United States
Environmental Protection
1=1 m m Agency
EPA/690/R-08/015F
Final
7-24-2008
Provisional Peer Reviewed Toxicity Values for
delta-Hexachlorocyclohexane
(CASRN 319-86-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
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
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-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-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
DELTA-HEXACHLOROCYCLOHEXANE (CASRN 319-86-8)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic 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 EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if 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 RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond 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 pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2008) does not report an RfD or RfC for delta-hexachlorocyclohexane
(delta-HCH). The HE AST (U.S. EPA, 1997) states that data are inadequate for quantitative risk
assessment for delta-HCH based on a Health and Environmental Effects Profile (HEEP) for
hexachlorocyclohexanes (U.S. EPA, 1987). Delta-HCH is not included in the Drinking Water
Standards and Health Advisory list (U.S. EPA, 2006). The CARA list (U.S. EPA, 1991, 1994)
includes only the previously mentioned HEEP (U.S. EPA, 1987). ATSDR (2005) developed a
Toxicological Profile for alpha-, beta-, gamma-, and delta-HCH but did not derive oral or
inhalation MRLs for delta-HCH. There is no Environmental Health Criteria Document available
for delta-hexachlorocyclohexane (WHO, 2008). ACGIH (2007), OSHA (2007), and NIOSH
(2008) have not established occupational health standards for delta-HCH.
On IRIS (U.S. EPA, 2008), delta-HCH is assigned to cancer Weight-of-Evidence Group
D, "Not Classifiable as to Human Carcinogenicity," based on no available human data and
inadequate animal data (verification date: 12/17/86). IARC (1987) did not assess the
carcinogenicity of delta-HCH in its assessment of hexachlorocyclohexane isomers.
Additionally, the carcinogenicity of delta-HCH has not been assessed by NTP (2005, 2008).
Delta hexachlorocyclohexane (DeltaHCH) is one of a series of isomers of the pesticide
lindane. Lindane itself (Gamma hexachlorocyclohexane (GammaHCH)), or the technical grade
mixture which is comprised approximately 8% of the delta isomer, has significantly more
toxicity information available than the delta isomer. In vivo testing of DeltaHCH, a lipophilic
neurodepressant agent has been largely inconclusive. In vivo results looked negative for cancer
in rats (Ito, et al., 1973, 1975) and negative for bodyweight changes and body temperature
changes (Camon, et al., 1988). In vitro studies in CHO cells showed some additivity between
delta and gamma isomers. In vitro studies point two mechanisms of toxicity, although there is
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cross-talk between the two pathways. The first appears to be related to the other HCH isomers
well known interaction with the GABA receptor in neuronal tissue. Unlike the gamma isomer
however, which is a GABA antagonist (like picrotoxin), delta is a partial allosteric agonist for
the GABA receptor. While GammaHCH appears to bind near the picrotoxin site, DeltaHCH
appears to involve (or overlap with) the binding site for barbiturates (Aspinwall et al 1997).
Tissue specificity of the DeltaHCH response is explained by a lack of responsiveness to GABA
receptors containing alpha 4, beta 1 or gamma 2L subunits. A chronic effects mechanism for
carcinogenesis would appear to be related to its action on Ca signaling. The delta isomer has
been repeatedly shown to cause the influx of calcium, and causing the activation of the protein
kinase C pathway, and the activation of c-fos.
Literature searches were conducted from the 1960s through December 2007 for studies
relevant to the derivation of provisional toxicity values for delta-HCH. Databases searched
include MEDLINE, TOXLINE (Special), BIOSIS, TSCATS/TSCATS 2, CCRIS, DART/ETIC,
GENETOX, HSDB, RTECS, and Current Contents.
FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR
DELTA-HEXACXHLOROC Y CLOHEXANE
The data are inadequate to derive a p-RfD for delta-HCH. No dose-response information
pertinent to any target organs is available in the current database; thus, the database lacks a study
that could serve as a suitable basis for derivation of an RfD for delta-HCH.
FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR
DELTA-HEXACXHLOROC Y CLOHEXANE
No inhalation toxicity data in humans or animals are identified; thus, no p-RfC could be
derived for delta-HCH.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
DELTA-HEXACXHLOROC Y CLOHEXANE
Because of the lack of carcinogenic data in humans or animals, under the 2005
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), this PPRTV document classifies
delta-HCH as having "Inadequate Information to Assess Carcinogenic Potential."
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR OR
INHALATION UNIT RISK FOR DELTA-HEXACXHLOROCYCLOHEXANE
Neither a p-OSF nor a p-IUR could be derived for delta-HCH because of the lack of
suitable oral or inhalation in both humans and animals.
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REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. 2007 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
ACGIH, Cincinnati, OH.
Aspinwall, L.S., I. Bermudez, L. A. King and K. A. Wafford, 1997. The Interactions of
H ex a ch1 orocy cl oh ex an e Isomers with Human T-Aminobutyric Acid \ Receptors Expressed in
Xenopus Oocytes. Pharm. Exp. Theraputics Vol. 282:1557-1564.
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for
Alpha-, Beta-, Gamma-, and Delta-Hexachlorocyclohexanes (HCH). Update. U.S. Department
of Health and Human Services, Public Health Service, Atlanta, GA.
Camon, L., Martinez, E., Artigas, F., Sola, C., Rodriguez-Farre, E., 1988. The Effect of Non-
Convulsant Doses of Lindane on Temperature and Body Weight. Toxicology, Vol. 49, Nos. 2/3,
Part 2, pages 389-394.
IARC (International Agency for Research on Cancer). 1987. Overall Evaluation of
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Ito, N., Nagasaki, H., Arai, M., Sugihara, S., and Makiura, S. 1973. Histologic and
ultrastructural studies on the hepatocarcinogenicity of benzene hexachloride in mice. Journal of
the National Cancer Institute. 51: 817-826.
Ito, N., Nagasaki, H., Aoe, H., Sugihara, S., Miyata, Y., Arai, M., Shirai, T. 1975. Brief
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OSHA (Occupational Safety and Health Administration). 2007. OSHA Standard 1910.1000
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slc.gov/OshStd data/1910 1000 TABLE Z-l.html.
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U.S. EPA. 1987. Health and Environmental Effects Profile for Hexachlorocyclohexanes.
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Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum,
Washington, DC; EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Available
online at http://www.epa.gov/raf.
U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-06-013. Washington, DC.
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U.S. EPA. 2008. Integrated Risk Information System (IRIS). Office of Research and
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WHO (World Health Organization). 2008. Online catalogs for the Environmental Health
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