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# Provisional Peer-Reviewed Toxicity Values for Compl ex Mixtures of Aliphatic and Aromatic Hydrocarbons

(CASRN Various)

Superfund Health Risk Technical Support Center

National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268

### i Commonly Used Abbreviations

BMD Benchmark Dose

HI Hazard Index IRIS Integrated Risk Information System

IUR inhalation unit risk

LOAEL lowest-observed-adverse-effect level

LOAEL ADJ 

### LOAEL adjusted to continuous exposure duration

LOAEL HEC 

### LOAEL adjusted for dosimetric differences across species to a human

NOAEL no-observed-adverse-effect level

NOAEL ADJ 

### NOAEL adjusted to continuous exposure duration

NOAEL HEC 

### NOAEL adjusted for dosimetric differences across species to a human

NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentrat ion p-RfD provisional oral reference dose p-sRfC provisional subchronic reference concentra tion p-sRfD provisional subchronic reference dose

RfC inhalation reference concentration

RfD oral reference dose RPF Relative Potency Factor UF uncertainty factor

UF A 

### animal to human uncertainty factor

UF C 

### composite uncertainty factor

UF D 

### incomplete to complete database uncertainty fact or UF H 

### interhuman uncertainty factor

UF L 

### LOAEL to NOAEL uncertainty factor

UF S 

### subchronic to chronic uncertainty factor

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1 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR COMPL EX MIXTURES OF ALIPHATIC AND AROMATIC HYDROCARBONS (CASRN Vario us)

Executive Summary This Provisional Peer-Reviewed Toxicity Value (PPR TV) document supports a fraction-based approach to risk assessment for comp lex mixtures of aliphatic and aromatic hydrocarbons. The approach takes into account prev ious efforts, most notably those of the Massachusetts Department of Environmental Protectio n (MADEP) and the Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG). These organizations use a fraction-based approach that defines petroleum hydrocarbon fractio ns on the basis of expected transport in the environment and analytical methods that may be appl ied to identify and quantify petroleum hydrocarbon environmental contamination. Toxicity values are selected or derived and used as surrogates to represent the toxicity of these fract ions; then, health risk information for the complex mixture is developed using chemical mixture risk assessment methods where dose-addition or response-addition is assumed acros s or within the fractions, as appropriate. For similar use by U.S. EPA, this PPRTV document presen ts toxicity values for aliphatic and aromatic hydrocarbon fractions—including subchronic and chronic reference doses (RfDs) and reference concentrations (RfCs), cancer weight-of-e vidence (WOE) assessments, oral slope factors (OSF) and inhalation unit risks (IUR). The se values have been obtained from the U.S. Environmental Protection Agency’s (EPA) Integrated Risk Information System (IRIS) (U.S. EPA, 2009o), U.S. EPA Health Effects Assessment Sum mary Table (HEAST) (U.S. EPA, 1997), and existing PPRTVs, or were derived using updated U.S. EPA methods to provide new provisional assessments (U.S. EPA, 2009a-i) when ne eded and supported by the data.

In the U.S. EPA’s approach, the potential health r isk of each of the six aliphatic or aromatic hydrocarbon fractions is represented in on e of three ways: 1) Surrogate Method: the toxicity value for a surroga te (similar) aliphatic or aromatic hydrocarbon mixture or compound is integrated with the exposure data for the entire mass of the fraction; 2) Component Method: the toxicity values for well-stu died individual chemicals that make up a large portion of the fraction are combined wit h their respective exposure estimates using a components-based method under an assumption of dose- or response-addition; or 3) Hybrid Method: a combination of 1) and 2) above is used for the same fraction and the results are combined under an assumption of dose- o r response-addition.

Table 1 summarizes the U.S. EPA approach and illust rates how these three methods are applied to the six hydrocarbon fractions. In the f irst column of Table 1, the hydrocarbon mixtures are first classified into Aliphatics and A romatics; each of these two major fractions is further separated into low-, medium-, and high-carb on range fractions in the second column. The fractions are defined by the number of carbon a toms (C) in the compounds of the fraction and, also, by the compounds’ equivalent carbon (EC) number index, which is related to their transport in the environment. The surrogate chemic als or mixtures selected to represent the toxicity of these fractions are shown in the third column. The components method may involve all of the compounds in the fraction, as is done fo r the low-carbon-range aromatics, or may involve only the compounds known to have certain to xicological properties, as is done for the carcinogenicity of the high-carbon-range aromatics. A combination of surrogate and component

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2 methods may be used for the mid-carbon-range aromat ics, if naphthalene and 2-methylnaphthalene are evaluated as target analyte s, as occurs in Massachusetts (MADEP, 2003). The remaining columns of Table 1 show the a vailability of noncancer and cancer toxicity values for use in this approach and, when available , indicates which table in this PPRTV

document contains that information.

Table 1. Aliphatic and Aromatic Fractionation and the Availability of Toxicity Values in

this PPRTV Document for Surrogate Chemicals or Mixt ures

Primary

Fractions Secondary

Fractions Surrogates and/or

Components Oral

Toxicity Value(s) Inhalation

Toxicty Value(s) Cancer Oral

Slope Factor

or RPF Cancer

Inhalation

Unit Risk

Low carbon range (C5–C8; EC5–EC8) Commercial hexane

or n -hexane (surrogates) Table 7 Table 8 No Value Table 9

Medium carbon range (C9–C18; EC > 8–EC16) Mid range aliphatic

hydrocarbon streams (surrogate) Table 7 Table 8 No Value Table 9 Aliphatics

High carbon

range (C19–C32; EC > 16–EC35) White mineral oil

(surrogate) Table 7 No Value(s) No Value No Value

Low carbon range (C6–C8; EC6–EC < 9) Benzene, ethylbenzene,

xylenes, and toluene (components) Table 7 Table 8 Table 9 Table 9

Medium carbon range (C9–C16; EC9–EC < 22) High-flash aromatic

naphtha (surrogate); naphthalene and 2-methylnaphthalene (components) Table 7 Table 8 No Value No Value Aromatics

High carbon

range (C17–C32; EC22–EC35) Fluoranthene (surrogate);

benzo[a]pyrene and six other Group B2 PAHs (components) Table 7 No Value(s) Table 9 No Value



### To estimate total health risk or hazard for the ent ire hydrocarbon mixture, the estimates for all six of the aromatic and aliphatic fractions are summed using an appropriate additivity method. Figures 1 and 2 provide a graphic illustr ation of how cancer and noncancer risk assessments are carried out, respectively. The ill ustrated noncancer assessment (Figure 2) is performed at a screening level, consistent with Sup erfund practice and guidance (1989). Use of surrogate mixture data and component-based methods is consistent with the U.S. EPA’s supplemental mixtures guidance (U.S. EPA, 2000). T he application of appropriate additivity methods for mixture components, also consistent wit h U.S. EPA (1986, 1989, 1993, 2000) mixtures guidance and methodology, is recommended t o estimate the potential total risk within

and across fractions. These methods include the ha zard index (HI) for noncarcinogenic effects, the relative potency factor (RPF) method for the ca rcinogenic effects of the high carbon range aromatic fraction, and response addition for carcin ogenic effects. By applying additivity concepts to the risk evaluation of these complex mi xtures, the U.S. EPA is applying a straightforward approach that incorporates a number of simplifying assumptions. Because assumptions for complex chemical mixtures are often difficult to substantiate, this U.S. EPA

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3 approach can be considered as a default approach th at can be used to evaluate potential health risks from exposures to aliphatic and aromatic hydr ocarbon mixtures when whole mixture toxicity data for a specific site are not available

.

Examine Uncertainties: Identify % of Hazard Index associated with screening values Sum fraction specific hazard indices assuming dose addition 

### Aliphatic

Fractions

HI i 

### = Aromatic

Fractions

HI i 

### =



# ∑

= 4

1 i i i 

### RfV E Hazard Index

Arom1 Fraction

Hazard Index

Arom3 Fraction Hazard Index Aliph1 Fraction 

# ∑

= 

## = 6

1 i i m 

## HI HI

Hazard Index Aliph2 Fraction

Hazard Index Aliph3 Fraction 

# ∑

= 3

1 i i

i 

### RfV E Hazard Index

Arom2 Fraction i = Benzene, Toluene, Ethylbenzene, Xylene

i = High Flash Aromatic Naphtha, Naphthalene, 2- MethylNaphthalene

ne Fluoranthe Arom 

## RfV E 3

Oils Mineral White Aliph 

## RfV E 3 AHS MidRange

2 

## RfV E Aliph b a hexane n Aliph 

## RfV E

, 1

−

Examine Uncertainties: Identify % of Hazard

Index associated with screening values Sum fraction specific hazard indices assuming dose addition 

### Aliphatic

Fractions

HI i 

### = Aromatic

Fractions

HI i 

### =



# ∑

= 4

1 i i i 

### RfV E Hazard Index

Arom1 Fraction

Hazard Index

Arom3 Fraction Hazard Index Aliph1 Fraction 

# ∑

= 

## = 6

1 i i m 

## HI HI

Hazard Index Aliph2 Fraction

Hazard Index Aliph3 Fraction 

# ∑

= 3

1 i i

i 

### RfV E Hazard Index

Arom2 Fraction i = Benzene, Toluene, Ethylbenzene, Xylene

i = High Flash Aromatic Naphtha, Naphthalene, 2- MethylNaphthalene

ne Fluoranthe Arom 

## RfV E 3

Oils Mineral White Aliph 

## RfV E 3 AHS MidRange

2 

## RfV E Aliph b a hexane n Aliph 

## RfV E

, 1

−

Sum fraction specific hazard indices assuming dose addition 

### Aliphatic

Fractions

HI i 

### = Aromatic

Fractions

HI i 

### =



# ∑

= 4

1 i i i 

### RfV E Hazard Index

Arom1 Fraction

Hazard Index

Arom3 Fraction Hazard Index Aliph1 Fraction 

# ∑

= 

## = 6

1 i i m 

## HI HI

Hazard Index Aliph2 Fraction

Hazard Index Aliph3 Fraction 

# ∑

= 3

1 i i

i 

### RfV E Hazard Index

Arom2 Fraction i = Benzene, Toluene, Ethylbenzene, Xylene

i = High Flash Aromatic Naphtha, Naphthalene, 2- MethylNaphthalene

ne Fluoranthe Arom 

## RfV E 3

Oils Mineral White Aliph 

## RfV E 3 AHS MidRange

2 

## RfV E Aliph b a hexane n Aliph 

## RfV E

, 1

−



### Figure 2. Fraction-based Noncancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons

a For inhalation, use commercial hexane, if n- hexane present at ≤ 53% of fraction

b For inhalation, use n- hexane, if present at >53% of fraction

Where:

HI

m = Screening Hazard Index for the Whole Mixture

HI i = Hazard Index Calculated for the i th Fraction

E i = Daily Oral or Inhalation Intake of the i th Chemical or Fraction (mg/kg-day or mg/m 3

,

respectively) RfV = Reference Value: Oral Reference Dose or Inhalati on Reference Concentration (RfC)

(mg/kg-day or mg/m 3 , respectively)

AHS = Aliphatic Hydrocarbon Streams

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4 Finally, when evaluating risk through the applicati on of these additivity methods, the U.S. EPA suggests that risk assessors carefully ide ntify the underlying assumptions of the risk estimate and describe the sources of support for th ese. The U.S. EPA also suggests that risk assessors carefully identify sources of uncertainty in their estimates. For the hydrocarbon fractions these assumptions include: the surrogate mixture or component(s) represent the toxicity of the entire fraction; independence of toxic actio n exists when adding carcinogenic risks within and across fractions under response addition; there is common toxicity within and across fractions for dose-addition-based methods (i.e., HI , RPF); and, synergistic or potentiating toxicological interactions among chemicals are not likely to happen at low environmental contamination levels. An important source of uncer tainty is the quality of the underlying toxicity data used to develop either a provisional or screen ing RfD or a provisional or screening cancer slope factor. To convey the difference in quality in the mixture risk assessment, the U.S. EPA suggests the risk assessors identify the percentage of the estimated risk or of the hazard index that is associated with screening toxicity estimate s (i.e., screening cancer slope factors or screening RfDs) and the percentage based on provisi onal estimates (i.e., provisional cancer slope factors or provisional RfDs). Such examinations of mixture risk estimates are consistent with mixture risk assessment practices (U.S. EPA, 2000; Rice et al., 2005).

Background On December 5, 2003, the U.S. Environmental Protec tion Agency's (U.S. EPA) Office of Superfund Remediation and Technology Innovation (OS RTI) revised its hierarchy of human health toxicity values for Superfund risk assessmen ts, establishing the following three tiers as the new hierarchy:

1) U.S. EPA's Integrated Risk Information System (I RIS). 2) Provisional Peer-Reviewed Toxicity Values (PPRT Vs) used in U.S. EPA's Superfund

Program. 3) Other (peer-reviewed) toxicity values, includin g

< Minimal Risk Levels produced by the Agency for Toxi c Substances and Disease Registry (ATSDR),

< California Environmental Protection Agency (CalEPA) values, and

< EPA Health Effects Assessment Summary Table (HEAST) values.

A PPRTV is defined as a toxicity value derived for use in the Superfund Program when

such a value is not available in U.S. EPA's IRIS. PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a r eview of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the U.S. EPA IRIS Program. All provisional toxicity values receive internal review by two U.S. EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PP RTVs do not receive the multiprogram consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all U.S. EPA programs, while PPRTVs a re developed specifically for the Superfund Program.

Because new information becomes available and scie ntific methods improve over time, PPRTVs are reviewed on a 5-year basis and updated i nto the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for

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5 that same chemical is retired. It should also be n oted that some PPRTV documents conclude that a PPRTV cannot be derived based on inadequate data.

Disclaimers

Users of this document should first check to see i f any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and Resource Conservation and Recovery Ac t (RCRA) program offices are advised to carefully review the information provided in this d ocument to ensure that the PPRTVs used are appropriate for the types of exposures and circumst ances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; ther efore, users should ensure that the values

contained in the PPRTV are current at the time of u se.

It is important to remember that a provisional val ue alone tells very little about the adverse effects of a chemical or the quality of evi dence on which the value is based. Therefore, users are strongly encouraged to read the entire PP RTV document and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the U.S. EPA Office of Research and Development’s National Cente r for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other U.S. EPA programs or external parties who may choose of their own initia tive to use these PPRTVs are advised that Superfund resources will not generally be used to r espond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pe nding IRIS toxicity values) may be directed to the U.S. EPA Office of Research and Development’ s National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.

INTRODUCTION

Background Contamination of the environment by aliphatic and aromatic hydrocarbons is widespread. The initial contaminating materials range from crud e oil to a wide variety of fuels and lubricating oils. These hydrocarbon products are complex mixtu res containing hundreds to thousands of hydrocarbon compounds—including aliphatic compounds (straight-chain, branched-chain, and cyclic alkanes and alkenes) and aromatic compounds (benzene and alkyl benzenes, polycyclic aromatic hydrocarbons [PAHs]). In addition, some o f these products contain nonhydrocarbon

additives or contaminants.

Once released to the environment, the composition of a hydrocarbon product will change due to weathering (i.e., differential fate and tran sport of its components). Partitioning of the mixture will occur, such that the more soluble and/ or volatile compounds will migrate to other locations and environmental media, leaving the rela tively nonmobile components (the weathered product) at the original location. Thus, the actua l aliphatic and aromatic hydrocarbon mixture to which a receptor population is exposed will vary wi th location, time, and environmental medium.

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6 The assessment of human health risks posed by hydr ocarbon-contaminated sites has involved analysis for “total petroleum hydrocarbons ” (TPH). TPH is a loosely defined aggregate that depends on the method of analysis as well as t he contaminating material; it represents the total mass of hydrocarbons without identifying indi vidual compounds. As TPH is not a consistent entity, the assessment of health effects and development of toxicity criteria such as oral reference doses (RfDs) and slope factors for t he complex mixture as a whole are problematic.

Some toxicity data are available for whole, unweat hered hydrocarbon products (e.g., as reviewed by ATSDR [1995] and IARC [2008a]). Howeve r, there are limitations to using the whole product data due to composition variability c aused by differences in the crude oils from which hydrocarbon products are refined, differences in the refining processes itself, and differences in formulations of the final products. In addition, the identity of the released material may not be known, or more than one product may have been released. Toxicity data for whole hydrocarbon products that are relatively heterogene ous are not necessarily applicable to the weathered materials or transport fractions to which exposure actually occurs.

The number of individually identified hydrocarbon components of various petroleum-derived fuels and crude oil has been esti mated at approximately 250 by the Total Petroleum Hydrocarbon Criteria Working Group (TPHCW G, 1997b, 1999; Weisman, 1998). At the time, toxicity data were available for about 95 of the identified compounds, but only about 25 were found by the TPHCWG (1997b) to have U.S. EPA t oxicity values or sufficient data to develop toxicity criteria. Thus, any attempt to as sess the health effects of TPH from the individual hydrocarbon components is impractical be cause many of the known components lack appropriate toxicity data and criteria. In additio n, the cost of analyzing individually for all known TPH constituents would be prohibitive.

In recognition of the impact of weathering, the in applicability of whole product toxicity data to many contamination scenarios, the impractic ality of chemically analyzing each constituent separately, and the need for risk-based assessment of hydrocarbons, an approach has been developed to assess aliphatic and aromatic hyd rocarbons on the basis of fractions with similar physical and chemical properties. The adva ntages of this approach are that these fractions can be defined analytically and that cons tituents of a fraction have similar environmental transport properties. This type of a pproach appears to have been initiated by the Massachusetts Department of Environmental Protectio n (MADEP) to assess TPH, and it has served as the starting point for the TPHCWG. These two groups continued to evolve their approaches somewhat independently. Key publication s and technical reports describing the MADEP approach include Hutcheson et al. (1996) and MADEP (1994, 1996, 1997, 2001, 2002, 2003, 2008). Key publications describing the TPHCW G approach are TPHCWG (1997a, b, 1998a, b, 1999), Twerdok (1999) and Weisman (1998). The following sections describe the U.S. EPA Approach. Appendix A contains related dis cussions on the existing approaches established or adopted by MADEP, TPHCWG, the Americ an Society for Testing and Materials (ASTM), and the Agency for Toxic Substances and Dis ease Registry (ATSDR).

U.S. EPA Approach: An Overview At the outset, it is important to emphasize that t he present U.S. EPA approach represents expert judgment for the purpose of establishing tox icity values, including PPRTVs, and a risk

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7 assessment method for evaluating complex mixtures o f aliphatic and aromatic hydrocarbons. As

further scientific advancements are made on the tox icology and chemical mixture risk assessment methodologies, it is anticipated that th ese toxicity values and this U.S. EPA approach will be revisited periodically and appropriate adju stments will be made.

A fractional approach, similar to those advanced b y the MADEP and TPHCWG (see separate discussions in Appendix A), is adopted by the U.S. EPA in this PPRTV document. In doing so, some modifications have been incorporated . The present PPRTV document is the principal document outlining the approach, the meth odology, and the definition of fractions, selection of surrogates or components, and derivati on/selection of toxicity values. In addition, there are nine accompanying PPRTV documents for n 

### -hexane, benzene, toluene, ethylbenzene, xylenes, commercial or practical grade hexane, midr ange aliphatic hydrocarbon streams, white mineral oil, and high-flash aromatic naphtha (U.S. EPA, 2009a-i). These are surrogate chemicals or mixtures selected for the six fractions (see Tab le 1 and discussion in following paragraphs), and for which complete toxicity and carcinogenicity assessments were not available from IRIS (U.S. EPA, 2009o) or existing PPRTVs.

Thus, collectively, this PPRTV document plus the n ine additional PPRTV documents constitute the entire PPRTV effort undertaken by th e U.S. EPA specifically for complex mixtures of aliphatic and aromatic hydrocarbons. A s shown in Table 1, prior to defining “fractions,” the components are first classified in to Aliphatics and Aromatics; each of these two major fractions is further separated into low-, med ium-, and high-carbon range fractions. Surrogate chemicals or mixtures are then selected ( see section below on method for surrogate compound or mixture selection) from the available t oxicity data for each of these fractions. In the U.S. EPA’s approach, the potential health risk of each of the six aliphatic or aromatic hydrocarbon fractions is represented in one of thre e ways: 1) Surrogate Method: the toxicity value for a surroga te (similar) aliphatic or aromatic hydrocarbon mixture or compound is integrated with the exposure data for the entire mass of the fraction; 2) Component Method: the toxicity values for well-stu died individual chemicals that make up a large portion of the fraction are combined wit h their respective exposure estimates using a components-based method under an assumption of dose- or response-addition; or 3) Hybrid Method: a combination of 1) and 2) above is used for the same fraction and the results are combined under an assumption of dose- o r response-addition.

The fractionation scheme described above is consist ent with the analytical chemistry performed on the field samples in the laboratory (Hutcheson e t al., 1996). Thus, in field offices of the U.S. EPA, it is anticipated that analytical informa tion in conjunction with the “fraction approach” described herein are to be used for risk assessment of complex mixtures of aliphatic and aromatic hydrocarbons on a specific site. In t hose fractions where components were isolated, these components may be evaluated individ ually according to a component method (U.S. EPA, 2000). The components either represent that whole fraction (e.g., aromatic low carbon range) or are indicators for the carcinogeni city of that fraction (e.g., aromatic high carbon range).

The rationale for U.S. EPA’s adoption of the fract ional approach developed by the

MADEP and TPHCWG is based on several factors. Firs t, the development of the “fraction approach” by MADEP and TPHCWG represents the collec tive wisdom and scientific consensus

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8 of numerous scientists involved from governmental a gencies, professional organizations, academia, and industry. Second, risk assessment of a chemical mixture, particularly one that is changing due to weathering, is a very difficult and complex issue. The “fraction approach” coupled with analytical information on complex mixt ures of aliphatic and aromatic hydrocarbons from a given hazardous waste site, represents a rea sonable, flexible, and best available methodology for risk assessment. Third, U.S. EPA s cientists have employed computational chemistry and statistical methods to assess the fra ctionation scheme and found supporting evidence for selecting the fractions in this report

.

Risk assessment for complex mixtures of aliphatic a nd aromatic hydrocarbons, using the fraction approach, is consistent with U.S. EPA mixt ures guidelines and supplemental guidance (U.S. EPA, 1986, 2000) and with specific guidance f or Superfund (e.g., U.S. EPA, 1989). The basic approach treats fractions as components of th e complex mixture and uses additivity

methods within and across fractions to conduct the risk assessment. Thus, the risk of exposure to a fraction, or several fractions at any given time is the sum of the risks within and across

fractions.

The U.S. EPA (2000) recommends use of dose-addition methods (HI or RPFs) for characterization of potential risk from exposure to a mixture of chemicals that are toxicologically

similar 1 

### . Response addition is recommended for mixture com ponents that act on different systems or produce effects that do not influence ea ch other, and, thus, can be assumed to act independently. Summaries of these methods are prov ided below. For further guidance, details, and discussion, see U.S. EPA (2000) and the other r eferences cited below.

Hazard Index (HI) (U.S. EPA, 2000)

• Assumes a common mode of action and similarly shape d dose-response curves across the components. The common mode of action assumption c an be based on the same target organ or similar effect.

• Component exposures (oral intakes or inhalation con centrations) are scaled by a measure of relative potency—typically the RfD for oral dose s and the RfC for inhalation exposure.

• The scaled intakes or concentrations are then summe d to provide an indicator of risk from exposure to the mixture.

• Exposures should be relatively low so that interact ion effects are not expected.

• Used extensively as an indicator of potential nonca ncer health risk. Method is commonly used in Superfund site assessments (U.S. EPA, 1989) , for which a screening approach is generally used to estimate the HI for all chemicals with pertinent exposure data and toxicity values, regardless of mode of action or ta rget organ. If the resulting HI is greater than unity, additional procedures, including estima ting HIs on a subset of components that have a similar mode of action or target organ may be used to further assess the potential hazard (U.S. EPA, 1989, 2000).

1 U.S. EPA (2000) defines “similar components” as sin gle chemicals that cause the same biologic activity or are expected to cause a type of biologic activity based on chemical structure. Evidence of similarity may include similarly shaped dose-response curves, or parallel log dose-probit response curves for quantal data on the number of animals (people) responding, and the same mechanism of action or toxic endpoint. These components may also be expected to have comparable characteristics for fat e, transport, physiologic processes, and toxicity.

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9 Relative Potency Factors (RPFs) (U.S. EPA, 2000)

• Assumes a common mode of action or similar toxicity and similarly shaped dose-response curves across the components at least in exposure levels of interest to the risk assessment. The common mode of action assumpt ion can be met by toxicological similarity but for specific conditions (endpoint, r oute, duration).

• Used when toxicity data are incomplete for some com ponents.

• Component exposures (oral intakes or inhalation con centrations) are scaled relative to the potency of an index chemical (typically the best-st udied component).

• Scaled intakes or concentrations are then summed, a nd the dose-response curve of the index chemical is used to generate a response (risk ) estimate for the mixture.

• Used for carcinogenic PAHs (U.S. EPA, 1993).

Response Addition (U.S. EPA, 2000)

• Assumes toxicological independence of action and is calculated using the law of statistical independence.

• Risk of an effect is estimated for each component u sing its dose-response curve (in percent responding) at the component’s exposure (or al intake or inhalation concentration).

• Risks are summed (simple sum for small number of ch emicals or using the independence formula for large number of chemicals) to yield a r isk estimate for the mixture.

• Exposures should be relatively low so that interact ion effects are not expected.

• Used extensively for cancer risk characterization. Used in Superfund site assessments (U.S. EPA, 1989).

The overall risk of exposure to complex mixtures of aliphatic and aromatic hydrocarbons

is the sum of the risks or HI’s from all fractions to which a population is exposed, as shown in Figures 1 and 2, respectively, and discussed in the following paragraphs. The quantitative exposure information for these individual chemicals or fractions/subfractions is based on analytical data from the hazardous waste sites. Fo r the sake of completeness, Figures 1 and 2 show a summation across all six fractions, but, dep ending on the source of the mixture and weathering and transport, exposure may be limited t o only one or a few fractions. Each of the six fractions is represented by (1) an individual s urrogate chemical; (2) a surrogate mixture; and/or (3) actual components (e.g., aromatic low ca rbon range, see Table 1). In the case of (1) and (2), the surrogate chemical or mixture is the e ntity that meets criteria for similarity with the fraction or its components (as discussed later in t his PPRTV), and for which there is sufficient information for derivation of toxicity values. In one instance (i.e., mid carbon range aromatic fraction, see Table 1), a surrogate mixture is sele cted to represent the remainder of the fraction after the components with different and more potent toxicities (i.e., naphthalene and 2- methylnaphthalene) are assessed individually. Figu res 1 and 2 provide a graphic illustration of

how cancer and noncancer risk assessments are carri ed out, respectively. The illustrated noncancer assessment (Figure 2) is performed at a s creening level, consistent with Superfund practice and guidance (1989).

By applying additivity concepts to the risk evaluat ion of these complex mixtures, the U.S. EPA is applying a straightforward approach tha t incorporates a number of simplifying assumptions. Because assumptions for complex chemi cal mixtures are often difficult to substantiate, this U.S. EPA approach can be conside red as a default approach that can be used to

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10 evaluate potential health risks from exposures to a liphatic and aromatic hydrocarbon mixtures when whole mixture toxicity data for a specific sit e are not available. These assumptions include: the surrogate mixture or component(s) repr esent the toxicity of the entire fraction; independence of toxic action exists when adding car cinogenic risks within and across fractions under response addition; there is common toxicity w ithin and across fractions for dose-addition-based methods (i.e., HI, RPF); and, s ynergistic or potentiating toxicological interactions among chemicals are not likely to happ en at low environmental contamination levels. Discussions are presented in the next sect ion of this document regarding how well each of the surrogate mixtures or component(s) represent s the toxicity of its associated fraction;

information from these discussions can be used in a risk characterization. Because the composition of hydrocarbon mixtures is complex and varies with time-dependent weathering and transport changes, it will be difficult to provide evidence that the other three assumptions mentioned here are being met for every exposure sce nario. For cancer risk estimation, response addition (for most chemicals) and RPFs (for PAHS) a re well-established chemical mixture methods. Response addition has been identified as a default method for evaluating carcinogenic risk for mixtures, assuming independence of toxic a ction, whose result is interpreted as the risk of any cancer regardless of tumor site (U.S. EPA, 1 989, 2000). The RPF method, based on an assumption of dose-addition, has long been used by U.S. EPA to evaluate seven PAHs for carcinogenicity (U.S. EPA, 1993); B[a]P has been us ed as the surrogate to represent the carcinogenicity of the other PAHs. These methods, shown in Figure 1, are recommended in this document and may be used as defaults within the fra ction approach to evaluate potential cancer risks. Application of the HI to the fractions, as shown in Figure 1 may be performed at a screening level, consistent with Superfund practice and guidance (U.S. EPA, 1989). Although exposures to the surrogate mixtures and components that represent the fractions may produce different toxic effects, it may be argued that a sc reening level HI is appropriate because it is unknown whether the effects caused by other compoun ds in the fractions may indeed cause similar toxicity across fractions. Finally, when t wo or more chemicals at a site are identified as having high exposure concentrations, the toxicology literature should be consulted for evidence of toxicological interactions among these chemicals . If synergism is found for these chemicals,

then this should be called out in the risk characte rization along with the quantitative risk or hazard estimates. In general, these four assumptio ns should be evaluated and verified whenever possible and the results articulated as part of the final risk characterization.

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### 9-30-2009

11 Cancer Risk

Arom1 Fraction

Data not supportive of toxicity-value

derivation



### Cancer Risk

Arom3 Fraction i = benzene, toluene, ethylbenzene, xylene

BaP

i 7

1 i i 

### CSF

RPF Dose × × 

# ∑

= i = B[a]P and 6 other Group

B2 PAHs with RPFs 

# ∑

= 

## = 6

1 i i 

## R Rm

Sum fraction specific risk estimates assuming

response addition 

### Aliphatic

Fractions

R i 

### = Aromatic

Fractions

R i 

### =

Cancer Risk Aliph1 Fraction CSF com-hexane × Dose Aliph1



### Cancer Risk Aliph2 Fraction CSF MidRangeAHS × Dose Aliph2



### Cancer Risk Aliph3 Fraction Data not supportive of toxicity-value

derivation 

### Cancer Risk

Arom2 Fraction i 4

1 i i 

### CSF Dose × 

# ∑

=

Examine Uncertainties: Identify % of risk estimate associated with screening values



### Cancer Risk

Arom1 Fraction

Data not supportive of toxicity-value

derivation



### Cancer Risk

Arom3 Fraction i = benzene, toluene, ethylbenzene, xylene

BaP

i 7

1 i i 

### CSF

RPF Dose × × 

# ∑

= i = B[a]P and 6 other Group

B2 PAHs with RPFs 

# ∑

= 

## = 6

1 i i 

## R Rm

Sum fraction specific risk estimates assuming

response addition 

### Aliphatic

Fractions

R i 

### = Aromatic

Fractions

R i 

### =

Cancer Risk Aliph1 Fraction CSF com-hexane × Dose Aliph1



### Cancer Risk Aliph2 Fraction CSF MidRangeAHS × Dose Aliph2



### Cancer Risk Aliph3 Fraction Data not supportive of toxicity-value

derivation 

### Cancer Risk

Arom2 Fraction i 4

1 i i 

### CSF Dose × 

# ∑

=

Examine Uncertainties: Identify % of risk estimate associated with screening values 

# ∑

= 

## = 6

1 i i 

## R Rm

Sum fraction specific risk estimates assuming

response addition 

### Aliphatic

Fractions

R i 

### = Aromatic

Fractions

R i 

### =

Cancer Risk Aliph1 Fraction CSF com-hexane × Dose Aliph1



### Cancer Risk Aliph2 Fraction CSF MidRangeAHS × Dose Aliph2



### Cancer Risk Aliph3 Fraction Data not supportive of toxicity-value

derivation 

### Cancer Risk

Arom2 Fraction i 4

1 i i 

### CSF Dose × 

# ∑

=

Examine Uncertainties: Identify % of risk estimate associated with screening values



### Figure 1. Fraction-based Cancer Risk Assessment fo r Complex Mixtures of Aliphatic and Aromatic Hydrocarbons

Where:

R

m = Risk posed by the mixture

Ri = Risk function associated with the i th fraction

Dose i = Oral Exposure Dose or Inhalation Exposure Conc entration for the i th fraction (mg/kg-day

or mg/m 3 , respectively)

CSF i = Cancer Slope Factor (OSF) or Inhalation Unit Ri sk (IUR) of surrogate chemical or

components in (mg/kg-day) -1 or ( μ g/m 3 ) -1 , respectively

Com-hexane = commercial hexane

AHS = Aliphatic Hydrocarbon Streams

RPF i = Relative Potency Factor for the i th PAH

BaP = Benzo(a)pyrene

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### 9-30-2009

12 In addition to describing the underlying assumptio ns when evaluating risks posed by hydrocarbon mixtures, risk assessors also will cons ider sources of uncertainty in the assessment. One source of uncertainty pertains to the quality o f the data underlying toxicity values. Differences or perceived differences in the quality of the underlying data led the U.S. EPA to categorize some hydrocarbon RfDs and cancer slope f actors as provisional values, while others with less information or lower quality information were categorized as screening values, which appear in appendices of the PPRTVs. For example, i n some cases, U.S. EPA could not determine whether the relevant toxicity data had un dergone independent, external, scientific peer review; in these cases, a screening RfD or screenin g cancer slope factor was developed (see Table 1). To convey this difference in the quality of the data used in the mixture risk assessment, the U.S. EPA suggests that risk assessors identify the percentage of the estimated risk or of the hazard index that is associated with screening toxi city estimates (i.e., screening cancer slope factors or screening RfDs) and the percentage based on provisional estimates (i.e., provisional cancer slope factors or provisional RfDs). It is l ikely that there will be less confidence in estimates utilizing a higher percentage of screenin g RfDs or screening cancer slope factors when compared to those estimates comprised of a lower pe rcentage of screening RfDs or screening cancer slope factors. Such examinations of mixture risk estimates are consistent with mixture risk assessment practices (U.S. EPA, 2000; Rice et al., 2005).

DEFINITION OF FRACTIONS AND DERIVATION/

SELECTION OF TOXICITY VALUES

Rationale and Recommendations for U.S. EPA Approach The U.S. EPA approach to evaluating complex mixtur es of aliphatic and aromatic hydrocarbons is fundamentally a fraction-based appr oach, building on the contributions of the

MADEP and the TPHCWG. Some modifications are recom mended in (1) fraction definition, (2) selection of a surrogate compound or mixture, or of a components-based method for the fraction, and (3) selection or derivation of toxicity values based on up-to-date methods and data.

Given the complexity of the problem and the number of individual compounds that are constituents of complex mixtures of aliphatic and a romatic hydrocarbons, a fraction approach is a practical method for assessing the health risks f rom exposure to these mixtures that accounts for variation in mixture composition across sites. MADEP (2003) establishes hydrocarbon fractions based first on molecular structure (aroma tic versus aliphatic), and then, secondly, on number of carbon atoms (C), using toxicologically s imilar groupings and excluding compounds with less than five carbons because their high vola tility precludes chronic exposure from spills/releases. The TPHCWG (1997a) also establish es hydrocarbon fractions based on molecular structure, but, as the second delineator, it uses equivalent carbon (EC) number index. This index is equivalent to the retention time of t he compounds on a boiling-point gas chromatography (GC) column (nonpolar capillary colu mn), normalized to the n- 

### alkanes. For example, benzene, a C6 aromatic compound has an EC of 6.5 because its boiling point and GC retention time are approximately halfway between th ose of n- 

### hexane (C6, EC6) and n- 

### heptane (C7, EC7). The assessment of transport fractions, as defined by the TPHCWG (1997a) for TPH, appears particularly useful because these fractions relate to transport in the environment (at least under certain conditions). Their transport can be modeled, and they are consistent with the

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### 9-30-2009

13 analytical methods used to quantify and identify hy drocarbons. These fractions are defined by the ranges of their EC number indices, which are re lated to their transport in the environment.

The following sections of this PPRTV document pres ent the aliphatic and aromatic fractions and discuss the available toxicity assess ments for individual compounds and similar mixtures (if any) for each fraction. Both the C an d EC ranges of the fractions are noted. In addition, recommendations are presented for a fract ion-based assessment of complex mixtures of aliphatic and aromatic hydrocarbons. The recommend ations include selection of appropriate surrogates or a components method for each fraction and selection of appropriate toxicity values for those surrogates/components.

The aliphatic hydrocarbon fractions are discussed first. These compounds pose a particular problem because little or no toxicity da ta are available for most of the individual constituents, and, although data for mixtures corre sponding to these fractions have been generated, many of the studies originally were unpu blished industry studies. Some of the studies

are now available as Toxic Substances Control Act T est Submissions (TSCATS) microfiche, or were provided by MADEP, and a few have been publish ed.

The aromatic hydrocarbon fractions, discussed subs equently, pose less of a problem because of the availability not only of toxicity da ta, but also, in many cases, of U.S. EPA RfDs

and cancer assessments. The definition of the frac tions, however, is not as clear.

As a preliminary step in identifying potential sur rogate compounds to represent the toxicity of the fractions or identifying compounds useful in a components method, a list of individual hydrocarbons was compiled and additional background searching was performed. The list included all individual hydrocarbons consi dered previously by the U.S. EPA NCEA’s Superfund Technical Support Center in the evaluatio n of hydrocarbons, as well as all those with toxicity data reviewed by MADEP (2003) or the TPHCW G (1997b). Similarly, a list of mixtures, primarily hydrocarbon streams, was compil ed from these sources. Background searching focused on the IRIS database (U.S. EPA, 2 009o), the HEAST (U.S. EPA, 1997), ATSDR Toxicological Profiles (ATSDR, 2008), the Che mical Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994), and the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006). Additionally, Ca lEPA (2008), the National Toxicology Program (NTP, 2008), the World Health Organization (WHO, 2008), and the International Agency for Research on Cancer (IARC, 2008a, b) were consulted for information. The U.S. EPA’s (2007a) High Production Volume (HPV) Cha llenge Program, and particularly the Petroleum HPV Testing Group (2007) publications, as well as the Organisation for Economic Co-operation and Development (OECD) HPV Programme S creening Information Data Set (SIDS) documents (OECD/SIDS, 2007) were searched fo r pertinent information. Additional pertinent individual compounds and mixtures encount ered during this background search were

added to the list for further consideration. On th e basis of the information found during background searches, some compounds and mixtures th at appeared to be possible candidates for use as surrogates were subjected to preliminary sea rching in MEDLINE (PUBMED) and TSCATS. If chosen for PPRTV development on the bas is of the results of the background searching or the preliminary searching, compounds a nd mixtures were then subjected to the full suite of searching (through 2009). The search deta ils are described in the front matter of the PPRTV documents (U.S. EPA, 2009a-i). Final lists o f candidate toxicity values for

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### 9-30-2009

14 consideration as surrogates for the aromatic and al iphatic fractions are compiled in Tables 2–6 of this document; the sources are identified in the le ft column as IRIS, PPRTV, HEAST, MADEP, TPHCWG, or ATSDR.

Method for Surrogate Compound or Mixture Selection The criteria used for selecting chemicals or mixtu res for potential use as surrogates, or for choosing a components method, are as follows:

• The surrogate mixture or compound had to be a relev ant aliphatic or aromatic hydrocarbon or composed exclusively of aliphatic or aromatic hydrocarbons.

• The surrogate mixture or compound had to have eithe r U.S. EPA toxicity values or adequate data for the derivation of toxicity values —particularly subchronic and chronic RfDs and/or RfCs. The ability to support the devel opment of a carcinogenicity assessment was desirable but not required.

• First preference was given to mixtures that are sim ilar 2 

### to the fraction in composition, and that have toxicity values or adequate toxicity data to support the derivation of toxicity

values.

o Criteria for similarity of composition included sim ilar C and EC number range, similar aliphatic or aromatic hydrocarbon component s, and purity (e.g., lack of contamination of aliphatic mixtures with aromatics and vice versa, and lack of contamination with nonaliphatic or aromatic hydroca rbon compounds).

o Toxicity considerations include similarity of effec t of the surrogate mixture with known toxicities of the individual components of th e fraction.

• If suitable mixture data were lacking, the next ste p was to select from the fraction a representative compound that was known or could be assumed to be similar toxicologically (defined previously), in terms of t ypes of effects in vivo and potency, to the other compounds in the fraction, and that had e ither suitable toxicity values or adequate toxicity data to support the derivation of toxicity values.

• If the components of the fraction varied highly in type or potency of toxic action, the more toxic component (e.g., n- 

### hexane, low carbon range aliphatic fraction) was us ed as the surrogate when it exceeded the percentage found in the surrogate mixture (e.g., commercial hexane, inhalation assessment) or when o ther suitable values were not available for the exposure route (oral). Alternati vely, the components with different and more potent toxicities (naphthalene and 2-methylnap hthalene) were recommended to be assessed separately, and the remaining mass of the fraction (medium carbon range aromatics) assessed using values for a surrogate mi xture (high-flash aromatic naphtha).

• If the toxicities of all the individual compounds w ere well characterized, toxicity values

were available or could be derived for the individu al compounds, and these compounds were monitored at sites of aliphatic or aromatic hy drocarbon contamination, then toxicity values were provided for the individual compounds t o support a components method

2 Similar mixtures are mixtures that differ slightly, but they are expected to have comparable character istics for fate, transport, physiologic processes, and toxicity. Th ese mixtures may have the same components but in sl ightly different proportions, or they have most component s in nearly the same proportions with only a few di fferent (more or fewer) components. Similar mixtures cause the s ame biologic activity or are expected to cause the same type of biologic activity due to chemical composition. Sim ilar mixtures act by the same mechanism of action o r affect the same toxic endpoint (U.S. EPA, 2000).

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### 9-30-2009

15 wherein the potential risk from exposure to each co mponent is assessed individually (e.g., the low carbon range aromatic fraction), followed b y application of appropriate additivity

methods.

• For the high carbon range aromatic fraction, a comp onents method was recommended for the carcinogenic (Group B2) PAHs, using an existing method, the RPF method, to assess carcinogenicity.

• Uncertainties regarding the suitability of the surr ogate compound or mixture to represent the toxicity of the fraction were discussed.

Toxicity Values for Aliphatic Fractions The aliphatic fractions as defined by MADEP in ter ms of C range are similar to the fractions as defined by the TPHCWG (1997a, b) in te rms of EC range. This provisional assessment adopts these fractions and lists both C and EC ranges.

Low Carbon Range Aliphatic Fraction: C5–C8, EC5–EC8

This fraction includes n- 

### pentane, n- 

### hexane, cyclohexane, the dimethylbutanes and methylpentanes, cyclopentane, n- 

### heptane, n- 

### octane, some branched chain alkanes including the trimethylpentanes, cyclohexane, methylcyclopentane, and methylcyclohexane. According to the TPHCWG, this fraction also includes some alkenes, s uch as 1-hexene. MADEP, however, includes alkenes with aromatics and says they are n ot present in high concentrations in petroleum products. Previous efforts by MADEP (2003) and TPH CWG (1997b) to identify toxicity data for hydrocarbons in this fraction reported toxicity data for n- 

### pentane, 2- and 3-methypentane,

n- 

### hexane, methylcyclopentane, cyclohexane, n- 

### heptane, methylcyclohexane, 2,2,4-trimethylpentane, and 1-hexene, as well as fo r two mixtures: commercial hexane and technical-grade heptane (MADEP, 2003; TPHCWG, 1997b ).

Commercial hexane generally contains approximately 50–53% n- 

### hexane (TPHCWG, 1997b; U.S. EPA, 2005b). The remaining co nstituents of commercial hexane are the following branched and cyclic C6 aliphatic comp ounds: 3-methylpentane, methylcyclopentane, 2-methylpentane, cyclohexane, 2 ,3-dimethylbutane, and <1% of several minor constituents. Technical-grade heptane, in th e only toxicity study located for this mixture (Truhaut et al., 1973), contained approximately 52% n- 

### heptane, with the remainder of the mixture consisting of the following C6-C8 aliphatic compounds: 2- and 3-methylhexane, 2,3-dimethylpentane, cyclohexane, methylcyclohexane , 2,4-dimethylhexane, and approximately 3% aromatic compounds (benzene and toluene). It di d not contain n- 

### hexane.

For this low carbon range aliphatic fraction, deri vations of toxicity values have been considered by the U.S. EPA, ATSDR, MADEP, and TPHCW G and are summarized in Table 2.

RfCs are available for n- 

### hexane and cyclohexane, but no RfDs are available o n IRIS (U.S. EPA, 2009o). A subchronic provisional RfD (p -RfD) and a subchronic p-RfC have been developed for n- 

### hexane (U.S. EPA, 2009c). The only aliphatic hydro carbon mixture in this fraction range that has sufficient toxicity data fo r derivation of oral or inhalation toxicity valuesFINAL9-30-200916Table 2. Toxicity Values for the Low-Carbon RangeAliphatic Fraction: C5–C8, EC5–EC8aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)Cancer WOEOSF (permg/kg-day)IUR (perμg/m3)DatebIRIS and PPRTV Values6 6n-HexaneRfD:Inadequate dataRfC:7 ×10-1, peripheral neuropathy,Huang et al., 1989Inadequate data NA NA 2005b6 6.59 CyclohexaneRfD:Inadequate dataRfC:6 × 100, reduced pup weight,DuPont HLR, 1997aInadequate data NA NA 20037 7n-Heptane Not assessed Not assessed Group D (notclassifiable)NA NA 1996

IRIS (U.S. EPA, 2009o )8 6.98 2,2,4-TrimethylpentaneRfD:Inadequate dataRfC:Inadequate data Inadequate data NA NA 20075 5n-PentaneINPROC6 6n-HexanesRfD:3 × 10-1, reducednerve conduction velocity(Ono et al., 1981)RfD:Not assessedsRfC: 2× 100, decreased motor nerveconduction velocity, Huang et al.,1989RfC:Not assessedNot assessed Not assessed Not assessed 2009b7 7n-HeptanesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataInadequate data Inadequate dataInadequate data 2004d

PPRTV (U.S. EPA, date in last column)7 7.22 MethylcyclohexanesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataCannot bedeterminedsuggestiveNA NA 2005a

PPRTV (U.S. EPA, date in last6 – Commercial hexanesRfD:Inadequate dataRfD:Inadequate datasRfC:27 × 100, clinical andhistopathological signs of neuropathy,IRDC, 1992a,bRfC:6 × 10-1, nasal epithelial cellhyperplasia, Biodynamics,1993a/Daughtrey et al.,1999SuggestiveevidenceInadequate data1.9 × 10-7pituitary adenomaor carcinoma,Biodynamics,1993b; Daughtreyet al., 1999(*ScreeningValue)2009fFINAL9-30-200917Table 2. Toxicity Values for the Low-Carbon RangeAliphatic Fraction: C5–C8, EC5–EC8aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)Cancer WOEOSF (permg/kg-day)IUR (perμg/m3)DatebOther Peer-Reviewed or Relevant Toxicity Values6 6n-HexanesRfD:6 × 10-1neuropathyand testicular atrophy,Krasavage et al., 1980RfD:6 × 10-2neuropathyand testicular atrophy,Krasavage et al., 1980sRfC:2 × 10-1adopted RfC on IRIS atthe time as sRfCNot assessed Not assessed Not assessed –

HEAST (U.S. EPA, 1997)7 7.22 Methylcyclohexane Not assessedsRfC:3 × 100, possible male rathyaline droplet nephropathy, Kinkeadet al., 1985RfC:3 × 100, possible male rathyaline droplet nephropathy, Kinkeadet al., 1985Not assessed Not assessed Not assessed –

MADEP (2003)6 6n-HexaneRfD:4 × 10-2, reducedbody weight (peripheralneuropathy at high dose),Krasavage et al., 1980RfC:2 × 10-1, neurotoxicity, 1993IRIS valueNot assessed Not assessed Not assessed –

TPHCW G (1997b)6 – Commercial hexaneRfD:5 × 100, extrapolatedfrom TPHCWG RfC1.84 × 101, neurotoxicity and othersystemic and portal of entry effects(several industry studies, mostlyreferenced to abstracts)Not assessed Not assessed Not assessed –

ATSDR (date in last column)6 6n-HexaneIntermediate MRL:Inadequate dataChronic MRL:InadequatedataIntermediate MRL:Inadequate dataChronic MRL:6 × 10-1ppm, reducedmotor nerve conduction velocity,Sanagi et al., 1980Not assessed Not assessed Not assessed 1999bFINAL9-30-200918Table 2. Toxicity Values for the Low-Carbon RangeAliphatic Fraction: C5–C8, EC5–EC8aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)Cancer WOEOSF (permg/kg-day)IUR (perμg/m3)DatebaComplete citations for the principal studies can befound in the source documents (e.g., IRIS [U.S. EPA, 2009o])bDate of IRIS assessment (last revision) or of PPRTVor ATSDR toxicological profile; dates for HEAST, MADEP and TPHCWG are provided in far left column oftable.ATSDR = Agency for Toxic Substances and Disease Registry, C = carbon number, EC = equivalent carbon number index, HEAST = Health Effects Assessment summary Table,INPROC = in process, IRIS = Integrated Risk Information System, IUR = inhalation unit risk, MADEP = Massachusetts Department of Environmental Protection, MRL =Minimal Risk Level, NA = Not applicable, OSF = oralslope factor, p- = provisional, PPRTV = Provisional Peer-Reviewed Toxicity Value, PTV = Provisional Toxicity Value(draft), RfC = inhalation reference concentration,sRfC = subchronic RfC, RfD = oral reference dose, sRfD = subchronic RfD, TPHCWG = Total Petroleum Hydrocarbon CriteriaWorking Group, WOE = weight of evidence

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19 is commercial hexane. Although the oral data do no t support derivation of RfDs, a subchronic p-RfC, a p-RfC, and a cancer assessment, including a screening 3 

### inhalation unit risk, have been developed for commercial hexane (U.S. EPA, 2009f). Updated literature searches were performed for cyclohexane in 2009, but no newer dat a that would support derivation of oral toxicity values or impact the inhalation RfC were f ound. n- 

### Heptane and methylcyclohexane were the subjects of PPRTV development; the data di d not support development of subchronic or chronic RfDs or RfCs for these compounds (U.S. EPA, 2004d, 2005a). Development of a

PPRTV for n- 

### pentane is in process; information from that PPRTV will be considered for use in evaluating hydrocarbon mixtures when this mixtures PPRTV document is revised.

ATSDR has considered n- 

### hexane, but it has not developed oral MRLs for this compound (ATSDR, 1999b). The HEAST (U.S. EPA, 1997) lists s ubchronic and chronic RfDs for

n- 

### hexane and subchronic and chronic RfCs for methylcy clohexane, but these values are superseded by the more recent PPRTV documents for t hese chemicals. MADEP (2003) has developed an RfD for n- 

### hexane and has adopted the previous IRIS RfC for th is compound (the current RfC became available in 2005). The TPHCWG (1997b) has derived an inhalation RfC for commercial hexane using methods inconsistent wi th current U.S. EPA practice, and they performed a route-to-route extrapolation of this va lue to derive an RfD.

As per MADEP’s (2003) update of its toxicity value s and the 2004 PPRTV on n- 

### heptane (which also covered technical-grade heptanes; U.S. EPA, 2004d), pertinent data for technical-grade heptane are limited to a single stu dy (i.e., Truhaut et al., 1973) that suggested peripheral neuropathy in rats exposed by inhalation . Information in the study, however, does not support development of toxicity values, and the mix ture contained both toluene and benzene, as previously described. Literature searches conducte d in 2009 revealed no newer data or any data on an aromatic-free heptane mixture that could be u sed to develop toxicity values.

Data on the individual aliphatic hydrocarbons of t his fraction suggest nervous system effects. While some of the compounds have central nervous system effects, as well as liver and kidney effects, peripheral neuropathy is the critic al effect of n- 

### hexane, mediated through its metabolite, 2,5-hexandione (a gamma-diketone; U.S. EPA, 2009o). Concern has focused on the potential for some of the other compounds in this f raction to be metabolized to gamma-diketones and, therefore, also cause peripheral neuropathy. As reviewed by MADEP (2003), studies with the putative gamma-diketone metabolites (e.g., 2,5- heptanedione, 3,6-octanedione) of some of the compounds in this fraction have suggested that they may cause peripheral neuropathy, but data showing that exposure to the parent compound m ay cause peripheral neuropathy are inadequate. For example, neither oral nor inhalati on exposure to n- 

### heptane caused peripheral neuropathy in rats in studies that specifically inv estigated this potential outcome (U.S. EPA, 2004d). In a study of the potential per ipheral neurotoxicity of n- 

### hexane isomers, 2-methylpentane, 3-methylpentane, and methylcyclope ntane were administered by gavage to rats in increasing amounts over the course of 8 weeks (O no et al., 1981). Although n- 

### hexane, administered in the same manner, significantly decr eased peripheral nerve conduction velocity (motor nerve, mixed nerve-distal portion, and mixed nerve-proximal portion of the tail), the other compounds were less effective or ineffective. The data, however, were reported graphically, no

3 Screening values are developed in the Appendix of a PPRTV. For example, in cases where a high degree of uncertainty exists. Screening values are intended for use in limited circumstances when no Tier 1, 2, or 3 values are

available.

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### 9-30-2009

20 clinical signs of neuropathy were seen for any of t he compounds, and histopathological examinations of the peripheral nerves were not cond ucted. Thus, the effects of these hexane isomers are not readily quantifiable and the clinic al significance of the isomer results is unclear. However, Krasavage et al. (1980) also directly show ed that none of these compounds produced toxicity to the extent that 2,5-hexandione did. Th is study showed a correlation between neurotoxicity index and the peak serum concentratio ns of 2,5-hexandione from several peripheral neurotoxicants including n- 

### hexane.

To represent the toxicity of this fraction, the in halation PPRTVs for commercial hexane (U.S. EPA, 2009f) are recommended, unless n- 

### hexane accounts for >53% of the analyzed fraction, in which case the n- 

### hexane toxicity values should be used (see Table 2) . Use of the mixture data better represents the toxicity of the fraction, although there are uncertainties with this method because it is predominantly a C6 mixtur e. Exposure to airborne commercial

mixtures has been associated in a few studies with neurological effects in workers (e.g., Passero et al., 1983), and a subchronic continuous inhalation exposure study of commercial hexane in experimental animals (IRDC, 1992a, b) rep orted peripheral neuropathy as the critical effect. In contrast, the critical effect for chron ic inhalation exposure to this mixture was nasal lesions. While histopathological evaluation of the respiratory tract was performed in the subchronic study, no adverse findings were observed . Therefore, a chronic p-RfC based on nasal and laryngeal lesions is protective for the periphe ral neuropathy seen in the subchronic continuous exposure study (IRDC, 1992a, b). Becaus e no oral toxicity values could be derived for commercial hexane, the oral toxicity of the fra ction can be assessed using the subchronic p-RfD for n- 

### hexane (U.S. EPA, 2009c). The data for commercial hexane are considered adequate to develop a quantitative estimate of canc er risk from inhalation exposure for this fraction. However, because the WOE indicates “ Suggestive Evidence for the Carcinogenic
Potential,” 

### there is some uncertainty associated with the quan tification. For these reasons, Appendix A of the commercial hexane PPRTV document contains a screening p-IUR that may be useful in certain instances (i.e., when n- 

### hexane accounts for ≤ 53% of this fraction). Please see the that Appendix for details (U.S. EPA, 2009f) . Table 2 lists these values and assessments.

Medium Carbon Range Aliphatic Fraction: C9–C18, EC > 8–EC16

This fraction includes n- 

### nonane, n- 

### decane, and longer chain n- 

### alkanes; a few n- 

### alkenes (e.g., tridecene); branched chain alkanes and alken es; and alkyl-substituted cycloalkanes (see comment about alkenes at the beginning of the previ ous section). Derivations of toxicity values for these compounds are not available from the U.S. EPA’s IRIS or HEAST, or from ATSDR, MADEP, or TPHCWG. PPRTVs for n- 

### nonane and n- 

### decane are completed; information from

those PPRTVs will be considered for use in evaluati ng hydrocarbon mixtures when this mixtures PPRTV document is revised. Limited toxicity data a re available for n- 

### undecane (VCCEP, 2004). ATSDR toxicological profiles and inhalation MRLs ar e available for various jet fuels and kerosene, but these mixtures have a substantial aro matic content and are therefore not suitable to represent the toxicity of this fraction. The toxic ity of this fraction may be better represented by dearomatized hydrocarbon streams and solvents that fall within this carbon range and have minimal (<1.0%) aromatic content. Subchronic oral toxicity studies were performed with the mixtures listed in the following bullets (note that the term n- 

### paraffins refers to n- 

### alkanes, the term isoparaffins refers to branched chain alkanes, and the terms naphthenes and cycloparaffins refer to cyclic alkanes):

### FINAL



### 9-30-2009

21 • C11

– C17 isoparaffin mixture, typical aromatic content < 0.05% (Anonymous, 1990);

• C9

– C12 isoparaffin/ n- 

### alkane/naphthene mixture with an aromatic content < 0.5% (Anonymous, 1991b);

• C10

– C13 isoparaffin/naphthene/ n- 

### alkane mixture with an aromatic content of 0.1% (Anonymous, 1991a).

Subchronic and 6-month inhalation toxicity studies have been performed with the following mixtures:

• C10

– C11 isoparaffin mixture with no aromatic content (P hillips and Egan, 1984);

• C11

– C12 dearomatized white spirit (paraffin/naphthene m ixture) with an aromatic content <0.5% (Phillips and Egan, 1984);

• C range not reported, dearomatized white spirit (co ntent not reported; Lund et al., 1996).

Subchronic toxicity and 2-year toxicity/carcinogen icity studies have been performed with the following mixture:

• C10

– C13 Stoddard Solvent IIC ( n- 

### paraffins, isoparaffins, cycloparaffins) with an aromatic content <1.0% (NTP, 2004).

Complete citations for these studies are provided in U.S. EPA (2009h). Some additional supporting toxicity studies on similar mixtures are available as well.

Table 3 lists the available toxicity information fo r this fraction. The MADEP (2003) and TPHCWG (1997b) have based their toxicity values for this fraction on some of the studies of aliphatic hydrocarbon streams. Other suitable data have not been located. The mixture data are considered preferable to single component data, as previously discussed. Accordingly, PPRTVs were derived based on the mixture data as part of t he effort to provide suitable toxicity values for this fraction (U.S. EPA, 2009h) using current U.S. EPA methods. These PPRTVs, listed in Table 3, are the recommended values for this fracti on and include subchronic and chronic p-RfCs and a provisional cancer WOE of “Suggestive Evidence of Carcinogenic Potential.” 

### In addition, Table 3 contains several screening values that may be useful in evaluating this fraction, developed in Appendix A of U.S. EPA (2009h). Becau se the toxicity data based on the three unpublished studies (Anonymous, 1990, 1991a,b) are not peer-reviewed, only screening chronic

or subchronic RfDs are available in Table 3. The d ata are considered adequate to develop a quantitative estimate of cancer risk from inhalatio n exposure. However, because the WOE

indicates “ Suggestive Evidence for the Carcinogenic Potential, ” 

### there is some uncertainty associated with the quantification. Appendix A of the PPRTV document on the Midrange Aliphatic Hydrocarbon Streams contains a screening p-IUR and screening chronic or subchronic RfDs that may be useful in certain instances (U.S. EPA, 2009h). Please see that Appendix for details. The screening IUR is listed in Table 3 (U .S. EPA, 2009h).FINAL9-30-200922Table 3. Toxicity Values for the Medium Carbon Range Aliphatic Fraction: C9–C18, EC > 8–EC16aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOEOSF (permg/kg-day)IUR(perμg/m3)DatebPPRTV Values9 9n-NonaneINPROC10 10n-DecaneINPROC

PPRTV (U.S. EPA, date in last column)9–18 8–16 Aliphatic hydrocarbonstreams/solvents withinthe C9–C18 range andcontaining <0.5% to <1%aromaticssRfD:1 × 10-1, liver, kidney andhematologic effects, Anonymous, 1990,1991a,b (*Screening Value)RfD:1 × 10-2, based on same study asthe sRfD(*Screening Value)sRfC:1 × 10-1, nasal goblet cellhypertrophy, NTP, 2004RfC:1 × 10-1, nasal goblet cellhypertrophy and adrenalhyperplasia, NTP, 2004SuggestiveevidenceInadequatedata4.5 × 10-6,benign ormalignantadrenalpheochromocytoma,NTP, 2004(*ScreeningValue)2009hOther Peer-Reviewed or Relevant Toxicity Values

MADEP (2003)9–18 8–16 Aliphatic hydrocarbonstreams within theC9–C18 range andcontaining<0.5% aromaticsRfD:1 × 10-1, liver effects,Anonymous, 1990, 1991a,bRfC:2 × 10-1, neurologicaleffects, Lund et al., 1995NotassessedNot assessed Not assessed–

TPHCW G (1997b)9–18 8–16 Aliphatic hydrocarbonstreams within theC9–C18 range andcontaining<0.5% aromaticsRfD:1 × 10-1, liver effects, unpublishedstudies not further referencedRfC:1 × 100, NOAELs, multiplestudiesNotassessedNot assessed Not assessed–aComplete citations for the principal studies can befound in the source documents (e.g., MADEP, 2003).bDate of PPRTV; dates for MADEP and TPHCWG are provided in far left column of table.*Screening values are developed in the Appendix ofa PPRTV. For example, in cases where a high degreeof uncertainty exists. Screening Values are intended for use in limitedcircumstances when no Tier 1, 2, or 3 values are available.C = carbon number, EC = equivalent carbon number index, INPROC = in process, IUR = inhalation unit risk, MADEP = Massachusetts Department of Environmental Protection,NOAEL = no-observed-adverse-effect level, OSF = oral slope factor, p- = provisional, PPRTV = Provisional Peer-Reviewed Toxicity Value, RfC = inhalation referenceconcentration, sRfC = subchronic RfC, RfD = oral reference dose, sRfD = subchronic RfD, TPHCWG = Total Petroleum Hydrocarbon Criteria Working Group, WOE =weight ofevidence

### FINAL



### 9-30-2009

23 High Carbon Range Aliphatic Fraction: C19–C32, EC > 16–EC35 This fraction includes longer n- 

### alkanes, such as eicosane, and branched and cyclic alkanes. Toxicity values are not available for the individual compounds. A search for toxicity information on eicosane in particular was desirable because MADEP (1994) had suggested it as a reference compound for this fraction, but data supp ortive of derivation of toxicity values were not located. Food-grade and medicinal-grade minera l oils are pure (aromatic-free) mixtures of aliphatic hydrocarbons that correspond to this carb on range fraction and have data suitable for toxicity-value derivation. Both MADEP (2003) and T PHCWG (1997b) have based RfDs on these data. To support this update of the PPRTV on aliphatic and aromatic hydrocarbons, literature searches on mineral oils were performed and the medical literature on mineral oils was consulted. Oral PPRTVs and a cancer assessment, in cluding a WOE of “ Inadequate Information to Assess the Carcinogenic Potential” 

### of white mineral oil, were derived (U.S. EPA, 2009 i) using current U.S. EPA methods. Table 4 summarizes the resulting values and the previous

MADEP and TPHCWG values. The PPRTVs are recommende d for assessment of this fraction.

Toxicity Values for Aromatic Fractions Low Carbon Range Aromatic Fraction: C6–C8, EC6–EC < 9 This fraction contains aromatic hydrocarbons in th e C6-C8 range: benzene, toluene. ethylbenzene, and o 

### -, m 

### -, and p 

### -xylenes (commonly referred to as BTEX). The TPHCW G (1997b) defined this fraction variously as EC > 7

– EC8 and EC5

– EC8. Benzene was not

included in the noncancer assessment because it was a carcinogenic indicator compound. Toluene, ethylbenzene, styrene, and xylene were inc luded, but, with the exception of toluene, the EC values for these C8 compounds are all >8 (and <9 ), so it appears that the TPHCWG (1997b) was using actual C number rather than EC number. T he MADEP recommended that the low-carbon-range aromatics (BTEX [MADEP 1994, 2003] and styrene [MADEP, 2003]) be assessed individually. It is unclear, however, whe ther styrene is a constituent of petroleum products. For example, styrene is not reported as a constituent of any of the petroleum mixtures including gasoline, kerosene, jet fuels, diesel fue l, fuel oils, lubricating and motor oils, and crude oil in the TPHCWG (1998b) Volume 2. The TPHCWG (19 97a) Volume 3 lists styrene as a constituent for only one mixture, diesel, at a very low weight percentage of <0.002%, which may mean that it was detected but was below the quantit ation limit. The reference provided for that information is a personal communication prepared fo r British Petroleum; thus, the information cannot readily be confirmed.

Because U.S. EPA toxicity values and cancer assess ments are available for the individual compounds in this fraction, and because the BTEX ro utinely are monitored at sites of aromatic hydrocarbon contamination, the recommendation for t his fraction is to assess the BTEX individually. Consistent with this recommendation, the low carbon range aromatic fraction is

defined as a C6

– C8 and EC6

– EC < 9 fraction so that it includes all of the BTEX . RfDs, RfCs, and cancer assessments are available on IRIS (U.S. EPA, 2009o) for these compounds, and provisional toxicity values were derived for subchr onic oral and inhalation exposure (U.S. EPA, 2009a-d) as part of this effort. The HE AST (U.S. EPA, 1997) lists some values or assessments for the compounds, but they are superse ded by the newer IRIS and PPRTV

assessments. ATSDR has derived MRLs for the BTEX a s well, but their methods sometimes

differ from U.S. EPA methods and some of their asse ssments of these compounds are older.

Table 5 summarizes these values and the bases for t heir derivations.FINAL9-30-200924Table 4. Toxicity Values for the High Carbon RangeAliphatic Fraction: C19–C32, EC > 16–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOEOSF (permg/kg-day)IUR(perμg/m3) DatebPPRTV Values

PPRTV (U.S. EPA, date in last column)19–32 >16–35 White mineral oilsgenerally in the C andEC range of interestsRfD:3 × 101lower end of humantherapeutic dose range for laxativeeffects, NASPGHN, 2006RfD:3 × 100, based on same data as thesRfDsRfC:NARfC:NAInadequateinformationto assessInadequatedataNA 2009iOther Peer-Reviewed or Relevant Toxicity Values

MADEP (2003)19–32 >16–35 White mineral oilsgenerally in the C andEC range of interestRfD:2 × 100, liver granuloma Smith etal., 1996RfC:Inadequate data, not volatile Not assessedNot assessedNot assessed –

TPHCWG (1997b)19–32 >16–35 White mineral oilsgenerally in the C andEC range of interestRfD:2 × 100, liver granuloma, Smith etal., 1996RfC:Not assessed Not assessedNot assessedNot assessed –aComplete citations for the principal studies can befound in the source documents (e.g., MADEP, 2003).bDate of PPRTV; dates for MADEP and TPHCWG are provided in far left column of table.C = carbon number, EC = equivalent carbon number index, IUR = inhalation unit risk, MADEP = Massachusetts Department of Environmental Protection; NA = Not applicable,OSF = oral slope factor, p- = provisional, PPRTV =Provisional Peer-Reviewed Toxicity Value, PTV = Provisional Toxicity Value (draft); RfC = inhalation referenceconcentration, sRfC = subchronic RfC, RfD = oral reference dose, sRfD = subchronic RfD, TPHCWG = TotalPetroleum Hydrocarbon Criteria Working Group, WOE= weight ofevidenceFINAL9-30-200925Table 5. Toxicity Values for the Low Carbon RangeAromatic Fraction: C6–C8, EC6–EC < 9aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOEOSF (permg/kg-day)IUR(perμg/m3) DatebIRIS and PPRTV Values6 6.5 BenzeneRfD:4 × 10-3, decreased lymphocytecount, Rothman et al., 1996,extrapolated from inhalationRfC:3 × 10-2, decreasedlymphocyte count, Rothman etal., 1996Group A(humancarcinogen),known/likelyhumancarcinogen1.5 × 10-2to5.5 × 10-2,leukemia,several studies,extrapolatedfrom inhalation2.2 × 10-2to7.8 × 10-6,leukemia,severalstudies2003/2000-cancer7 7.58 TolueneRfD:8 × 10-2, increased kidney weight,NTP, 1990RfC:5 × 100, neurologicaleffects, multiple studiesInadequatedataNA NA 20058 8.5 EthylbenzeneRfD:1 × 10-1, liver and kidney lesions,Wolf et al., 1956RfC:1 × 100, developmentaleffects, Andrew et al., 1981;Hardin et al., 1981Group D (notclassifiable)NA NA 1991

IRIS (U.S. EPA, 2009o)8 8.6–8.81XylenesRfD:2 × 10-1, decreased body weight,increased mortality, NTP, 1986RfC:1 × 10-1, impaired motorcoordination, Korsak et al.,1994InadequatedataNA NA 20036 6.5 BenzenesRfD:1 × 10-2, decreased lymphocytecount, Rothman et al., 1996,extrapolated from inhalation (U.S. EPA,2009o)RfD:Not assessedsRfC:8 × 10-2, decreasedlymphocyte count, Rothman etal., 1996RfC:Not assessedNot assessed Not assessed Notassessed2009a7 7.58 ToluenesRfD:8 × 10-1, increased kidney weight,NTP, 1990RfD:Not assessedsRfC:5 × 100, neurologicaleffects, multiple studies, U.S.EPA, 2009oRfC:Not assessedNot assessed Not assessed Notassessed2009d8 8.5 EthylbenzenesRfD:5 × 10-2, centrilobular hepatocytehypertrophy, Mellert et al., 2007RfD:Not assessedsRfC:9 × 100, ototoxicity,Gagnaire et al., 2007RfC:Not assessedNot assessed Not assessed Notassessed2009b

PPRTV (U.S. EPA, date in last column)8 8.6–8.81XylenessRfD:4 × 10-1, reduced body weight,Wolfe et al., 1988aRfD:Not assessedsRfC:4 × 10-1,neurologicaleffects, Korsak et al., 1994RfC:Not assessedNot assessed Not assessed Notassessed2009eFINAL9-30-200926Table 5. Toxicity Values for the Low Carbon RangeAromatic Fraction: C6–C8, EC6–EC < 9aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOEOSF (permg/kg-day)IUR(perμg/m3) DatebOther Peer-Reviewed or Relevant Toxicity Values6 6.5 Benzene Not assessedsRfC:[Comment: ContactSuperfund Health RiskTechnical Support Center]RfC:Not assessedNot assessed Not assessed 2.9 × 10-2(permg/kgday),leukemia–7 7.58 ToluenesRfD:2 × 100, altered liver and kidneyweight, NTP, 1989RfD:Not assessedsRfC:[Comment: Contact theSuperfund Health RiskTechnical Support Center]RfC:Not assessedNot assessed Not assessed Notassessed–8 8.5 EthylbenzenesRfD:[Comment: Contact SuperfundHealth Risk Technical Support Center]RfD:Not assessedsRfC: [Comment: ContactSuperfund Health RiskTechnical Support Center]RfC:Not assessedNot assessed Not assessed Notassessed–

HEAST (U.S. EPA, 1997)8 8.6–8.81XylenessRfD:[Comment: Contact SuperfundHealth Risk Technical Support Center]RfD:Not assessedsRfC:Not assessedRfC:Not assessedNot assessed Not assessed Notassessed–6 6.5 BenzeneIntermediate MRL:Inadequate dataChronic MRL:5 × 10-4, extrapolatedfrom inhalationIntermediate MRL:6 × 10-3ppm, delayed spleniclymphocyte reaction to antigens(Rosenthal and Snyder, 1987)RfC:3 × 10-3ppm, decreasedB-lymphocyte counts, Lan et al.,2004a,bNot assessed Not assessed Notassessed2007a7 7.58 TolueneIntermediate MRL:2 × 10-2, regionalincreases in brain monoamineneurotransmitters, Hsieh et al., 1990bChronic MRL:Inadequate dataIntermediate MRL:Inadequatedata; use chronic MRLChronic MRL:8 × 10-2ppm(3 × 10-1mg/m3), color visionimpairment, Zavalic et al.,1998aNot assessed Not assessed Notassessed2000

ATSDR (date in last column)8 8.5 EthylbenzeneIntermediate MRL:Inadequate dataChronic MRL:Inadequate dataIntermediate MRL:1 × 100ppm, developmental effects,Andrew et al., 1981Chronic MRL:Inadequate dataNot assessed Not assessed Notassessed1999cFINAL9-30-200927Table 5. Toxicity Values for the Low Carbon RangeAromatic Fraction: C6–C8, EC6–EC < 9aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOEOSF (permg/kg-day)IUR(perμg/m3) Dateb

ATSDR (date in last column)8 8.6–8.81XylenesIntermediate MRL:4 × 10-1,neurotoxic effects (NTP, 1986)Chronic MRL:2 × 10-1, decreased bodyweight gain and survival (NTP, 1986)sRfC:6 × 10-1ppm, neurotoxiceffects, Korsak et al., 1994RfC:5 × 10-2ppm, respiratoryand neurological effects, Uchidaet al., 1993Not assessed Not assessed Notassessed2007baComplete citations for the principal studies can befound in the source documents (e.g., IRIS [U.S. EPA, 2009o]).bDate of IRIS assessment (last revision) or of PPRTV; date for the HEAST is provided in far left columnof table.ATSDR = Agency for Toxic Substances and Disease Registry, C = carbon number, EC = equivalent carbon number index, HEAST = Health Effects Assessment summary Table,IRIS = Integrated Risk Information System, IUR = inhalation unit risk, MRL = Minimal Risk Level, NA =Not applicable, OSF = oral slope factor, PPRTV = Provisional PeerReviewed Toxicity Value, PTV = Provisional ToxicityValue (draft), RfC = inhalation reference concentration, sRfC = subchronic RfC, RfD = oral referencedose, sRfD =subchronic RfD, RPF = Relative potency factor, WOE= weight of evidence

### FINAL



### 9-30-2009

28 The IRIS RfDs, RfCs, and cancer assessments and th e PPRTVs (subchronic p-RfDs and subchronic p-RfCs) provided in Table 5 are the reco mmended values for assessment of the components of this fraction.

Medium Carbon Range Aromatic Fraction: C9–C16, EC9– EC < 22 The MADEP (2003) grouped the entire range of aroma tics from C9

– C32 into a single

fraction for the assessment of oral noncancer toxic ity and divided the fraction into C9

– C18 and

C19

– C32 fractions for the assessment of inhalation nonc ancer toxicity. The TPHCWG (1997a, b) defined their transport fractions by EC number rather than C number, but in selecting and deriving toxicity values, they actually used th e C number range of C>8

– C16 rather than the EC number range (TPHCWG, 1997b). For the aromatic hydrocarbons, the difference between C and EC can be large (e.g., the C16 compound fluoran thene has an EC of 21.85). An EC range of

EC9

– EC < 22 is recommended in this document, which corr esponds to a C range of about

C9

– C16, for this medium carbon range aromatic fraction based on environmental transport and toxicological considerations—including volatility a nd carcinogenicity. This fraction is virtually the same as the fraction defined by the TPHCWG (199 7b).

This medium carbon range aromatic fraction include s longer chain and multi-substituted benzenes (e.g., cumene [isopropylbenzene], n- 

### propylbenzene, methylethylbenzenes, and trimethylbenzenes), indan, methylindans, naphthalen es, and some lower molecular weight PAHs (e.g., acenaphthylene, acenaphthene, fluorene, phen anthrene, anthracene, and pyrene). As listed in Table 6, toxicity values and cancer assessments are available for some of these individual compounds. IRIS values include RfDs for cumene, na pththalene, 2-methylnaphthalene, 1,1-biphenyl, acenaphthene, fluorene, anthracene, a nd pyrene, RfCs for cumene and naphthalene and only qualitative cancer assessments for many of these compounds with the exception of an oral slope factor (OSF) for benzo(a)pyrene. Also l isted in Table 6 are a mix of provisional toxicity values including values for p-RfDs, subchr onic p-RfDs, p-RfCs, subchronic p-RfCs, pOSFs, screening RPFs, cancer assessments, and scree ning p-RfDs, subchronic p-RfDs, p-RfCs and subchronic p-RfCs (see entries for n- 

### propylbenzene, 1,3,5-trimethylbenzene, 1,2,4-trimethylbenzene, high-flash aromatic naphtha , 2-methylnaphthalene, 1-methylnaphthalene, anthracene, pyrene, and benz(a )anthracene). A PPRTV for 1,2,3- trimethylbenzene is completed (U.S. EPA, 2009k); in formation from that PPRTV will be considered for use in evaluating hydrocarbon mixtur es when this mixtures PPRTV document is revised. Table 6 includes both the medium and high carbon range fractions to facilitate evaluation of the selected C and EC ranges for thes e two fractions, and because of the overlap between ranges in the MADEP approach and the TPHCWG ’s classification by C rather than the EC number range.FINAL9-30-200929Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) DatebIRIS and PPRTV Values9 9.13 Cumene(isopropylbenzene)RfD:1 × 10-1, increased kidneyweight, Wolf et al., 1956RfC:4 × 10-1, increasedkidney and adrenal weights,Cushman et al., 1995Group D (notclassifiable)NA NA 199710 11.69 NaphthaleneRfD:2 × 10-2, decreased bodyweight, BCL, 1980RfC:3 × 10-3, nasal lesions,NTP, 1992Group C(possiblehumancarcinogen)InadequatedataInadequatedata199811 12.84 2-MethylnaphthaleneRfD:4 × 10-3, alveolar proteinosis,Murata et al., 1997Inadequate data InadequatedataNA NA 200312 14.26 1,1-BiphenylRfD:5 × 10-2, kidney damage,Ambrose et al., 1960Inadequate DataGroup D (notclassifiable)NA NA 1989/199112 15.06 Acenaphthylene Not assessed Not AssessedGroup D (notclassifiable)InadequatedataInadequatedata199112 15.5 AcenaphtheneRfD:6 × 10-2, hepatotoxicity,U.S. EPA, 1989Not Assessed Not assessedNotassessedNotassessed199413 16.55 FluoreneRfD:4 × 10-2, decreased red bloodcells, packed cell volume and Hgb,U.S. EPA, 1989Not assessedGroup D (notclassifiable)NA NA 199014 19.36 Phenanthrene Not assessed Not assessedGroup D (notclassifiable)NA NA 1990

IRIS (U.S. EPA, 2009o), RPF from U.S. EPA (1993)14 19.43 AnthraceneRfD:3 × 10-1, freestanding NOEL,U.S. EPA, 1989Not AssessedGroup D (notclassifiable)NA NA 1993/1991FINAL9-30-200930Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) Dateb16 20.8 PyreneRfD:3 × 10-2, kidney effects,U.S. EPA, 1989Not assessedGroup D (notclassifiable)NA NA 1993/199116 21.85 FluorantheneRfD:4 × 10-2, kidney, liver,hematologic and clinical effects,U.S. EPA, 1988Not assessedGroup D (notclassifiable)NA NA 1993/199018 26.37 Benz(a)anthracene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=0.1NotassessedNotassessed1994

IRIS (U.S. EPA, 2 009o), RPF from U.S. EPA (1993)18 27.41 Chrysene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=0.001InadequatedataInadequatedata199420 30.14 Benzo(b)fluoranthene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=0.1InadequatedataInadequatedata1994

IRIS (U.S. EPA, 2009o), RPF from U.S. EPA20 30.14 Benzo(k)fluoranthene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=0.01InadequatedataInadequatedata1994FINAL9-30-200931Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kgday)IUR(perμg/m3) Dateb20 31.34 Benzo(a)pyrene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=17.3× 100,forestomach(larynx,esophagus)4 data setsNotassessed199422 33.92 Dibenz(a,h)anthracene Not assessed Not assessed Group B2(probablehumancarcinogen),RPF=1InadequatedataInadequatedata199422 34.14 Benzo(g,h,i)perylene Not assessed Not assessedGroup D (notclassifiable)NA NA 1990

IRIS (U.S. EPA, 2009o), RPF from U.S. EPA22 35.01 Indeno(1,2,3-c,d)pyreneNot assessed Not assessed Group B2(probablehumancarcinogen),RPF=0.1InadequatedataInadequatedata1994

PPRTV (U.S. EPA, date in last column)9 9.47n-PropylbenzenesRfD:1 × 10-1, liver and kidneytoxicity, based on IRIS RfD forethylbenzene, Wolf et al., 1956,using a surrogate analysisRfD:1 × 10-1, liver and kidneytoxicity, based on IRIS RfD forethylbenzene, Wolf et al., 1956,using a surrogate analysis(*Screening Values)sRfC:1 × 100, developmentaltoxicity, based on IRIS RfCfor ethylbenzene, Andrews etal., 1981; Hardin et al., 1981,using a surrogate analysisRfC:1 × 100, developmentaltoxicity, based on IRIS RfCfor ethylbenzene, Andrews etal., 1981; Hardin et al., 1981,using a surrogate analysis(*Screening Values)InadequatedataNA NA 2009jFINAL9-30-200932Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kgday)IUR(perμg/m3) Dateb9 9.62 1,3,5-TrimethylbenzenesRfD:1 × 10-1, increased liverweight, Koch Industries, 1995RfD:1 × 10-2, increased liverweight, Koch Industries, 1995(*Screening Values)sRfC:1 × 10-2, Wiaderna etal., 2002RfC:Inadequate dataInadequatedataNA NA 2009k9 9.84 1,2,4-TrimethylbenzenesRfD:Inadequate dataRfD:Inadequate datasRfC:7 × 10-2, decreasedclotting time, Korsak et al.,2000RfC:7 × 10-3, based on sRfCstudyInadequatedataInadequatedataInadequatedata2007f9 10.06 1,2,3-TrimethylbenzeneINPROC10 9.84 tert-ButylbenzenesRfD:Inadequate dataRfD:Inadequate datasRFC:Inadequate dataRfC:Inadequate dataInadequatedataInadequatedataInadequatedata2004a,b,c10 9.98 sec-ButylbenzenesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataInadequatedataInadequatedataInadequatedata2004a,b,c10 10.5n-ButylbenzenesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataInadequatedataInadequatedataInadequatedata2004a,b,c

PPRTV (U.S. EPA, date in last column)9-10 High-flash aromaticnaphthasRfD:3 × 10-1, anemia,Bio/Dynamics, 1990bRfD:3 × 10-2, from sRfD study(*Screening Values)sRfC:1 × 100maternal bodyweight depression, McKee etal.,1990RfC:1 × 10-1, from sRfCstudyInadequateinformationto assessInadequatedataInadequatedata2009g11 12.84 2-MethylnaphthalenesRfD: 4 × 10-3, alveolar proteinosis,Murata et al., 1997RfD:Not assessedsRfC:Inadequate dataRfC:Inadequate dataInadequatedataNA NA 2007c

PPRTV (U.S. EPA, date in last column)11 12.99 1-MethylnaphthaleneRfD:7 × 10-3(*Screening value)sRfC:Inadequate dataRfC:Inadequate dataSuggestiveevidence2.9× 10-2Inadequatedata2008FINAL9-30-200933Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) Dateb12 15.06 AcenaphthylenesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataInadequatedataNA NA 2009l14 19.36 PhenanthrenesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataGroup D (notclassifiable)NA NA 2009m14 19.43 AnthracenesRfD:1 × 100free standing NOEL,Wolfe, 1989 (RfD on IRIS)sRfC:Inadequate dataRfC:Inadequate dataInadequatedataNA NA 2009n16 20.8 PyrenesRfD:3 × 10-1, kidney damage,U.S. EPA, 1989RfD:Not assessedsRfC:Inadequate dataRfC:Inadequate dataNot likely tobe a humancarcinogenInadequatedataInadequatedata2007e18 26.37 Benz(a)anthracenesRfD:Not assessedRfD:Inadequate datasRfC:Not assessedRfC:Inadequate dataNot assessed,RPF=0.1(*ScreeningValue)InadequatedataNotassessed2007b

PPRTV (U.S. EPA, date in last column)20 31.34 PerylenesRfD:Inadequate dataRfD:Inadequate datasRfC:Inadequate dataRfC:Inadequate dataInadequatedataInadequatedataInadequatedata2007dOther Peer-Reviewed or Relevant Toxicity Values9 9.13 Cumene(isopropylbenzene)sRfD:4 × 10-1, increased kidneyweight, Wolf et al., 1956sRfC:9 × 10-2CNS effect,nasal irritation, Monsanto Co.,1986RfC:9 × 10-3, CNS effect,nasal irritation, Monsanto Co.,1986Not assessedNotassessedNotassessed–12 14.26 1,1-BiphenylsRfD:5 × 10-2kidney damage,Ambrose et al., 1960 (RfD on IRIS)RfC:considered not verifiableby RfD/RfC Work GroupNot assessedNotassessedNotassessed–

HEAST (U.S. EPA, 1997)12 15.5 AcenaphthenesRfD:6 × 10-1, liver effects, U.S.EPA, 1989Not assessed Not assessedNotassessedNotassessed–FINAL9-30-200934Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) Dateb13 16.55 FluorenesRfD:4 × 10-1, decreased red bloodcells, U.S. EPA, 1989Not assessed Not assessedNotassessedNotassessed–14 19.43 AnthracenesRfD:3 × 100, freestanding NOEL,U.S. EPA, 1989RfC:considered not verifiableby RfD/RfC Work GroupNot assessedNotassessedNotassessed–16 20.8 PyrenesRfD:3 × 10-1, kidney damage,U.S. EPA, 1989RfC:considered not verifiableby RfD/RfC Work GroupNot assessedNotassessedNotassessed–

HEAST (U.S. EPA, 1997)16 21.85 FluoranthenesRfD:4 × 10-1, kidney, liver andhematologic effects, U.S. EPA,1988RfC:considered not verifiableby RfD/RfC Work GroupNot assessedNotassessedNotassessed–

MADEP (2003)9-10 High flash aromaticnaphthaNot assessedRfC:5 × 10-2, increased liverweight and possible CNSeffects, Clark et al., 1989Not assessedNotassessedNotassessed–

TPHCWG (1997b)9 9.47 High-flash aromaticnaphtha (called C9Aromatics byTPHCWG)Not assessedRfC:2 × 10-1, increased liverand kidney weight, Clark etal., 1989Not assessedNotassessedNotassessed–10 11.69 NaphthaleneIntermediate MRL:6 × 10-1,transient CNS signs rat dams, NTP,1991Chronic MRL: Inadequate dataIntermediate MRL:Inadequate dataChronic MRL:7 × 10-4ppm(3 × 10-3mg/m3), nasallesions, NTP, 2000Not assessedNotassessedNotassessed2005

ATSDR (date in last column)11 12.84 2-MethylnaphthaleneIntermediate MRL:InadequatedataChronic MRL:4 × 10-2, alveolarproteinosis, Murata et al., 1993Intermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed2005FINAL9-30-200935Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) Dateb

ATSDR (date in last column)11 12.99 1-MethylnaphthaleneIntermediate MRL:InadequatedataChronic MRL:7 × 10-2, alveolarproteinosis, Murata et al., 1997Intermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed200512 15.5 AcenaphtheneIntermediate MRL:6 × 10-1,livereffects, U.S. EPA, 1989cChronic MRL: Inadequate dataIntermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed199513 16.55 FluoreneIntermediate MRL:4 × 10-1, livereffects, U.S. EPA, 1989eChronic MRL: Inadequate dataIntermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed199514 19.43 AnthraceneIntermediate MRL:1 × 101, freestanding NOAEL (concern for livereffects), U.S. EPA, 1989dChronic MRL: Inadequate dataIntermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed1995

ATSDR (date in last column)16 21.85 FluorantheneIntermediate MRL:4 × 10-1, livereffects, U.S. EPA, 1989eChronic MRL: Inadequate dataIntermediate and chronicMRL: Inadequate dataNot assessedNotassessedNotassessed1995FINAL9-30-200936Table 6. Toxicity Values for the Medium and High Carbon Range Aromatic Fractions:C9–C16, EC9–EC < 22 and C17–C32, EC22–EC35aDerived Value

SourceC EC NameOral (mg/kg-day) Inhalation (mg/m3)CancerWOE, RPFOSF (permg/kg-day)IUR(perμg/m3) DatebaComplete citations for the principal studies can befound in the source documents (e.g., IRIS [U.S. EPA, 2009o]).bDate of IRIS assessment (last revision), PPRTV, orATSDR toxicological profile; dates for HEAST, MADEP, and TPHCWG are provided in far left column oftable.*Screening values are developed in the Appendix ofa PPRTV. For example, in cases where a high degreeof uncertainty exists . Screening Values are intendedfor use in limited circumstances when no Tier 1, 2,or 3 values are available.RPF = Relative potency factor (U.S. EPA, 1993) listed with IRIS Cancer WOE for convenience of the reader.ATSDR = Agency for Toxic Substances and Disease Registry, C = carbon number, CNS = central nervous system, EC = equivalent carbon number index,HEAST = Health Effects Assessment summary Table, INPROC = in process, IRIS = Integrated Risk Information System, IUR = inhalation unit risk, MADEP =Massachusetts Department of Environmental Protection, MRL = Minimal Risk Level, NA = Not applicable, NOEL = no-observed-effect level, OSF = oral slopefactor, p- = provisional, PPRTV = Provisional Peer-Reviewed Toxicity Value, PTV = Provisional ToxicityValue (draft), RfC = inhalation referenceconcentration, sRfC = subchronic RfC, RfD = oral reference dose, sRfD = subchronic RfD, RPF = Relativepotency factor, TPHCWG = Total PetroleumHydrocarbon Criteria Working Group, WOE = weight ofevidence

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### 9-30-2009

37 A mixture of predominantly C9

– C10 alkylbenzenes, high-flash aromatic naphtha, has been studied toxicologically. Basing a value for a t least the alkyl benzenes on a mixture, rather than a single chemical, is preferable since the dat a support development of toxicity values. Although MADEP (2003) and TPHCWG (1997b) derived in halation RfCs for this mixture, some additional studies were located, including oral stu dies, and it was considered advisable to perform an updated assessment using current U.S. EP A methods. Therefore, a PPRTV document was developed for high-flash aromatic naph tha (U.S. EPA, 2009g). The PPRTVs for high-flash aromatic naphtha, listed in Table 6, inc lude subchronic and chronic p-RfCs. In addition, Table 6 contains several screening values for high-flash aromatic naphtha that may be useful in evaluating this fraction, developed in Ap pendix A of U.S. EPA (2009g). Because the toxicity data based on the three unpublished studie s (Bio/Dynamics Inc., 1990a,;b; Mobil Oil Corporation, 1994) are not peer-reviewed, only scre ening chronic or subchronic RfDs are

available in Table 6. Subchronic and chronic RfD v alues for individual alkylbenzenes in Table 6 ( n- 

### propylbenzene, 1,3,5-trimethylbenzene) are also lim ited to screening values due to database

weaknesses.

The effects of compounds in this fraction are comm only kidney, liver, and body weight effects. Hematological effects are seen with some of these compounds. The subchronic and chronic p-RfCs and subchronic and chronic screening RfDs derived for high-flash aromatic naphtha are the same order of magnitude as those fo r the single compounds in this fraction, including biphenyl and the low molecular weight PAH s. Exceptions on IRIS are the 2-methylnaphthalene RfD, which is an order of magni tude lower and is based on alveolar proteinosis, and the naphthalene RfC, which is two orders of magnitude lower and based on nasal lesions. Other exceptions are the p-RfD for 1-methylnaphthalene, which is, however, only a screening value, and subchronic p-RfC and p-RfC v alues for 1,3,5-trimethylbenzene and 1,2,4-trimethylbenzene.

According to MADEP (2003), both naphthalene and 2- methylnaphthalene are target analytes assessed separately under the Massachusett s Contingency Plan. The recommendation in this PPRTV is to assess exposure to these compounds separately if possible, using their specific toxicity values (oral RfD and subchronic p-RfD for 2-methylnaphthalene, oral RfD and inhalation RfC for naphthalene). Their mass should be subtracted from the total fraction mass before use of the high-flash aromatic naphtha toxic ity values listed in Table 6 for the remaining fraction. Specific monitoring data are unlikely to be available for 1-methylnaphthalene or the trimethylbenzene isomers, but if such data are avai lable, then these chemicals could be treated similarly to naphthalene and 2-methylnaphthalene.

Because high-flash aromatic naphtha is a mixture o f predominantly C9

– C10 alkylbenzenes, the provisional values for this mixt ure are most relevant to the alkylbenzene portion of this fraction. Although there may be gr eater uncertainty involved in using these values when the fraction includes less closely stru cturally-related compounds, the available toxicity values for these other compounds (1,1-biph enyl, and the lower molecular weight PAHs, listed in Table 6) are similar to those for high-fl ash aromatic naphtha, which supports the use of that mixture as a surrogate for the fraction. Carc inogenicity data are generally inadequate for compounds in this fraction and also for high-flash aromatic naphtha.

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38 High Carbon Range Aromatic Fraction: C17–C32, EC22– EC35 To help readers understand clearly the U.S. EPA ap proach for this fraction, a brief explanation is provided here, followed by more exte nsive discussions below. For noncancer oral toxicity values, fluoranthene, an IRIS and HEAST li sted chemical, was selected as a surrogate. Since this fraction is basically nonvolatile, no in halation toxicity values were attempted. For cancer toxicity values, seven PAH are to be evaluat ed together as indicator components for this fraction, using the RPF method. As shown in Table 6, these seven are IRIS-listed B2 carcinogenic PAHs with RPFs from U.S. EPA, 1993 (i. e., benzo[a]pyrene, benz[a]anthracene, chrysene, benzo[b]fluoranthene, benzo[k]fluoranthen e, dibenz[a,h]anthracene, indeno[1,2,3-c,d]pyrene).

As explained previously, MADEP grouped the entire range of aromatics from C9

– C32 into a single fraction for the assessment of oral n oncancer toxicity and divided the fraction into

C9

– C18 and C19

– C32 fractions for the assessment of inhalation nonc ancer toxicity. The TPHCWG (1997a) defined their transport fractions by EC number rather than C number, but in selecting and deriving toxicity values, they actual ly used the C number ranges. Because the EC value for aromatic hydrocarbons is higher than the C value, the low end of their fraction range actually was EC22, rather than the stated EC > 16 ( TPHCWG, 1997b). The use of the EC number range of EC22

– EC35 is recommended in this document, which corresp onds to a C number range of about C17

– C32, for the high carbon range aromatic fraction ba sed on environmental transport and toxicological considera tions, including volatility and carcinogenicity. This fraction is virtually the sa me as the fraction defined by the TPHCWG (1997b).

This fraction includes the medium and high molecul ar weight PAHs, which generally are not volatile when released to soil or water (ATSDR, 1995) 4 

### . Although PAHs can bind to soil particulates, methods and data to estimate toxicity values or assess risk from inhaled soil-particulate-bound PAHs are not available.

Data on noncancer toxicity are limited for the PAHs of this fraction, and RfDs, RfCs, and

MRLs have not been derived for them. The noncancer oral toxicity of this fraction can be assessed through the use of the oral toxicity value s for fluoranthene. Although fluoranthene is a C16 compound, it has an EC of 21.85, which is very close to the lower end (22) of the EC range

for this fraction. The RfD for fluoranthene is ava ilable on IRIS and the subchronic RfD, based on the same study, is listed in the HEAST. Table 6 reports these values. The uncertainty involved in the use of fluoranthene as a surrogate for the noncancer oral toxicity of this fraction is high due to the lack of relevant data on the non cancer toxicity of the compounds in this

fraction.

A cancer slope factor is available only for the Gro up B2 (probable human carcinogen) PAH benzo(a)pyrene. The other six Group B2 PAHs ca n be assessed using the RPFs estimated and recommended by U.S. EPA (1993). This is an ind icator component method that assumes the carcinogenicity of the fraction is approximated by the components with known carcinogenicity

4 When released to air through combustion processes, these PAHs exist primarily in the particulate phase —except for chrysene and benzo(a)anthracene, which can exist pa rtially in the vapor phase (ATSDR, 1995). PAHs cre ated and released to air by combustion, however, are not wit hin the scope of this document on aliphatic and aro matic hydrocarbons.

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### 9-30-2009

39 and quantitative estimates (slope factor or RPF). When U.S. EPA develops new RPFs for additional PAHs or recommends changes in the curren t set of seven RPF values for evaluation of the PAHs, these can be incorporated into the risk a ssessment.

CONCLUSIONS AND RECOMMENDATIONS

Building upon the contributions of MADEP and TPHCW G to the fractional approach for evaluation of hazard/risk of exposure to petroleum hydrocarbons (see Appendix A), this PPRTV document updates and expands the selection and deri vation of toxicity values to include both subchronic and chronic RfDs and RfCs, as well as ca ncer WOE assessments, OSFs, and IURs. Newer data and updated U.S. EPA methods are used to provide new provisional assessments (U.S. EPA, 2009a-i) as needed and supported by the available data. The approach is generally consistent with the MADEP and the TPHCWG approaches , using toxicity values for a surrogate compound or similar mixture to represent the toxici ty of the fraction. Where the components of the fraction vary in type or potency of toxic actio n, it is recommended that the more toxic component (e.g., n- 

### hexane of the low range aliphatic fraction) be used as the surrogate when it exceeds the percentage in the surrogate mixture (e. g., commercial hexane, inhalation assessment), or when other suitable values are not available for the exposure route (oral). In some cases, a components method is recommended: i.e ., for the BTEX (low carbon range aromatic fraction); and for seven PAHs of the high carbon range aromatic fraction, which are IRIS-listed Group B2 (probable human carcinogen) ca rcinogenic PAHs with RPFs from U.S. EPA (1993). A combination components and surrogate mixture approach is recommended for the medium carbon range aromatic fraction, with the target analytes naphthalene and 2-methylnaphthalene assessed separately using their specific toxicity values (oral for both compounds and inhalation for naphthalene). The mas s of the target analyte(s) is subtracted from the fraction mass, which is then assessed using tox icity values for the surrogate mixture (highflash aromatic naphtha).

The recommended toxicity values and cancer assessm ents and methods are summarized in Table 7 (noncancer oral), Table 8 (noncancer inh alation), and Table 9 (cancer oral and inhalation). The rationales for these recommendati ons have been presented in previous sections of this document. The use of additivity methods (U .S. EPA, 1986, 1989, 1993, 2000) is recommended when applicable to assess potential ris k within and across fractions. These

methods include the HI for noncancer effects of ora l and inhalation exposure, RPFs for the Group B2 (probable human carcinogen) PAHs, and resp onse addition for assessing cancer risk across fractions. These methods are essentially co mponent-based methods wherein the fractions (or in the cases described previously, individual c hemicals in the fraction) are considered components of aliphatic and aromatic hydrocarbons.

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40 Table 7. Recommended Oral Noncancer Toxicity Value s for Aliphatic and Aromatic Hydrocarbon Fractions a

Aliphatics

Fraction: Surrogate or Components sRfD (mg/kg-day) Source RfD (mg/kg-day) Source

Low carbon range C5–C8, EC5–EC8:

n- hexane 3 × 10 -1 , reduced nerve

conduction velocity, Ono et al., 1981 PPRTV

(U.S. EPA, 2009c) Not assessed under

IRIS program IRIS (U.S. EPA,

2009j)

Medium carbon range C9–C18, EC > 8–EC16:

Hydrocarbon

streams or solvents within the range and containing <1%

aromatics 1 × 10 -1 , liver, kidney

and hematologic effects, Anonymous, 1990, 1991a,b (*Screening value) PPRTV

(U.S. EPA, 2009h) 1 × 10 -2 , liver, kidney

and hematologic effects, Anonymous, 1990, 1991a,b (*Screening value) PPRTV

(U.S. EPA, 2009h)

High carbon range C19–C32, EC > 16–EC35:

White mineral oils generally within the

range 3 × 10 1 , lower end of

human therapeutic dose range for laxative effects, NASPGHN,

2006 PPRTV

(U.S. EPA, 2009i) 3 × 10 0 , lower end of

human therapeutic dose range for laxative effects, NASPGHN,

2006 PPRTV

(U.S. EPA, 2009i)

Aromatics

Fraction: Surrogate or Components sRfD (mg/kg-day) Source RfD (mg/kg-day) Source

Low carbon range C6–C8, EC6–EC < 9:

Benzene 1 × 10 -2 , decreased

lymphocyte count, Rothman et al., 1996, extrapolated from inhalation, U.S. EPA, 2009j PPRTV

(U.S. EPA, 2009a) 4 × 10 -3 , decreased

lymphocyte count, Rothman et al., 1996, extrapolated from

inhalation IRIS

(U.S. EPA, 2009j)

Toluene 8 × 10 -1 , increased

kidney weight, NTP,

1990 PPRTV

(U.S. EPA, 2009d) 8 × 10 -2 , increased

kidney weight, NTP,

1990 IRIS

(U.S. EPA, 2009j)

Ethylbenzene b 5 × 10 -2 , centrilobular

hepatic hypertrophy, Mellert et al., 2007 PPRTV

(U.S. EPA, 2009b) 1 × 10 -1 , liver and

kidney lesions, Wolf et al., 1956 IRIS

(U.S. EPA, 2009j)

Xylenes 4 × 10 -1 , reduced body

weight, Wolfe et al.,

1988a PPRTV

(U.S. EPA, 2009e) 2 × 10 -1 , decreased

body weight, increased mortality, NTP, 1986 IRIS

(U.S. EPA, 2009j)

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41 Table 7. Recommended Oral Noncancer Toxicity Value s for Aliphatic and Aromatic Hydrocarbon Fractions a

Aromatics (cont’d)

Fraction: Surrogate or Components sRfD (mg/kg-day) Source RfD (mg/kg-day) Source

Medium carbon range C9–C16, EC9–EC < 22:

High flash aromatic naphtha (except naphthalene and 2-naphthalene) 3 × 10 -1 , anemia,

Bio/Dynamics, 1990b (*Screening Value) PPRTV

(US. EPA, 2009g) 3 × 10 -2 , anemia,

Bio/Dynamics, 1990b (*Screening Value) PPRTV

(US. EPA, 2009g)

Naphthalene Not available – 2 × 10 -2 , decreased body weight, BCL,

1980 IRIS

(U.S. EPA, 2009j)

2-Methylnaphthalene 4 × 10 -3 , alveolar

proteinosis, Murata et al., 1997 PPRTV

(U.S. EPA, 2007c) 4 × 10 -3 , alveolar

proteinosis, Murata et al., 1997 IRIS

(U.S. EPA, 2009j)

High carbon range C17–C32, EC22–EC35:

Fluoranthene 4 × 10 -1 , kidney, liver

and hematologic effects, U.S. EPA,

1988 HEAST

(U.S. EPA, 1997) 4 × 10 -2 , kidney, liver,

hematologic and clinical effects, U.S.
EPA, 1988 IRIS

(U.S. EPA, 2009j)

a Complete citations for the principal studies can be found in the source documents (e.g., IRIS [U.S. EP A, 2009j]).

b The lower sRfD relative to the RfD for ethylbenzene reflects the more recent derivation of the sRfD (n ew critical study, BMD modeling).

*Screening values are developed in the Appendix of a PPRTV. For example, in cases where a high degree of uncertainty exists. Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3 values are

available. C = carbon number, EC = equivalent carbon number in dex, HEAST = Health Effects Assessment summary Tabl e, IRIS = Integrated Risk Information System, PPRTV = Provisional Peer-Reviewed Toxicity Value, RfD = ora l reference dose, sRfD = subchronic RfD

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42 Table 8. Recommended Inhalation Noncancer Toxicity Values for Aliphatic and Aromatic Hydrocarbon Fract ions a

Aliphatics

Fraction: Surrogate or Components sRfC mg/m 3 ) Source RfC (mg/m 3 ) Source

Low carbon range C5–C8, EC5–EC8:

n- hexane, if present

at >53% of fraction 2 × 10 0 , Decreased

motor nerve conduction velocity, Huang et al., 1989 PPRTV

(U.S. EPA, 2009c) 7 × 10 -1 , peripheral

neuropathy, Huang et al., 1989 IRIS

(U.S. EPA, 2009j)

Commercial hexane, if n- hexane

present at ≤ 53% of

fraction 27 × 10 0 , clinical and

histopathological signs of neuropathy, IRDC, 1992a,b PPRTV

(U.S. EPA, 2009f) 6 × 10 -1 , nasal

epithelial cell hyperplasia, Biodynamics, 1993a; Daughtrey et al.,1999 PPRTV

(U.S. EPA, 2009f)

Medium carbon range C9–C18, EC > 8–EC16:

Hydrocarbon

streams or solvents within the range and containing <1%

aromatics 1 × 10 -1 , nasal goblet

cell hypertrophy, NTP,

2004 PPRTV

(U.S. EPA, 2009h) 1 × 10 -1 , nasal goblet

cell hypertrophy and adrenal hyperplasia,
NTP, 2004 PPRTV

(U.S. EPA, 2009h)

High carbon range C19–C32, EC > 16–EC35:

White mineral oils generally within the

range NA, not volatile PPRTV (U.S. EPA, 2009i) NA, not volatile PPRTV (U.S. EPA, 2009i)

Aromatics

Fraction: Surrogate or Components sRfC( mg/m 3 ) Source RfC (mg/m 3 ) Source

Low carbon range: C6–C8, EC6–EC < 9:

Benzene 8 × 10 -2 , decreased

lymphocyte count, Rothman et al., 1996 PPRTV

(U.S. EPA, 2009a) 3 × 10 -2 , decreased

lymphocyte count, Rothman et al., 1996 IRIS

(U.S. EPA, 2009j)

Toluene 5 × 10 0 , neurological

effects, multiple studies, U.S. EPA, 2009j PPRTV

(U.S. EPA, 2009d) 5 × 10 0 , neurological

effects, multiple

studies IRIS

(U.S. EPA, 2009j)

Ethylbenzene 9 × 10 0 , ototoxic

effects, Gagnaire et al.,

2007 PPRTV

(U.S. EPA, 2009b) 1 × 10 0 , developmental

effects, Andrew et al., 1981; Hardin et al.,

1981 IRIS

(U.S. EPA, 2009j)

Xylenes 4 × 10 -1 , neurological

effects, Korsak et al.,

1994 PPRTV

(U.S. EPA, 2009e) 1 × 10 -1 , impaired

motor coordination, Korsak et al., 1994 IRIS

(U.S. EPA, 2009j)

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43 Table 8. Recommended Inhalation Noncancer Toxicity Values for Aliphatic and Aromatic Hydrocarbon Fract ions a

Aromatics (cont’d)

Fraction: Surrogate or Components sRfC( mg/m 3 ) Source RfC (mg/m 3 ) Source

Medium carbon range C9–C16, EC9–EC < 22:

High flash aromatic naphtha (except naphthalene) 1 × 10 0 , maternal body

weight depression, McKee et al.,1990 PPRTV

(U.S. EPA, 2009g) 1 × 10 -1 , maternal

body weight depression, McKee et al.,1990 PPRTV

(U.S. EPA, 2009g)

Naphthalene Not available – 3 × 10 -3 , nasal lesions,

NTP 1992 IRIS

(U.S. EPA, 2009j)

High carbon range C17–C32, EC22–EC35:

NA, not volatile – NA, not volatile –

a Complete citations for the principal studies can be found in the source documents (e.g., IRIS [U.S. EP A, 2009j]).

C = carbon number, EC = equivalent carbon number in dex, IRIS = Integrated Risk Information System, NA = Not applicable, PPRTV = Provisional Peer-Reviewed Toxic ity Value, RfC = inhalation reference concentration

, sRfC = subchronic RfC

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44 Table 9. Recommended Cancer Assessments for Aliphatic and Aromatic Hydrocarbon Fractions a

Aliphatics

Fraction: Surrogate or Components Cancer WOE, RPF OSF (per mg/kg-day) IUR (per μ g/m 3 ) Source

Low carbon range C5–C8, EC5–EC8:

Commercial hexane, if n- hexane

present at ≤ 53% of

the fraction Suggestive evidence Inadequate data 1.9 × 10 -7

, pituitary adenoma or carcinoma, Biodynamics, 1993b; Daughtrey et al., 1999 (*Screening value) PPRTV

(U.S. EPA, 2009f)

Medium carbon range C9–C18, EC > 8–EC16:

Petroleum streams

or solvents within the range and containing <1%

aromatics Suggestive evidence NA 4.5 × 10 -6 , benign or malignant adrenal pheochromocytoma,
NTP, 2004 (*Screening Value) PPRTV

(U.S. EPA, 2009h)

High carbon range C19–C32, EC > 16–EC35 :

White mineral oils generally within the

range Inadequate

information to assess Inadequate data NA, not volatile PPRTV (U.S. EPA, 2009i)

Aromatics

Fraction: Surrogate or Components Cancer WOE, RPF OSF (per mg/kg-day IUR (per μ g/m 3 ) Source

Low carbon range C6–C8, EC6–EC < 9:

Benzene Group A (human

carcinogen); known/likely human carcinogen 1.5 × 10 -2 to 5.5 × 10 -2

,

leukemia, several studies, extrapolated

from inhalation 2.2 × 10 -2 to 7.8 × 10 -6

,

leukemia, several

studies IRIS

(U.S. EPA, 2009j)

Toluene Inadequate data NA NA IRIS (U.S. EPA, 2009j)

Ethylbenzene Group D (not

classifiable) NA NA IRIS (U.S. EPA, 2009j)

Xylenes Inadequate data NA NA IRIS (U.S. EPA, 2009j)

Medium carbon range C9–C16, EC9–EC < 22:

High flash aromatic naphtha (except naphthalene) Inadequate

information to assess Inadequate data Inadequate data PPRTV (US. EPA, 2009g)

Naphthalene Group C (possible

human carcinogen) Inadequate data Inadequate data IRIS (U.S. EPA, 2009j)

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45 Table 9. Recommended Cancer Assessments for Aliphatic and Aromatic Hydrocarbon Fractions a

Aromatics (cont’d)

Fraction: Surrogate or Components Cancer WOE, RPF OSF (per mg/kg-day IUR (per μ g/m 3 ) Source

High carbon range C17–C32, EC22–EC35:

Benzo(a)pyrene Group B2 (probable

human carcinogen),

RPF=1 7.3 × 10 0 , forestomach

(larynx, esophagus)

4 data sets NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Benz(a)anthracene Group B2 (probable

human carcinogen),

RPF=0.1 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Chrysene Group B2 (probable

human carcinogen),

RPF=0.001 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Benzo(b)fluoranthene Group B2 (probable

human carcinogen),

RPF=0.1 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Benzo(k)fluoranthene Group B2 (probable

human carcinogen),

RPF=0.01 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Dibenz(a,h)anthracene Group B2 (probable

human carcinogen),

RPF=1 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

Indenol(1,2,3-c,d)

pyrene Group B2 (probable

human carcinogen),

RPF=0.1 Inadequate data, use

RPF NA, not volatile IRIS (U.S. EPA, 2009j); U.S. EPA,

1993

a Complete citations for the principal studies can be found in the source documents (e.g., IRIS [U.S. EP A, 2009j]).

*Screening values are developed in the Appendix of a PPRTV. For example, in cases where a high degree of uncertainty exists. Screening Values are intended f or use in limited circumstances when no Tier 1, 2, or 3 values are

available. C = carbon number, EC = equivalent carbon number in dex, IRIS = Integrated Risk Information System, IUR = inhalation unit risk, NA = Not applicable, OSF = or al slope factor, PPRTV = Provisional Peer-Reviewed Toxicity Value, RPF = Relative potency factor (U.S. EPA, 199 3), WOE = weight of evidence

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### 9-30-2009

46 REFERENCES

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ASTM (American Society for Testing and Materials). 2002. E 1739-95 (reapproved 2002): Standard Guide for Risk-based Corrective Action App lied at Petroleum Release Sites. ASTM, West Conshohocken, PA.

ATSDR (Agency for Toxic Substances and Disease Regi stry). 1995. Toxicological Profile for Polycyclic Aromatic Hydrocarbons (Update). Agency for Toxic Substances and Disease Registry, U.S. Public Health Service, Atlanta, GA. Online. http://www.atsdr.cdc.gov/ toxpro2.html.

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MADEP (Massachusetts Department of Environmental Pr otection). 1997. Characterizing Risks Posed by Petroleum Contaminated Sites: Implementati on of the MADEP VPH/EPH Approach. Public Comment Draft. Bureau of Waste Site Cleanup , Boston, MA. Online. http://www.state. ma.us/dep/bwsc/vph_eph.htm.

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MADEP (Massachusetts Department of Environmental Pr otection). 2003. Updated Petroleum Hydrocarbon Fraction Toxicity Values for the VPH/EP H/APH Methodology. Office of Research and Standards, Massachusetts Department of Environmental Protection, Boston, MA. Online. http://www.state.ma.us/dep/bwsc/vph_eph.htm

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NTP (National Toxicology Program). 2008. Manageme nt Status Report. Available online at http://ntp-server.niehs.nih.gov/cgi/iH_Indexes/ALL_ SRCH/iH_ALL_SRCH_Frames.html.

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### hexane and its isomers on the peripheral nerve. Int. Arch . Occup. Environ. Health. 48:289–294.

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TPHCWG (Total Petroleum Hydrocarbon Criteria Workin g Group). 1997b. Volume 4. Development of Fraction Specific Reference Doses (R fDs) and Reference Concentrations (RfCs) for Total Petroleum Hydrocarbons (TPH). Amherst Sc ientific Publishers, Amherst, MA. Online. http://www.aehs.com/publications/catalog/co ntents/tph.htm.

TPHCWG (Total Petroleum Hydrocarbon Criteria Workin g Group). 1998a. Volume 1. Analysis of Petroleum Hydrocarbons in Environmental Media. Amherst Scientific Publishers, Amherst, MA. Online. http://www.aehs.com/publicati ons/catalog/contents/tph.htm.

TPHCWG (Total Petroleum Hydrocarbon Criteria Workin g Group). 1998b. Volume 2. Composition of Petroleum Mixtures. Amherst Scienti fic Publishers, Amherst, MA. Online. http://www.aehs.com/publications/catalog/contents/t ph.htm.

TPHCWG (Total Petroleum Hydrocarbon Criteria Workin g Group). 1999. Volume 5. Human

Health Risk-Based Evaluation of Petroleum Release S ites: Implementing the Working Group Approach. Amherst Scientific Publishers, Amherst, MA. Online. http://www.aehs.com/ publications/catalog/contents/tph.htm.

Truhaut R., P. Laget, G. Piat et al. 1973. [Preli minary electrophysiological results following experimental poisoning with technical hexane and he ptane in white rats.] Arch. Mal. Prof. Med. Trav. Secur. Soc. 34:417–426. [French]

Twerdok, L.E. 1999. Development of toxicity crite ria for petroleum hydrocarbon fractions in the Petroleum Hydrocarbon Criteria Working Group ap proach for risk-based management of total petroleum hydrocarbons in soil. Drug Chem. T oxicol. 22:275–291.

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### 9-30-2009

49 U.S. EPA (U.S. Environmental Protection Agency). 1 986. Guidelines for the Health Risk Assessment of Chemical Mixtures. Fed. Reg. 51(185 ):34014–34025. Online. http://www.epa.gov/iris/backgr-d.htm.

U.S. EPA (U.S. Environmental Protection Agency). 1 989. Risk Assessment Guidance for Superfund Volume I. Human Health Evaluation Manual (Part A). U.S. Environmental Protection Agency, Washington, DC. EPA540189002. Online. http://www.epa.gov/oswer/ riskassessment/ragsa/pdf/rags-vol1-pta_complete.pdf

.

U.S. EPA (U.S. Environmental Protection Agency). 1 991. Chemical Assessments and Related Activities (CARA). U.S. Environmental Protection A gency, Office of Health and Environmental Assessment, Washington, DC. April.

U.S. EPA (U.S. Environmental Protection Agency). 1 993. Provisional Guidance for Quantitative Risk Assessment of Polycyclic Aromatic Hydrocarbons. U.S. Environmental Protection Agency, Environmental Criteria and Asses sment Office, Cincinnati, OH. NTIS

PB94-116571.

U.S. EPA (U.S. Environmental Protection Agency). 1 994. Chemical Assessments and Related Activities (CARA). U.S. Environmental Protection A gency, Office of Health and Environmental Assessment, Washington, DC. December.

U.S. EPA (U.S. Environmental Protection Agency). 1 997. Health Effects Assessment Summary Tables. Annual Update. FY-1997. U.S. Environment al Protection Agency, Office of Research and Development, Office of Emergency and Remedial R esponse, Washington, DC. July 1997.

EPA/540/R-97/036. NTIS PB97-921199.

U.S. EPA (U.S. Environmental Protection Agency). 2 000. Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtu res. U.S. Environmental Protection Agency, Risk Assessment Forum, Washington, DC. EPA /630/R-00/002. Online. http://www.epa.gov/iris/backgr-d.htm.

U.S. EPA (U.S. Environmental Protection Agency). 2 004a. Provisional Peer Reviewed Toxicity

Values for n- 

### Butylbenzene(CASRN 104-51-8), sec-Butylbenzene(CASR N 135-98-8), and tertButylbenzene (CASRN 98-06-6) Derivation of a Carcin ogenicity Assessment. U.S. Environmental Protection Agency, Superfund Technica l Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 004b. Provisional Peer Reviewed Toxicity

Values for n- 

### Butylbenzene(CASRN 104-51-8), sec-Butylbenzene(CASR N 135-98-8), and tert-Butylbenzene (CASRN 98-06-6) Derivation of Sub chronic and Chronic RfCs. U.S. Environmental Protection Agency, Superfund Tec hnical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

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50 U.S. EPA (U.S. Environmental Protection Agency). 2 004c. Provisional Peer Reviewed Toxicity

Values for n- 

### Butylbenzene(CASRN 104-51-8), sec-Butylbenzene(CASR N 135-98-8), and tertButylbenzene (CASRN 98-06-6) Derivation of Subchron ic and Chronic RfDs. U.S. Environmental Protection Agency, Superfund Tec hnical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 004d. Provisional Peer Reviewed Toxicity

Values for n- 

### Heptane (CASRN 142-82-5). U.S. Environmental Prote ction Agency, Superfund Technical Support Center, National Center for Envir onmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 005a. Provisional Peer Reviewed Toxicity Values for Methylcyclohexane (CASRN 142-82-5). U.S . Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 005b. Toxicological Review of n- 

### Hexane (CAS No. 110-54-3) in Support of Summary Informatio n on the Integrated Risk Information System (IRIS). Integrated Risk Information Systems , U.S. Environmental Protection Agency, Washington, DC. EPA/635/R-03/012. Online. http:// www.epa.gov/iris/toxreviews/.

U.S. EPA (U.S. Environmental Protection Agency). 2 006. 2006 Edition of the Drinking Water

Standards and Health Advisories. U.S. Environmenta l Protection Agency, Office of Water, Washington, DC. EPA/822/R-02/038. Online. http://w ww.epa.gov/waterscience/drinking/ standards/dwstandards.pdf.

U.S. EPA (U.S. Environmental Protection Agency). 2 007a. High Production Volume (HPV) Challenge Program. U.S. Environmental Protection A gency. Online. http://www.epa.gov/ chemrtk/index.htm and http://cfpub.epa.gov/hpv%2Ds/

.

U.S. EPA (U.S. Environmental Protection Agency). 2 007b. Provisional Peer Reviewed Toxicity Values for Benz[a]anthracene (CASRN 56-55-3). U.S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 007c. Provisional Peer Reviewed Toxicity Values for 2-Methylnaphthalene (CASRN 91-57-6). U. S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 007d. Provisional Peer Reviewed Toxicity Values for Perylene (CASRN 198-55-0). U.S. Environ mental Protection Agency, Superfund Technical Support Center, National Center for Envir onmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 007e. Provisional Peer Reviewed Toxicity Values for Pyrene (CASRN 129-00-0). U.S. Environme ntal Protection Agency, Superfund Technical Support Center, National Center for Envir onmental Assessment, Cincinnati, OH.

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51 U.S. EPA (U.S. Environmental Protection Agency). 2 007f. Provisional Peer Reviewed Toxicity Values for 1,2,4-Trimethylbenzene (CASRN 95-63-6). U.S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 008. Provisional Peer Reviewed Toxicity Values for 1-Methylnaphthalene (CASRN 90-12-0). U. S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009a. Provisional Peer Reviewed Subchronic Toxicity Values for Benzene (CASRN 71-43 -2). U.S. Environmental Protection Agency, Superfund Technical Support Center, Nationa l Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009b. Provisional Peer Reviewed Subchronic Toxicity Values for Ethylbenzene (CASRN 100-41-4). U.S. Environmental Protection Agency, Superfund Technical Support Cent er, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009c. Provisional Peer Reviewed Subchronic Toxicity Values for n- 

### Hexane (CASRN 110-54-3). U.S. Environmental Protec tion Agency, Superfund Technical Support Center, Nationa l Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009d. Provisional Peer Reviewed Subchronic RfDs and RfC Toxicity Values for Toluene (CASRN 108-88-3). Superfund Technical Support Center, National Center for Envir onmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009e. Provisional Peer Reviewed Subchronic Toxicity Values for Xylenes (CASRN 1330- 20-7). U.S. Environmental Protection Agency, Superfund Technical Support Center, Nationa l Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009f. Provisional Peer Reviewed Toxicity

Values for Commercial or Practical Grade Hexane. U .S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009g. Provisional Peer Reviewed Toxicity Values for High-Flash Aromatic Naphtha (CASRNs 6472 4-95-6 and 8845-25-4). U.S. Environmental Protection Agency, Superfund Technica l Support Center, National Center for Environmental Assessment, Cincinnati, OH.

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52 U.S. EPA (U.S. Environmental Protection Agency). 2 009h. Provisional Peer Reviewed Toxicity Values for Midrange Aliphatic Hydrocarbon Streams. U.S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009i. Provisional Peer Reviewed Toxicity Values for White Mineral Oil (CASRNs 8012-95-1 and 8020-83-5). U.S. Environmental Protection Agency, Superfund Technical Support Cent er, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009j. Provisional Peer Reviewed Toxicity

Values for n 

### -Propylbenzene (CASRN 103-65-1). U.S. Environmenta l Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009k. Provisional Peer Reviewed Toxicity Values for 1,3,5-Trimethylbenzene (CASRN 108-67-8). U.S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009l. Provisional Peer Reviewed Toxicity Values for Acenaphthylene (CASRN 208-96-8). U.S. Environmental Protection Ag ency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009m. Provisional Peer Reviewed Toxicity Values for Phenanthrene (CASRN 85-01-8). U.S. Environmental Protection Agency, Superfund Technical Support Center, National Center for Environmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009n. Provisional Peer Reviewed Toxicity Values for Anthracene (CASRN 120-12-7). U.S. Envir onmental Protection Agency, Superfund Technical Support Center, National Center for Envir onmental Assessment, Cincinnati, OH.

U.S. EPA (U.S. Environmental Protection Agency). 2 009o. Integrated Risk Information System (IRIS). Online. U.S. Environmental Protection Age ncy, Office of Research and Development, National Center for Environmental Assessment, Washi ngton, DC. Online. http://www.epa.gov/iris/. Accessed August, 2009.

VCCEP (Voluntary Children’s Chemical Evaluation Pro gram). 2004. Voluntary Children’s Chemical Evaluation Program (VCCEP) Tier 1 Pilot Su bmission. n- 

### Alkane Category: Decane, Undecane, Dodecane (CAS Nos. 124-18-5, 1120-21-4, 1 12-40-3). Docket Number OPPTS–00274D. American Chemistry Council n- 

### Alkane VCCEP Consortium. Sponsors: Chevron Phillips Chemical Company LP, Sasol North A merica Inc., Shell Chemical LP. June 17, 2004.

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53 Wang, C. Y., Yang, R. S. H., Rice, G., Colman, J., Teuschler, L. In preparation. A Computational Approach to Assessing Total Petroleum Hydrocarbons Mixture. Part I. Support and validation of fraction-based approach for TPH m ixture risk assessment. Manuscript under

internal review.

Weisman, W.H. 1998. Total petroleum hydrocarbon c riteria working group: A risk-based approach for the management of total petroleum hydr ocarbons in soil. J. Soil Contam. 7:1–15.

WHO (World Health Organization). 2008. Environmen tal Health Criteria Monographs (EHCs). Online. http://www.inchem.org/pages/ehc.html.

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54 APPENDIX A. EXISTING APPROACHES FOR EVALUATING COM PLEX

MIXTURES OF ALIPHATIC AND AROMATIC HYDROCARBONS

Massachusetts Department of Environmental Protectio n (MADEP) Approach

The MADEP recommended the use of a combination ind icator compound and fraction approach for the assessment of health effects from petroleum hydrocarbons in soil and water, with a focus on oral exposure (Hutcheson et al., 19 96; MADEP, 1994). Subsequently, MADEP (1996, 1997, 2001) published public comment a nd final drafts regarding implementation of their approach. These drafts and the final version of the implementation document (MADEP, 2002) contained some modifications to take into account the strengths of the TPHCWG approach (discussed in the next section of this document)—particularly the TPHCWG-determined transport properties of hydrocarb on fractions, which are related to the equivalent (or relative) carbon number indices for the compounds (TPHCWG, 1997a). In addition, these documents incorporated inhalation a ssessment and inhalation reference concentrations (RfCs). In 2003, MADEP updated the MADEP (1994) report, providing new and revised petroleum hydrocarbon fraction toxicity val ues, and a review of the literature to support the derivations of these values (MADEP, 2003). The MADEP approach is as follows:

Carcinogenic Effects

• Specific hydrocarbon indicator compounds that have U.S. EPA cancer potency factors are assessed; these are benzene and benzo(a)pyrene.

• MADEP is reviewing the U.S. EPA (1993) relative pot ency factors (RPFs) for PAHs, and

in the meantime recommends the use of those values and the slope factor for benzo(a)pyrene for cancer assessment of the high-ca rbon-range aromatics (MADEP, 2008).

Noncarcinogenic Effects

• Hydrocarbon fractions are established based on mole cular structure (aromatic versus aliphatic), and then on number of carbon atoms (C), using toxicologically similar groupings and excluding compounds with less than fi ve carbons because their high volatility precludes chronic exposure from spills/r eleases. Analytical methods for these fractions are suggested.

• With the exception of the aromatic C5-C8 fraction, the toxicity of each fraction initially was represented by the RfD for a representative “re ference compound” from the fraction, usually chosen because of the availability of an Rf D on IRIS or adequate data to support derivation of an RfD. The toxicities of other comp ounds in the subclass were assumed to equal that of the reference compound. Some of thes e fractions include subfractions that were combined because of similarity of toxicity acr oss fractions or limitations in the toxicity data. The approach is now broadened to in clude the selection of similar mixtures to represent the toxicity of a fraction and the inc lusion of inhalation toxicity values.

The MADEP (1994, 2001, 2003; Hutcheson et al., 199 6) approach assumes additivity of the hydrocarbon fractions and the indicator compoun ds in assessing the potential for adverse effects of petroleum hydrocarbons on human health ( dose-addition using the hazard index [HI] approach for noncarcinogenic effects and RPF approa ch for carcinogenic PAHs; response addition for carcinogenic effects across fractions)

.

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55 Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG) Approach The TPHCWG (1997a, b; Weisman, 1998) also recommen ded a combination indicator compound and fraction approach for TPH, which diffe red from the MADEP approach: (1) in its application only to soil contamination (to develop risk-based screening levels [RBSLs]); (2) in the elimination of assessment for noncarcinogenic e ffects if carcinogens are present above regulatory criteria; (3) in the basis for selection of the fractions; and (4) initially, in a more extensive use of toxicity data for mixtures to repr esent the toxicity of the fraction. Subsequently, the TPHCWG (1999) appeared to broaden its focus to include RBSLs for groundwater as well as for soil. Some of the TPHCWG hydrocarbon fractions include subfractions that were combined for toxicological assessment because of similarity of toxicity across fractions or limitations in the toxicity data. The TPHCWG approach is as follows:

Carcinogenic Effects

• Specific carcinogenic indicator compounds (i.e., be nzene, benzo[a]pyrene) are assessed.

• The use of (relative) potency factors and the benzo (a)pyrene slope factor is mentioned for benzo(a)anthracene, indeno(1,2,3-cd)pyrene, dibenzo (a,h)anthracene, chrysene, benzo(b)fluoranthene and benzo(k)fluoranthene, but they are not further described or

referenced.

Noncarcinogenic Effects These effects are assessed only if the carcinogenic indicator compounds are not detected or are below regulatory criteria.

• Hydrocarbon fractions are established based on mole cular structure (aromatic versus aliphatic) and then on the basis of equivalent carb on (EC) number index. This index is equivalent to the retention time of the compounds o n a boiling point gas chromatography (GC) column (nonpolar capillary column), normalized to the n- 

### alkanes. For example, benzene, a C6 aromatic compound, has an EC of 6.5 b ecause its boiling point and GC retention time are approximately halfway between th ose of n- 

### hexane (C6, EC6) and

n- 

### heptane (C7, EC7). Physical and chemical propertie s of hydrocarbons that are useful in predicting fate and transport (vapor pressure, solu bility, partition coefficient, Henry’s Law constants) are predictably related to the EC an d can be estimated using algorithms. The mass of the carcinogenic indicator compounds is subtracted from the mass of the

fraction.

• Following subtraction of the mass of the carcinogen ic hydrocarbons, the noncancer effects of the remaining mass of each fraction are assessed by comparison with a surrogate compound or mixture.

The TPHCWG (1997a, b; 1999) approach assumes addit ivity of the hydrocarbon fractions and the indicator compounds in assessing the potential for adverse effects of petroleum hydrocarbons on human health, as in deriving risk-b ased screening levels for soil (dose-addition using HI approach for noncarcinogenic effects and R PFs for carcinogenic PAHs).

One caveat to this fate and transport fraction app roach is that simplified models, such as the ones used by the TPHCWG (1997a) to perform the fraction groupings, neglect cosolvency effects and saturation of active sorption sites in soils (for nonionic hydrophobic chemicals, the organic carbon content of soil is the primary soil property controlling sorption). The actual

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56 transport properties at a waste site may be signifi cantly influenced by the quantity of material spilled or leaked into the soil (e.g., 500 gallons of gasoline will behave differently than 500 mL). For example, although PAHs may have a strong predic ted adsorption to soil, when present in a large spill, they may initially have no or very low sorption due to cosolvent and saturation effects. As the spill migrates and becomes diluted , however, the influence of cosolvent and

saturation effects will diminish. Another observat ion with regard to the approach to selection of fractions is that it appears to focus on petroleum hydrocarbons identified in petroleum fuels (JP-4, JP-5, JP-8, kerosene, diesel, and fuel oil # 2) and crude oil. Although lubricating oils such as motor oil and mineral-based hydraulic fluids are included in the volumes on analytical methods and composition of petroleum mixtures (TPHC WG, 1998a, b), they are not included in the volume on selection of fractions (TPHCWG, 1997a ). The lubricating oils contain high molecular weight branched alkanes and cyclic alkane s with >1 ring that are not well represented in the petroleum products of focus. Nevertheless, the toxicity assessments did consider these constituents in deriving toxicity values for the fr actions that include them. The term “fate and transport fraction” is something of a misnomer as t he fractions are based on properties that will affect transport, and do not take into account fate processes. The TPHCWG (1999) accordingly changed its nomenclature to “transport fraction” an d that term is used in this PPRTV document.

American Society for Testing and Materials (ASTM) A pproach ASTM (1995) developed a Standard Guide for Risk-Ba sed Corrective Action Applied at Petroleum Release Sites (RBCA, pronounced “Rebecca” ). RBCA, reapproved in 2002 (ASTM, 2002) is a tiered decision-making framework for the integration of site assessment, remedial action selection and monitoring with U.S. EPA-recommended risk and exposure assessment. It includes any chemical that may be a ssociated with petroleum product releases, including nonhydrocarbon constituents and additives , such as lead, methyl tert-butyl ether, and ethylene dibromide. The RBCA approach focuses on i ndicator compounds, assuming that a significant portion of the total potential impact o n human health from all chemicals in a petroleum product spill is due to the indicator com pounds, termed chemicals of concern. The risk or hazard of exposure to each chemical of conc ern is assessed separately during the derivation of Tier 1 (general) RBSLs, and Tier 2 an d Tier 3 site-specific target levels (SSTLs)

for contaminated media. The RBSLs and SSTLs are ba sed on carcinogenicity for chemicals that have been classified as carcinogens and on RfDs or RfCs for chemicals that have not been classified as carcinogens. Each pathway of exposur e is assessed separately. Thus, the RBSLs for toluene are based on hazard quotients of 1 for each potential pathway and the RBSLs for

benzene are based on cancer risks of 1× 10 -6 

### and 1 × 10 -4 

### for each potential pathway. The rationale presented for this approach is that the r isk-based screening levels “are typically for a limited number of chemical(s) of concern considered at most sites.” RBCA mentions—but does not recommend or explain—the use of additivity appr oaches for mixtures of chemicals for Tier 2

and Tier 3 assessments.

Selection of the chemicals of concern for various petroleum products in the ASTM (1995, 2002) RBCA approach is based on concent rations in the product, solubility and mobility, toxicological properties, aesthetic chara cteristics (e.g., odor), and availability of

sufficient information to conduct risk assessments. For gasoline, kerosene, and jet fuels, commonly selected hydrocarbon chemicals of concern are benzene, toluene, ethylbenzene, and xylene (BTEX). Additional chemicals of concern for kerosene and jet fuels are PAHs. For diesel fuel, light fuel oils, and heavy fuel oils, the commonly selected hydrocarbon chemicals of

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57 concern are PAHs. ASTM (1995, 2002) developed exam ple Tier 1 RBSLs for benzene, ethylbenzene, toluene, mixed xylenes, naphthalene, and benzo(a)pyrene for various media and exposure pathways, using U.S. EPA cancer and noncan cer toxicity values and U.S. EPA exposure assessment methods.

The TPHCWG (1999) discussed how the TPHCWG fractio ns and toxicity criteria may be used with any risk-based decision framework, includ ing the ASTM (1995) RBCA, and provided example calculations of RBSLs. MADEP (2001, 2002), under the Massachusetts Contingency Plan, uses a tiered risk assessment approach simila r to the ASTM (1995, 2002) RBCA.

Agency for Toxic Substances and Disease Registry (A TSDR) Approach ATSDR (1999a) developed a toxicological profile on TPH that recommended an indicator compound/fraction approach, based on an e valuation and synthesis of the MADEP and TPHCWG approaches, and a consideration of the ASTM approach. ATSDR (1999a) used

ATSDR MRLs and U.S. EPA cancer assessments to evalu ate the toxicity and carcinogenicity of the compounds and fractions. The recommendations w ith regard to selection of the fractions are similar to those in this report. ATSDR (1999a) not ed that an assumption of additivity underlies use of a surrogate toxicity value from a representa tive compound to assess the health effects of

the entire mass of the fraction. ATSDR discussed t he use of an HI method (called index of concern by ATSDR) for the constituents (BTEX) of th e low-carbon-range aromatics.