United States
Environmental Protection
1=1 m m Agency
Provisional Peer Reviewed Toxicity Values for
(CASRN 72-20-8)
Derivation of an Oral Slope Factor
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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

National Ambient Air Quality Standards
no-observed-adverse-effect level
NOAEL adjusted to continuous exposure duration
NOAEL adjusted for dosimetric differences across species to a human
no-observed-effect level
oral slope factor
provisional inhalation unit risk
provisional oral slope factor
provisional inhalation reference concentration
provisional oral reference dose
physiologically based pharmacokinetic
parts per billion
parts per million
Provisional Peer Reviewed Toxicity Value
red blood cell(s)
Resource Conservation and Recovery Act
Regional deposited dose ratio (for the indicated lung region)
relative exposure level
inhalation reference concentration
oral reference dose
Regional gas dose ratio (for the indicated lung region)
sister chromatid exchange
Safe Drinking Water Act
square centimeters
Toxic Substances Control Act
uncertainty factor

volatile organic compound

ENDRIN (CASRN 72-20-8)
Derivation of an Oral Slope Factor
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
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.

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.
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
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.
IRIS (U.S. EPA, 2001) classifies endrin in cancer weight-of-evidence Group D, not
classifiable as to human carcinogenicity, based on inadequate human and animal data. This
assessment, which was verified 10/19/88, is also found on the Drinking Water Standards and
Health Advisories list (U.S. EPA, 2000). OPP also lists endrin in Group D. No cancer
assessment for endrin is contained in the HEAST (U.S. EPA, 1997). Relevant documents in the
CARA list (U.S. EPA, 1991, 1994) include a Health Effects Assessment (U.S. EPA, 1987) and a
Drinking Water Criteria Document (U.S. EPA, 1992). Neither of these documents derived an
oral slope factor for endrin due to the absence of adequate data showing an increase in tumors in
treated animals. IARC (1974, 1987) assigned endrin to Group 3, not classifiable as to its
carcinogenicity to humans, based on lack of human data and inadequate animal data. Reviews by
ATSDR (1996), WHO (1992), and Bus and Leber (2001), and the NTP (2001a,b) management
status report and health and safety reports, were consulted for relevant information. Literature
searches were conducted from 1986 to October 2001 for studies relevant to the derivation of an

oral slope factor for endrin. The databases searched were: TOXLINE, MEDLINE,
period August-October 2001, BIOSIS and NTIS.
Human Studies
Cohort mortality studies of workers exposed to endrin and other organochlorine
pesticides have found no evidence for an association between endrin and cancer in humans, but
had low statistical power to detect an effect. One study, reviewed by U.S. EPA (1992, 2001),
reported no increase in cancer deaths among workers exposed to endrin and other
organochlorine pesticides, but was limited by short follow-up time (12 years), no exposure data,
and few deaths. A study of workers in a Dutch endrin manufacturing plant, described by WHO
(1992) and ATSDR (1996), found no evidence of increased cancer rates after 4-13 years of
exposure and 15 years of follow-up, but the small size of the cohort gave the study low statistical
power. No additional data regarding carcinogenicity of endrin in humans following oral
exposure were located.
Animal Studies
The animal carcinogenicity data for endrin have previously been characterized as
inadequate by U.S. EPA (1992, 2001). Negative results were reported for two strains of mice,
but one study was confounded by high mortality among low-dose males because of accidental
overdosing. Negative results in a dog study were considered inconclusive because of the
relatively short study duration. Although NCI (1978) reported negative results for
carcinogenicity in rats (because of inconsistencies in dose-relationships and statistical
significance for the observed tumor increases), U.S. EPA (1992, 2001) considered the results
suggestive; furthermore, the study was limited by a less-than-lifetime dosing regimen. One
investigator independently reevaluated tumor data from the NCI (1978) study and concluded that
results were positive; however, his criteria for classifying lesions appeared to differ from those of
other investigators. No more recent animal carcinogenicity data for endrin were located.
Other Studies
Endrin yielded mostly negative results for genotoxicity in bacteria and mammalian cells
in vitro (U.S. EPA, 1992, 2001; ATSDR, 1996). With or without metabolic activation, endrin
did not produce reverse mutations in Salmonella typhimurium or Escherichia coli, but did yield
positive results in an SOS test evaluating induction of reporter-gene activity in E. coli PQ37
(Venkat et al., 1995). Endrin was not mutagenic in mouse lymphoma cells, and did not induce
DNA repair or unscheduled DNA synthesis in primary cultures of rat or hamster hepatocytes.
Endrin did not increase the frequencies of sister chromatid exchanges in human lymphoid cells.

Rats and mice gavaged with single doses of endrin had significant increases in DNA single-
strand breaks in liver and brain (Hassoun et al, 1993; Bagchi et al, 1992, 1993, 1995, 2000), and
single-strand DNA breaks were also detected in fetal mouse livers following maternal oral
administration of 4.5 mg/kg of endrin (Hassoun and Stohs, 1996); however, the same studies
reported concomitant increases in lipid peroxidation in those tissues, suggesting that the observed
DNA damage is due to endrin-induced oxidative damage, rather than a direct genotoxic effect of
A provisional oral slope factor for endrin cannot be derived because there are no adequate
human or animal oral cancer data demonstrating carcinogenic activity.
ATSDR (Agency for Toxic Substances and Disease Registry). 1996. Toxicological Profile for
Endrin and Endrin Aldehyde. Update. August 1996. ATSDR, U.S. Public Health Service,
Atlanta, GA.
Bagchi, M., E.A. Hassoun, D. Bagchi and S.J. Stohs. 1992. Endrin-induced increases in hepatic
lipid peroxidation, membrane micro viscosity and DNA damage in rats. Arch. Environ. Contam.
Toxicol. 23: 1-5.
Bagchi, D., E. Hassoun, P. Akubue et al. 1993. Comparative effectrs of endrin on hepatic lipid
peroxidation and DNA damage, and nitric oxide production by peritoneal macrophages from
C57BL/6J and DBA/2 mice. Comp. Biochem. Physiol. C. 105:
Bagchi, D., M. Bagchi, E.A. Hassoun and S.J. Stohs. 1995. In vitro and in vivo generation of
reactive oxygen species, DNA damage and lactate dehydrogenase leakage by selected pesticides.
Toxicology. 104: 129-140.
Bagchi, D., J. Balmoori, M. Bagchi et al. 2000. Role of p53 tumor suppressor gene in the
toxicity of TCDD, endrin, naphthalene, and chromium (VI) in liver and brain tissues of mice.
Free Radic. Biol. Med. 28: 895-903.
Bus, J.S. and A.P. Leber. 2001. Miscellaneous chlorinated hydrocarbon pesticides. In: Patty's
Toxicology, 5th ed, E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley, New York.
Vol.5, p. 621-688.

Hassoun, E.A. and S.J. Stohs. 1996. TCDD, endrin and lindane induced oxidative stress in fetal
and placental tissues of C57BL/6J and DBA/2J mice. Pharmacol. Toxicol. Endocrinol. 115: 11-
Hassoun, E.A., M. Bagchi, D. Bagchi and S.J. Stohs. 1993. Comparative studies on lipid
peroxidation anbd DNA-single strand breaks induced by lindane, DDT, chlordane and endrin in
rats. Comp. Biochem. Physiol. C. 104:427-431.
IARC (International Agency for Research on Cancer). 1974. Endrin. Some Organochlorine
Pesticides. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man.
Vol.5, p. 157-171. Lyon, France.
IARC (International Agency for Research on Cancer). 1987. Overall Evaluations of
Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. IARC Monographs on
the Evaluation of the Carcinogenic Risk of Chemicals to Man. Supplement No. 7, p. 63. Lyon,
NCI (National Cancer Institute). 1978. Bioassay of Endrin for Possible Carcinogenicity. CAS
No. 72-20-8. NIH Publication No. 79-812. NCI-CG-TR-12. PB-288 461.
NTP (National Toxicology Program). 2001a. Health and Safety Information for Endrin. Online.
http://ntp-server.niehs.nih.gov/htdoct/CHEM H&S/NTP Chem7/Radian72-20-8.html
NTP (National Toxicology Program). 2001b. Endrin. CASNO 72-20-8. Testing status.
Online. http://ntp-server.niehs.nih.gov/htdocs/Results Status/Resstate/10391-A.Html
U.S. EPA. 1987. Health Effects Assessment for Endrin. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria Assessment Office, Cincinnati, OH for the
Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities. (CARA) Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1992. Drinking Water Criteria Document for Endrin. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Water, Washington, DC. NTIS PB92-173384.
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.
EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Standards and Health Advisories. Office of Water,
Washington, DC. Summer 2000. EPA 822-B-00-001. Online.
http://www.epa. gov/ost/drinking/standards/dwstandards.pdf
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa. gov/ iris/
Venkat, J.A., S. Shami, K. Davis et al. 1995. Relative genotoxic activities of pesticides
evaluated by a modified SOS microplate assay. Environ. Mol. Mutagen. 25: 67-76.
WHO (World Health Organization). 1992. Endrin. Environ. Health Criteria 130. Geneva,