risk With...

Higher

- End
HEC 99 Lower

- End
HEC 50 H igher

- End
HEC 50 Higher

- End
HEC 99 Lower

- End
HEC 50 Higher

- End
HEC 50
Small Commercial Degreaser operator (user) YES b NO b YES - YES NO YES

Small Commercial Degreaser operator (non

- user) YES NO YES YES NO YES

Consumer Degreaser (user)

Not Applicable (N/A) YES NO YES

Consumer Degreaser (non

- user) YES NO YES

Consumer Clear Protective Coating Spray (user) YES YES YES

Consumer Clear Protective Coating Spray (non

- user) NO NO NO

a HEC 50 represents the typical human HEC; HEC 99 represents the sensitive human HEC. the terms “low

- end” and “high

- end” represent the minimum and maximum values for the data presented in Table 3

- 19. Changes are meant to
be from the non

- cancer MOEs listed in Table s 3

- 21, 3

- 23 and 3

- 24.

b In general, a “YES” means a change in one or more risk values from “potential risk” to “no risk”. A “NO” means there were no changes from the risk assessment as presented in the main body of this risk assessment.

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Page 69 

## D. D ISCUSSION OF 

## K EY 

## S OURCES OF 

## U NCERTAINTY AND 

## D ATA 

## L IMITATIONS

Uncertainties in the E xposure A ssessment

The production volume and release information on TCE are estimates

, actual TCE production or import into the US may differ from these estimates

. The 2011 production volume and use data reported here ( Glauser and Funda, 2012 ) are rece nt and considered reliable. It seems clear that the vast majority of the TCE used in the US is as an intermediate for the production of a refrigerant and the second highest use (in terms of production volume) is as a degreaser.
Confidence in the remaining uses ( i.e.

, <2 percent of the production volume) is less certain.

For small commercial /industrial degreasing facilities, environmental releases of and workplace exposures to TCE were estimated based on several data sources ( i.e., NAICS, NEI

, and TRI)

. Furt h er, certain assumptions were made in developing these estimates ( e.g. , effectiveness of workplace controls, operating hours, number of workers per facility, the number of small commercial/industrial facilities ) and various “what

- if” scenarios w ere evaluated to quan t ify “typical” and “worst

- case” workplace exposure estimates. Though the uncertainty in these assumptions was not extensively evaluated, EPA did compare its rele a se and exposure estimates to values in the literature; EPA estimates and literature values were of the same order of magnitude. For the purposes of this assessment, “typical” and “worst

- case” estimates represent exposure values to which workers are likely exposed to during (1) routine working
conditions

, and (2) non

- routine (ep isodic) working conditions, respectively.

Although TCE products intended for use by consumers were found by EPA, t here is some uncertainty in terms of the nature and extent of the consumer use of TCE in general. Furthermore, for the exposure estimations in this risk assessment, the use patterns assumed for the two hobbyist products, including mass of product used per event, duration of event, and events per year, are hypothetical and are not based on consumer product survey data.
Therefore , they are likely the source of the greatest uncertainties/data gaps in the exposure estimates for the two hobbyist products. However, there is a high degree of confidence in the consumer product weight fractions identified for the two hobbyist products evaluated in this assessment. Also, there is a medium to high degree of confidence in certain modeling inputs to
the E

- FAST /CEM model, including vapor pressure, molecular weight, room volumes, wh ole house volume, air exchange rate, body weight, and inhalation rate.

Because the E

- FAST 2 /CEM model output s for exposure to the user and non

- user hobbyist scenarios are reported in mg/kg

- bw /day, it was necessary to convert these values to air
concentrati on s (ppm) in order to perform the non

- cancer and cancer risk assessment. This
conversion introduces some uncertainty, but it is not apparent whether it may over - or under

estimate exposure s.

Finally, although it was assumed that dermal exposure to the TC E use scenarios was less significant compared with the inhalation exposure, EPA expects dermal exposures under some

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Page 70 

### conditions. Thus, total exposure may be underestimated because combining dermal and inhalation exposures was not done in this risk assessme nt

. This would likely be an issue of concern in those exposure scenarios which resulted in a “no

- risk” finding . A dditiona l exposure via the dermal route could lead to an alternative risk finding. However, use of the lower

- end
HEC 99 

### value for hazard – which represents a sensitive human HEC – does provide a certain
amount of conservatism that can provide a counterweight to not considering dermal exposure.

Uncertainties in the H azard A ssessment

The hazard information available on TCE is quite large and includes many studies with both
humans and animals. Virtually all of the information on TCE hazard for this risk assessment was taken from the recent IRIS publication ( US EPA, 2011c ) , in which dozens of pages are devoted to discussions of uncertainty throug hout the document 24



### . Only the uncertainties germane to the specifics of this risk assessment are discussed

.

In developing an RfC or RfD, uncertainty is captured by the use of uncertainty factors (UFs).

D epending on the POD, UFs of between 10 and 1, 000 were used to derive candidate RfD/RfCs. In this risk assessment, rather than using a single value ( i.e. , the RfC) to evaluate inhalation exposures for the scenarios identified, it was decided to evaluate the range of data evaluated by the IRIS program to derive the RfC. This resulted in the identification of 32 PODs from 27
studies for use in the non

- cancer risk assessment ; of which 17 PODs from 12 inhalation studies
were chosen and from which six hazard values were identifi ed for use in this risk assess ment

. The PODs covered both acute ( i.e., neurotoxicity and developmental toxicity) and chronic ( i.e., liver, kidney, immunotoxicity, reproductive toxicity) endpoints. For the cancer risk assessment,
the IRIS IUR was used.

The use of PODs for each major adverse effect

, adds a level of confidence to the hazard and risk
assessment. Because the database for TCE exposure s to animals and humans is very robust

, using specific adverse effect s with the appropriate exposure scenario s raises the confidence
that th e risk estimations are relevant for real world exposures

.

As pointed out in the IRIS T oxicological Review ( US EPA, 2011c )

, there is uncertainty associated
with each POD

. 25 

### In this risk assessment

, these individual UFs may be minimized given that EPA used a maximum value for each endpoint type for the inhalation studies used in our analysis

. By focusing only on inhalation studies and using lower

- end HEC 99 

### values, OPPT has increased

24 For example, the confidence pertaining to the knowledge of the metabolism of TCE in both animals and humans will not be discussed here. The PBPK model developed for TCE tries to take this into account. Associated with the metabolism issue is the uncertainty of extrapolating from one route of exp osure to another; which is one reason why OPPT chose to use only the inhalation studies identified by IRIS.

25 UFs = uncertainty factors; UF L = uncertainty in extrapolating from a LOAEL to a NOAEL; UF A = uncertainty in extrapolating from animals to humans (“interspecies UF”); UF H = uncertainty to address variation in human susceptibility (“intraspecies UF”); UF s = uncertainty in extrapolating data from less

- than lifetime studies;
UF D = uncertainty due t o incomplete database.

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Page 71 

### the likelihood that risks are not under

- estimated. Furthermore, use of the l ower

- end HEC for
th e 99 th 

### percentile , although conservative, presents an interesting picture of the likely hazard of
TCE. As seen below, there is an approximate1000

- fold difference between the lowest (0.013 ppm) and highest ( 11 ppm) lower

- end HEC 99 

### :

• Neurotoxicity = 4.8 ppm

• Developmental Toxicity = 6.2 ppm

• Liver toxicity = 9.1 ppm

• Kidney toxicity = 0.013 ppm

• Immune s ystem = 11 ppm

• Male reproductive toxicity = 0.5 ppm

By choosing only one of these values ( e.g., the lowest), the risk picture would be quite different than if another ( e.g., the highest) single value is used; there is a 1000

- fold difference between
these two values. However, by presenting all six endpoints in the context of the exposure duration of concern, a “full” hazard/risk picture is observed.

As s hown in Table 3 -26 , using different HEC 50 

### and HEC 99 

### values does change the risk picture somewhat for some exposure scenarios; primarily eliminating acute effect risk concerns for neurotoxicity for consumer users and non

- users of both the degreaser and clea r protective coating spray scenarios. However, regardless of the hazard value used within the bounds identified in this assessment, chronic effects concerns continue to exist for the small
commercial worker for most scenarios

, and for all scenarios with kidney toxicity as the endpoint
of concern.

Uncertainties in the Risk Assessment

The uncertainties discussed above for both the exposure and hazard portions of this risk
assessment can be discussed in a qualitative manner. First, the range of values in the exposure
estimations for the worker and consumer scenarios is not large

. Including all scenarios for users and non

- users, the range in exposure values for the worker (1 to 63 ppm)

, and the two

consumer uses (0.1 to 2 ppm) is between 60 and 20 fold, respectively. The hazard values ( i.e., using the lowest HEC 99 

### values) ranged from <2 to almost 1,000 for the acute toxicity endpoints
and for the chronic toxicity endpoints , respectively :

• Acute toxicity: 4. 8 to 6.2 ppm (neurotoxicity and developmental toxicity, respectively)

• Chronic toxicity: 0.013 to 9.1 ppm (for kidney and liver toxicity, respectively).

Thus, understanding that the exposure estimates may be an over - or under

- estimation, the
choice in the hazard value used will likely have a greater influence on the outcome of the risk
assessment for the uses discussed in this risk assessment.

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## C ONCLUSIONS

TCE is a volatile organic compound that is produced/imported into the US in large quantities ( i.e., >250 million lb s per year ), the majority (~85 percent) of which is used as an intermediate chemical for manufacturing refrigerant chemicals. Much of the remainder ( i.e., ~15 percent ) is used as a solvent for metals degreasing. A relatively small percenta ge ( i.e., ~2 percent ) is used in a variety of applications

, including as a solvent for metal degreasing by consumers who work on their own cars, bikes, etc. ( i.e. , DIY hobbyists) and as an ingredient in other hobbyist products, including a clear protective coating spray used in the arts/crafts field, a film cleaner, a toner aide, and a mirror edge sealant. EPA ’s assessment focused on uses of TCE as a degreaser
both in small commercial settings and consumers , and the consumer use of TCE in a clear protective coating spray by indivi duals in the arts/crafts field

.

The results of this risk assessment indicate possible acute and chronic non

- cancer risk concerns for occupational ( i.e., small commercial settings) degreaser s and bystanders (n on

- users)

. There
are also cancer risk concerns for this population:

• For the commercial degreaser user and non

- user, non

- cancer MOEs were less than 30 (potential risk concern) for acute toxicity effects ( i.e., developmental toxicity and neurotoxicity) an d chronic effects ( i.e., liver, kidney, and immune system effects).

• For the commercial degreaser user and non

- user, using the IRIS IUR, the cancer risks were all below the benchmark value ( i.e., potential risk concern).

Results of evaluating the two consumer use products suggest acute, non

- cancer risks to users of
both types of product s for both developmental toxicity and neurotoxicity

. For non

- users, EPA ’s analysis suggests there is potential concern for the degreaser exposure scenario (for both developmental toxicity and neurotoxicity ); whereas no concern was identified for either effect for the clear pro tective spray non

- user scenario:

• For the hobbyist de greaser user and non

- user and for the hobbyist clear protective spray users, the acute, non

- cancer MOEs for developmental toxicity were less than 30 (potential risk concern).

• The hobbyist clear protective spray non

- user scenario resulted in an MOE of grea ter than 30 (no risk concern) for both developmental toxicity and neurotoxicity

The use of the consumer products is infrequent, and thus, EPA did not conduct either a chronic

non

- cancer or cancer risk assessment for these use scenarios.

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re lated issues. Notice, request for comments. Fed. Regist. 75 (59), 15500

- 15572.

US EPA (2011a). Letter to Lisa P. Jackon, EPA Administrator, Re: Review of EPA's draft assessment entitled "Toxicological Review of Trichloroethylene" (October 2009)

. US Environmental Protection Agency Science Advisory Board, Office of the Administrator, Washington, DC. EPA

- SAB

- 11

- 002.

US EPA (2011b). Vocabulary catalog list detail - Integrated Risk Information System (IRIS) glossary

. US Environmental Protection Agenc y, Office of Research and Development, National Center for Environmental Assessment, Washington, DC. http://ofmpub.epa.gov/sor_internet/registry/termreg/searchandretrieve/glossariesandkeywordlists/sea rch.do?details=&glossaryName=IRIS%20Glossary . Accessed November 4, 2012.

US EPA (2011c). Toxicological review of trichloroethylene (CAS No. 79

- 01

- 6). In support of summary information on the Integrated Risk Information System (IRIS)

. US Environmental Protection Agency, Integrated Risk Information System, Washington, DC. http://www.epa.gov/iris/s updocs/0199index.html

. Accessed November 7, 2012. EPA/635/R

- 09/011F.

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Page 83 US EPA (2011d). Expsoure factors handbook. Final

. US Environmental Protection Agency, Washington,
DC. http://cf pub.epa.gov/ncea/risk/recordisplay.cfm?deid=236252 . Accessed September 5, 2012. EPA/600R

- 090052F.

US EPA (2011e). Toxic chemical release inventory reporting forms and instructions. Revised 2011
version

. US Environmental Protections Agency. EPA260R10001.

US EPA (2012a). Estimation Programs Interface Suite for Microsoft Windows, v4.10

. US Environmental Protection Agency, Washington, DC. http://www.epa.gov/opptintr/exposure/pubs/episuite dl.htm

. Accessed November 7, 2012.

US EPA (2012b). AEGL program

. US Environmental Protection Agency, Office of Pollution Prevention and Toxics, Washington, DC. http://www.epa.gov/oppt/aegl/ . Accessed October 30 , 2012.

US EPA (2012c). TSCA work plan chemicals

. US Environmental Protection Agency. http://www.epa.gov/oppt/existingchemicals/pubs/workplans.html . Accessed November 9, 2012.

Vernon, R. J., and Ferguson, R. K. (1969). Effects of trichloroethylene on visual motor performance. Arch.
Environ. Health 18 , 894

- 900. (as cited in US EPA, 2008a).

Wackett, L. P., Brusseau, G. A., Householder, S. R., and Hanson, R. S. (1989). Survey of microbial oxygenases: trichloroethylene degradation by propane

- oxidizing bacteria. Appl. Environ. Microbiol.
55 (11), 2960

- 2964.

Wadden, R. A., Scheff, P. A., and Fra nke, J. E. (1989). Emission factors for trichloroethylene vapor degreasers. Am. Ind. Hyg. Assoc. J. 50 (9), 496

- 500.

Wakeham, S. G., Davis, A. C., and Karas, J. A. (1983). Mesocosm experiments to determine the fate and persistence of volatile organic comp ounds in coastal seawater. Environ. Sci. Technol. 17 (10), 611

- 617.

Weast, R. C., and Selby, S. M. (1966). Ethene, trichloro

- . In CRC Handb. Chem. Phys. 47th ed., p. C

- 314. The Chemical Rubber Co, Cleaveland, OH.

Wilson, J. T., and Wilson, B. H. (1985). Biotransformation of trichloroethylene in soil. Appl. Environ.
Microbiol. 49 (1), 242

- 243.

Woolhiser, M., Krieger, S., Thomas, J., and Hotchkiss, J. (2006). Trichloroethylene (TCE): Immunotoxicity potential in CD rats following a 4

- week vapor inhalation e xposure . Unpublished report, Midland, MI. (as cited in US EPA, 2011c).

Xu, H., Tanphaichitr, N., Forkert, P., Anupriwan, A., Weerachatyanukul, W., Vincent, R., Leader, A., and Wade, M. (2004). Exposure to trichloroethylene and its metabolites causes impa irment of sperm fertilizing ability in mice. Toxicol. Sci. 82 , 590

- 597. (as cited in US EPA, 2011c).

Xu, J. Q., Kochanek, K. D., Murphy, S. L., and Tejada

- Vera, B. (2010). Deaths: Final Data for 2007

. National Center for Health Statistics, Hyattsville, MD

. http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_19.pdf

. Accessed November 9, 2012.

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Page 84 Xu, X., Yang, R., Wu, N., Zhong, P., Ke, Y., Zhou, L., Yuan, J., Li, G., Huang, H., and Wu, B. (2009 ). Severe hypersensitivity dermatitis and liver dysfunction induced by occupational exposure to trichloroethylene.
Ind. Health 47 , 107

- 112. (as cited in US EPA, 2011c).

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Page 85 

# Appendices

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Page 86 

## Appendix A **: Regulatory History of TCE at the US EPA** 

The purpose of this section is to provide a brief regulatory history of TCE from the perspective
of the EPA. TCE has been subject to 25 final rules and notices issued by the Agency from 1979
to 2009 that were relevant or significant with regard to TCE. T hese 25 rules and notices were promulgated by EPA’s OAR, OPPT, OSWER, and OW.

OW initially identified TCE as a “toxic pollutant” in 1979 ( US EPA, 1979b )

. TCE was classified as a “priority pollutant” in 1982 and no discharges of TCE were allowed from steam electric power generating point sources ( US EPA, 1982 )

. OW then established a non

- enforceable maximum contaminant level goal (MCLG) of 0 mg/L for TCE in 1985 ( US EPA, 1985b )

. Two years later, OW

set a maximum contaminant level ( MCL ) of 0.005 mg/L for drinking water ( US EPA, 1987a ) and
set an effluent limitation of 69 μg/L maximum per day and 26 μg/L maximum per month average for new and existing sources discharging to POTWs from the organic chemicals, plastics, and synthetic fibers industrial category ( US EPA, 1987b )

. The following year, 1988 , OW prohibited injection of TCE into class I underground injection wells ( US EPA, 1988 )

. TCE was identified by OW as a bioaccumulative chemical of concern pollutant in 1995 for a final water quality guidance for the great lakes system. This established water quality criteria for protection of human health by sett ing a human cancer value (HCV) of 29 μg/L for drinking
water and 370 μg/L for non

- drinking water for the G reat L akes system ( US EPA, 1995 )

. Then, in
1998 , OW identified TCE as a possible human carcinogen by establishing a national primary drinking water regulation that specified the following consumer confidence report health effect language: “some people who drin k water containing trichloroethylene in excess of the MCL [0.005 mg/L] over many years could experience problems with their liver and may have an increased risk of getting cancer ” ( US EPA, 1998d ) . OW identified TCE’s major sources in drinking water originating from “discharge from metal degreasing sites and other factories ( US EPA, 1998d ) .” OW is currently evaluating and revising TCE’s MCL based upon analytical feasibility ( US EPA, 2010 )

.

OAR has listed TCE as a HAP from several different industrial emission sources in multiple rules ( US EPA, 1985a , 1986 , 1994b , 1998c , 2001b , 2002 , 2003 , 2004 , 2007c , 2009 ) as well as a “probable or possible human carcinogen” from operations including printing, coating, and dyeing of fabrics and other textiles ( US EPA, 2003 )

. OAR classified TCE as a group I chemical for emission standards for equipment leaks in the synthetic organic chemical manufacturing industry ( US EPA, 1994a )

. In addition, OAR identified TCE as a s ubstitute for two ozone depleting chemicals, methyl chloroform and CFC

– 113, for metals, electronics, and precision cleaning, in 2007 ( US EPA, 2007d )

.

OSWER set a reportable quantity of 100 lb s (45.4 kg) for releases of TCE from vessels or
facilities in 1989 ( US EPA, 1989 )

. OSWER also set a minimum required detection limit for TCE of
37 mg/kg for hazardous waste combustors in 1998 ( US EPA, 1998b )

.

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Page 87 

### Although OPPT has only issued two notices relevant to TCE ( US EPA, 1994c , 2000 ) , other voluntary information collection activities for TCE have occurred in the past. These activities were primarily the result of two separate but related voluntary information collection activities: data gaps identified by ATSDR ( US EPA, 1994c ) and data gaps identified for pilot chemicals for EPA’s Voluntary Children’s Chemical Evaluation Program (VCCEP) ( US EPA, 2000 )

.

EPA published a notice for voluntary solicitati on of testing proposals in order to be considered for an enforceable consent agreement (ECA) negotiation in 1994 for 12 substances, including
TCE ( US EPA, 1994c )

. T his notice was based on data gaps identified by ATSDR in coordination
with EPA. After ATSDR updated its data needs for TCE in 1999 ( ATSDR, 1999 ) , the Halogenated Solvents Industry Alliance, Inc. (HS IA) responded with its intent to fulfill four of seven identified data needs. These four data needs included developmental neurotoxicity, developmental toxicity, immunotoxicity, and neurotoxicity via the oral route. HSIA entered into a
memorandum of unde rstanding (MOU) with ATSDR in June of 2001 to fulfill these four data
needs.

Over the course of the next several years, from 2001 to 2007 , HSIA completed and submitted two studies to the Agency: a developmental toxicity and an immunotoxicity study via th e inhalation route in rats. These two studies had been planned to be extrapolated to the human oral route using PBPK modeling. In addition, HSIA had planned to fulfill the data need for neurotoxicity via the oral route using PBPK modeling of existing published data from the
inhalation route. Also, HSIA had planned to conduct a developmental neurotoxicity study in

rats via the oral route. HSIA did not fulfill its MOU for these four planned studies due to several factors, including problems securing an ap propriate lab, discontinuation of a strain of rat previously used in their completed studies, and discrepancies with ATSDR regarding the completeness of the three aforementioned studies using PBPK modeling.

Since 2008 , no further action has been taken by OPPT with regards to TCE and its existing data gaps identified by ATSDR.

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Page 88 

## Appendix B **: 2006**  **I nventory Update Rule**  **Data for TCE** 

The 2006 Chemical Data Reporting, or CDR, records indicate TCE production volume (PV) to be
100 to 500 Mlbs . Since all importers and manufacturers are not required to report, CDR data likely underestimates actual TCE PV. For the purposes of this draft assessment, the low end of TCE PV was taken to be 100 Mlbs/yr while the high end was taken to be 500 Mlbs/yr.

The data tables below were taken from ( US EPA, 2006b ).

Table B

- 1. US EPA 2006 IUR Data for TCE.
Company and Site Information

Company Site City State Zip Code Manufacture Import Site
Limited

Basic Chemicals Company, LLC Basic Chemicals
Co – Wichita
Plant Wichita KS 67215 Yes No No

Chemcentral Corporation Chemcentral
International Pompano Beach FL 33069 No Yes N/A

Ineos Chlor Americas, Inc. Ineos Chlor Americas, Inc. Wilmington DE 1981 0 No Yes N/A

JSL Chemical Corporation JSL Chemical Corporation Palm Beach FL 33480 No Yes N/A

Oxy Vinyl, LP Oxy Vinyls – LaPorte La Porte TX 77571 Yes No Yes

PPG Industries,
Inc. PPG Industries

– Lake Charles Lake Charles LA 70602 Yes No No

TR International, Incorporated TR International
Inc – Seattle Seattle WA 98101 No Yes N/A

The Dow
Chemical Company Dow Chemical

– Freeport, TX Freeport TX 77541 Yes No No

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Page 89 Table B

- 2. National Chemical Information

. Production v olume (aggregated) 100

- < 500 million lb s

Maximum c oncentration (at m anufacture or i mport site) > 90%
Physical forms(s) Liquid

Number of manufacturing, processing, and use sites (aggregated) ≥ 1, 000

Number of reasonably likely to be exposed industrial manufacturing, processing, and use workers (aggregated) ≥ 1, 000

Was industrial processing or use information reported? Yes

Was commercial or consumer use information reported? Yes

Table B

- 3. Summary of TCE Uses.

Type of Processing Industrial Sector (Based on NAICS) Industrial Function

Not readily obtainable (NRO) NRO NRO
Processing as a reactant CBI Intermediates

Processing as a reactant Industrial gas manufacturing Intermediates

Processing as a reactant Other basic organic chemical manufacturing Intermediates

Processing as a reactant Other basic organic chemical manufacturing Other

Processing; incorporation into formulation, mixture, or reaction product All other chemical product and preparation manufacturing Solvents (that become part of product formulation o r mixture)

Processing; incorporation into formulation, mixture, or reaction product Invalid data provided Adhesives and binding agents

Processing; incorporation into formulation, mixture, or reaction product Machine shops Solvents (for cleaning or degreasing)

Processing; incorporation into formulation, mixture, or reaction product Paint and coating manufacturing Solvents (that become part of product formulation or mixture)

Processing; repackaging Other basic organic chemical manufacturing Other

Processing; repackaging Other chemical and allied products merchant wholesalers Solvents (for cleaning or degreasing)

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Page 90 Table B

- 4. TCE Use Category Summary.

Commercial/Consumer Product Category Maximum Concentration in Related Consumer/Commercial Product Category Intended for Use in
Children’s Products in Related Product Category
Adhesives and sealants > 90% No

Lu br i cants, greases, and fuel
additives > 90% No

Paints and coatings 1

- 30% No
Other > 90% No

NRO NRO NRO

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Page 91 

## Appendix C **: NAICS Codes for TCE Degreasing** 

An analysis of the North American Industry Classification System (NAICS) identified 78 different industries (NAICS codes are listed in T able C-1 ).

Table C

- 1. TCE Used as a Degreaser Primarily in These Industries ( US Census, 2008 ).

NAICS Codes

33121 331210 332811 334413 336411

33272 331419 332812 334414 336413

33341 331421 332813 334417 336414

33422 332111 332912 334419 336510

33512 332112 332913 334513 337125

33531 332116 332919 334515 337127

33634 332117 332994 335121 339114

33641 33 2211 33 2996 335211 339992

33999 33 2212 33 2999 335312 339995

3 1499 9 332311 333132 335313 339999

3 2111 3 332313 333298 335911 488111

3 2311 6 332431 333311 335921 493110

3 2518 8 332510 333415 335929 8 1131 0

3 2599 8 33 2618 333921 335999 9 2811 0

3 2629 9 332721 333994 336321

331111 332722 333999 336340



### Each number listed is a different industry that may be associated with TCE/degreasing operations. Those interested may go to the following URL and type in a code

- http://www.census.gov/eos/www/naics/ ( US Census, 2008 ) 

### ). For example, the following results
are seen when the listed numbers are searched:

3 3121:

33121 Iron and Steel Pipe and Tube Manufacturing from Purchased Steel T

331210 Iron and Steel Pipe and Tube Manufacturing from Purchased Steel



### 332811 (results below slightly edited for simplicity)

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Page 92 Metal Heat Treating - This U.S. industry comprises establishments primarily engaged in heat treating, such as annealing, tempering, and brazing, and cryogenically treating metals and metal products for the trade.

Establishments primarily engaged in both fabricating and heat treating metal products are classified in the Manufacturing sector acco rding to the product made.

Annealing metals and metal products for the trade

Brazing (i.e., hardening) metals and metal products for the trade

Burning metals and metal products for the trade

Cold treating metals for the trade

Cryogenic treating metals for the trade

Hardening (i.e., heat treating) metals and metal products for the trade

Heat treating metals and metal products for the trade

Shot peening metal and metal products for the trade

Tempering metals and metal products for the trade

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## Appendix **D: Calculations for Small Commercial Worker**  **Degreaser Exposures**

In Figure E-1 , a solvent degreasing facility is partitioned into two zones: the n ear -f ield and the
f ar -f ield ( Keil et al. , 2009 ) . This is done because in occupational settings

, contam inant levels in
the n ear -f ield are considered to provide a better representation of a worker’s personal breathing zone than those in the f ar -f ield; potential worker exposures depend on how close a
worker is to the emission source. Also, for this risk assessment
, the far

- field exposures will represent bystanders, or non

- users. In other words, those individuals who are in the building (and perhaps even the room)

, but are not physically close to the volatile source as shown in Figure D- 1.

Figure D- 1. An Illustration of an Imperfectly Mixed Room; Near

- Field/Far

- Field Approximation of a Solvent Cleaning Facility; Potential Worker Exposures Depend on How Close a Worker is to the Emission (Volatile) Source.

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For the purposes of mass transfer from and to the n ear -f ield, the f ree s urface a rea , is defined to be the surface area that is available for mass transfer; the

, 

### will not necessarily be equal to the surface area of the n ear -f ield. For instance, if the n ear -f ield is defined to be a rectangular region, as illustrated in Figure D- 1, the n ear -f ield floor will not be available for mass
transfer ; thus

, the

, 

### will be less than the actual surface area of the n ear -f ield:

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Based on the model inputs in Table D-1 , potential workplace TCE inhalation exposure values can
be estimated for workers in the near

- field and for non

- users in the far

- field (see Table D-2 ). The majority of data regarding worker exposure to TCE was obtained from degreasing operations; the data indicated that exposure is likely to vary, although mean TWA concentrations were generally consistent and usual ly ranged from ≤50 to 100 ppm ( ATSDR, 1997 ) . This is similar to the exposure values presented in the EU Risk Assessment for TCE ( EC, 2004 ) . The “ t ypical” exposure values in Table D-2 are also similar, being of the same order of magnitude.

Table D- 1. Near

- Field/Far

- Field Model Inputs.

Parameter Units Parameter Values

Comments Small Industrial/
Commercial Facilities

Q FF ft 3 /minute 500 (worst case) 3,000 (typical) US EPA (1991 )

V NF cm/second 10 ~50 th percentile; Baldwin and Maynard (1998 )

L NF ft 10 Assumes volatile source is centered in the fear

field and worker activities are within 5 feet of the emitting source W NF ft 10

H NF ft 6 Adequate height to capture a typical worker’s breathing zone

FSA ft 2 180 Equation (5)

G g/minute 16.73 No local exhaust ventilation (LEV); see Table 3

- 7 in main body of this report.

G g/minute 1.67 With LEV; potential operating TCE emissions reduced by 90%; Wadden et al. (1989 )



### Results of the calculations are shown below in Table E-2.

Table D- 2. Potential W orkplace TCE I nhalation E xposures and N umber of W orkers E xposed; N o LEV.

Type of Facility Potential Workplace TCE Inhalation Exposures (8 -h ou r TWA)

Near

- Field Far

- Field
Typical (ppm) Worst Case (ppm) Number of
Workers Typical (ppm) Worst Case (ppm) Number of
Workers

Small i ndustrial/

c ommercial 17 63 7, 415 9 55 17

, 79 6



### The potential workplace inhalation exposures in Table D-2 do not take LEV into account. Engineering controls, such as LEV , are recommended if practical ( Arkema, 2011 ) . The use of

LEV can reduce potential operating TCE emissions into the workplace by approximately

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90 percent ( Wadden et al. , 1989 ) . Based on the model inputs in Table D- 1, potential workplace TCE exposures in the presence of LEV are presented in Table D- 3.

Table D-3

. Potential W orkplace TCE I nhalation E xposures and N umber of W orkers E xposed; W ith LEV.

Type of Facility Potential Workplace TCE Inhalation Exposures (8 -h ou r TWA)

Near

- Field Far

- Field
Typical (ppm) Worst Case (ppm) Number of
Workers Typical (ppm) Worst Case (ppm) Number of
Workers

Small i ndustrial/

c ommercial 2 6 7

, 415 1 5 17

, 79 6

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## Appendix **E: Converting E** 

**- FAST ADRs to Concentration in Air** 

The exposure values generated using the E

- FAST/CEM models are in mg/kg

- bw /d ay ( notes 10 and 11 ). The only output in the acute exposure scenario expressed as a concentration is the peak concentration, which represents the maximum concentration in air calculated by the model during any 10

- second time step during (in this case) 24 hours. This value is not a realistic
one to use, even as a worst

- case scenario (all peak concentrations can be found in documents
cited in notes 10 and 11 ).

Thus, to convert the E

- FAST CEM outputs from mg/kg

- bw /d ay to ppm, the following methodology was used: u sing the equation from the E

- FAST manual to calculate the ADR (acute dose rate)

.

The general expression for the p otential a cute d ose r ate (ADR pot 

### ) is as follows:

where:

ADR pot 

### = p otential a cute d ose r ate (mg/kg

- bw/ day)
Cair = e xposure concentration (mg/m 3 

### )
InhR = i nhalation rate (m 3 

### /h ou r) FQ = f requency of product use (events/year)

DEv = d uration of an event (h ou r/event)

ED = e xposure duration (years of product usag e)
BW = b ody weight (kg)
AT = a veraging time (days)

Rearranging and simplifying this equation to calculate an approximation for C air 

### over the
24

- hour averaging time for the ADR POT 

### results in the following equation:

This simplification is reasonable since the averaging time for acute exposure is one day (24 hours). In both scenarios, the frequency is just once per day. Although the duration of the event for the two consumer scenarios is either one hour (degreaser) or 0.5 hour s (clear protective coating spray) 26 

### , for the purposes of this exercise and to conve rt the model output to

26 However, for the user in both scenarios, the inhalation rates were slightly higher during use of the product, as stipulated in the model outputs. Thus, for the degreaser use, an inhalation rate of 0.74 m 3 /hour (for 21 to 78 year olds, 0.72 m 3 /hour for the 16 to 20 year olds ) was used for one hour, and 0.611 m 3 /hour ( for 21 to 78 yr olds,
0.679 m 3 /hour for the 16 to 20 yr olds ) for the remaining 23 hours. For the clear protective coating spray use, the

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a more useable exposure value to compare to the hazard value, there is no correction for this difference. This assumption is still conservative since the values generated are reasonably high exposures that probably overestimate the actual exposures.

This is borne out by comparing the values calculated for the hobbyist degreaser scenarios ( 2 ppm for the 16 to 20 year olds and the 21 to 78 year olds) to the estimate for the small commercial operators in which the typical and worst

- case values of 2 and 6 ppm, respectively

, were estimated for the local exhaust ventilation (LEV) scenario (the same values without LEV were 17 and 63 ppm, respectively)

.

An example calculation is presented below, since the final value is in mg/m 3 

### and the desired units will be in ppm. All calculate d values are presented in Table E- 1.

For the clear protective coating spray use, 21 - to 78

- yr

- old user:

ADR pot 

### = 0.45 mg/kg

- bw /d ay InhR (during use; 0.5 hours) = 0.74 m 3 

### /h ou r InhR (other times; 23.5 hours) = 0.611 m 3 

### /h ou r BW = 80 kg ( using 201 1 Exposure Factors Handbook, US EPA, 2011d )

C air 

### = (0.45)(80)/[0.74 x 0.5) + [0.611 x 23.5) = 2.4 mg/m 3 

### ; converting to ppm 27 

### = 0.446 ppm (converted to 0.4 ppm to use a single significant figure given the assumptions in the back

calculation).

Table E- 1. Estimated TCE Inhalation Calculated Concentration in Air (Over Course of Day) from Use of Two Hobbyist Products Indoors at Residences.

Ages Clear Protective Coating Spray User
ADR pot (ppm) Clear Protective Coating Spray Non

- user ADR pot (ppm) Solvent Degreaser
User ADR pot (ppm) Solvent Degreaser
Non

- user ADR pot (ppm)

<1 NA 0.1 NA 0.8

1-2 NA 0.1 NA 0.8

3-5 NA 0.1 NA 0.8

6

- 10 NA 0.1 NA 0.8

11

- 15 NA 0.1 NA 0.8

16

- 20 0.4 0.1 2 0.8

>21 0.4 0.1 2 0.8

higher, user inhalat ion rate was used for 0.5 hour s , with the “normal” rate used for 23.5 hours. This correction was not done for any bystander ( non

- user ) scenario.

27 ppm = mg/m 3 /5.374

.

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Page 99 

## Appendix **F : Hazard Values Identified for use in this Risk Assessment** 

Table F

- 1. Studies Identified In US EPA (2011c ) For Use In Dose

- Response Assessment For TCE.

Target Organ Species Route of Exposure a Range of Doses or
Concentrations b Duration POD Type c Effect HEC 50 (ppm) HEC 99 (ppm) Reference

Liver Mouse Inhalation 37

- 3,600 ppm 30

- 120 days BMDL = 21.6 ppm Increased liver weight/ body weight
ratio 25 9.1 1

Rat Inhalation 100

- 1,000 ppm 28 days BMDL = 25 ppm 53 19 2

Mouse Oral (g) 100

- 3,200 mg/kg

bw/day 6 weeks BMDL = 82 mg/kg

bw/day 32 11 3

Kidney Rat Inhalation 100

- 600 ppm 104 weeks BMDL = 40.2 ppm Pathology changes in
renal tubule 0.28 0.038 4

Mouse Oral (g) 869

- 2,339 d mg/kg

bw/day 90 weeks LOAEL = 620 mg/kg

bw/day 3.9 0.5 5

Rat Oral (g) 500

- 1,000 mg/kg

bw/day 104 weeks BMDL = 9.45 mg/kg

bw/day 0.042 0.0056 6

Mouse Inhalation 37

- 3,600 ppm 30

- 120 days BMDL = 34.7 ppm Increased kidney weight/body weight

ratio 0.88 0.12 1

Rat Inhalation 100

- 1,000 ppm 28 days BMDL = 15.7 ppm 0.099 0.013 2

Neuro

toxicity Human Inhalation Mean exposure of
CxT Mean of 16 years LOAEL = 14 ppm Trigeminal nerve
effects 14 5.3 7

Rat Oral (drw) 25

- 47 mg/kg

bw/day 8 weeks LOAEL = 47 mg/kg

bw/day Demyelination of hippocampus 18 7.1 8

Rat Inhalation 50

- 300 ppm 6 weeks LOAEL = 12 ppm Changes in
wakefulness 13 4.8 9

Rat Oral (g) 1,000 mg/kg

bw/day 6 weeks LOAEL = 710 mg/kg

bw/day Loss of neurons 126 47 10

Rat Inhalation 300 ppm 24 days LOAEL = 300 ppm Decreased regeneration of sciatic

nerve 274 93 11

Mouse Inhalation 150

- 300 ppm 24 days LOAEL = 150 ppm 378 120

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Page 100 Table F

- 1. Studies Identified In US EPA (2011c ) For Use In Dose

- Response Assessment For TCE.

Target Organ Species Route of Exposure a Range of Doses or
Concentrations b Duration POD Type c Effect HEC 50 (ppm) HEC 99 (ppm) Reference

Immuno

toxicity Mouse Oral (drw) 1.4

- 14 ppm 27

- 30 weeks LOAEL = 0.35 mg/kg

bw/day Decreased thymus weight 0.092 0.033 12

Mouse Oral (drw) 1.4

- 14 ppm 27

- 30 weeks LOAEL = 0.35 mg/kg

bw/day Increased anti

- dsDNA 0.092 0.033 12

Mouse (auto

immune

prone strain) Inhalation 500

- 2,000 ppm 8 weeks LOAEL = 70 ppm Changes in
immunoreactive

organs 97 37 13

Mouse Oral (drw) 0.1

- 5.0 mg/mL 4 or 6 months LOAEL = 18 mg/kg

bw/day Immunosuppression 4.8 1.7 14

Rat Inhalation 100

- 1,000 ppm 28 days BMDL = 24.9 ppm Immunosuppression 29 11 2
Reproduct

ive toxicity Human (male) Inhalation Mean exposure = 29.6 ppm Measured values after an
8- hour work shift; mean years on job was 5.1 BMDL = 1.4 ppm Sperm effects 1.4 0.5 15

Mouse (male) Inhalation 1,000 ppm 6 weeks LOAEL = 180 ppm Sperm effects 190 67 16

Rat (male) Inhalation 376 ppm 2- 10 weeks, 12 weeks, 24 weeks LOAEL = 45 ppm Sperm effects and male reproductive
tract effects 32 13 17

Mouse (male) Inhalation 1,000 ppm 19 days over 4 weeks,
1-4 weeks LOAEL = 180 ppm Effects on epididymis epithelium 190 67 18

Rat (male) Oral (drw) 143

- 270 mg/kg

bw/day 14 days LOAEL = 141 mg/kg

bw/day Decreased in vitro fertilization 16 9.3 19

Rat (fem) Oral (g) 475

- 1,125 mg/kg

bw/day 9 days (during gestation) LOAEL = 475 mg/kg

bw/day Delayed parturition 98 37 20

Rat (both sexes) Oral (f) 72

- 389 mg/kg

bw/day 18 weeks LOAEL = 389 mg/kg

bw/day Decreased mating (both sexes exposed) 204 71 21

### DRAFT DO NOT CITE OR QUOTE

Page 101 Table F

- 1. Studies Identified In US EPA (2011c ) For Use In Dose

- Response Assessment For TCE.

Target Organ Species Route of Exposure a Range of Doses or
Concentrations b Duration POD Type c Effect HEC 50 (ppm) HEC 99 (ppm) Reference

Develop

mental toxicity Rat (female) Inhalation 100 ppm 13 days (during gestation) LOAEL =17 ppm Increased resorptions 16 6.2 22

Rat (female) Oral (g) 475

- 1,125 mg/kg

bw/day 9 days (during gestation) BMDL = 32.2 mg/kg

bw/day Increased resorptions 29 28 20

Rat (female) Inhalation 100 ppm 13 days (during gestation) LOAEL = 17 ppm Decreased fetal weight 16 6.2 22

Rat (female) Oral (drw) 0.0025

- 1,100 ppm 22 days (throughout gestation) BMDL = 0.0207 mg/kg

- bw/day Heart malformations 0.012 0.0037 23

Rat (male pups) Oral (g) 50 and 290 mg/kg

bw/day PNDs 10

- 16 LOAEL = 50 mg/kg

bw/day Decreased rearing activity 8 3 24

Rat (female) Oral (drw) 312

- 1,250 mg/L From gestation through 21 days post

- partum LOAEL = 45 mg/kg

bw/day Increased exploratory behavior in male pups 22 8.4 25

a g = gavage, drw = drinking water, f = feed

b Controls (or zero dose/concentration) are not presented, so a sense of the lowest and highest values is understood.

c POD type can be NOAEL, LOAEL, or BMDL; the IRIS program adjusted all values to continuous exposure.

d Reported doses were TWAs on the days in which animals received a dose (66 weeks
over the 90

- week period).

Reference List ( all as cited in US EPA, 2011c ):
1 = Kjellstrand et al. (1983 )
2 = Woolhiser et al. (2006 )
3 = Buben and O'Flaherty (1985 )
4 = Maltoni and Cotti (1986)
5 = NCI (1976 )
6 = NTP (1988 )
7 = Ruijten et al. (1991 )
8 = Isaacson et al. (1990 ) 9 = Arito et al. (1994 )
10 = Gash et al. (2008 )
11 = Kjellstrand et al. (1987 )
12 = Keil et al. (2009 )
13 = Kaneko et al. (2000 )
14 = Sanders et al. (1982 )
15 = Chia et al. (1996 )
16 = Xu et al. (2004 )
17 = Kumar et al. (2000 ); Kumar et al. (2001 )
18 = Forkert et al. (2002 ); Kan et al. (2007 )
19 = DuTeaux et al. (2004 )
20 = Narotsky et al. (1995 )
21 = NTP (1986 )
22 = Healy et al. (1982 )
23 = Johns on et al. (2003 )
24 = Fredriksson et al. (1993 )
25 = Taylor et al. (1985 )