EPA-540/1-86-056
Environmental Protection
Agency
oe of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
s»EPA
HEALTH EFFECTS ASSESSMENT
FOR LINDANE
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EPA/540/1-86-056
September 1984
HEALTH EFFECTS ASSESSMENT
FOR LINDANE
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
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DISCLAIMER
The Information in this report has been funded wholly or in part by the
United States Environmental Protection Agency under Contract No. 68-03-3112
to Syracuse Research Corporation. It has been subject to the Agency's peer
and administrative review, and it has been approved for publication as an
EPA document. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with Undane.
All estimates of acceptable Intakes and carcinogenic potency presented In
this document should be considered as preliminary and reflect limited
resources allocated to this project. Pertinent toxlcologlc and environ-
mental data were located through on-line literature searches of the Chemical
Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The
basic literature searched supporting this document 1s current up to
September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The fol-
lowing Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Hexachloro-
cyclohexane. Environmental Criteria and Assessment Office, Cincin-
nati, OH. EPA 440/5-80-054. NTIS PB81-117657.
U.S. EPA. 1985. Drinking Water Criteria Document for Undane.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH, OHEA for the Office of Drinking Water, Washington,
DC. Final draft.
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of con-
cern). The first, the AIS or acceptable Intake subchronlc, 1s an estimate of
an exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards expo-
sures from toxicants In ambient air or water where lifetime exposure Is
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It Is an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980b) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable expo-
sure for a given route with the Implicit assumption that exposure by other
routes Is Insignificant.
111
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Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained 1n U.S. EPA (1983a).
For compounds for which there 1s sufficient evidence of carc1nogen1dty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
Llndane, given orally, produced an Increase 1n Hver tumors 1n mice 1n
one study. Other animal bloassays (rats and mice) have been negative or
equivocal. Data concerning the cardnogenldty of Undane to humans are not
available. The U.S. EPA (1980a) used the mouse liver tumor data to cal-
culate a carcinogenic potency factor for Undane. The q-j* 1s 1.326
(mg/kg/day)"1 No data are available to assess the potential cardnogenl-
dty of Undane following inhalation exposure.
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ACKNOWLEDGEMENTS
TECHNICAL REVIEW
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
EDITORIAL REVIEW
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
TECHNICAL SUPPORT SERVICES
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112.
v1
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3
2.1. ORAL 3
2.2. INHALATION 3
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 4
3.1. SUBCHRONIC 4
3.1.1. Oral 4
3.1.2. Inhalation 7
3.2. CHRONIC 8
3.2.1. Oral 8
3.2.2. Inhalation 9
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 12
3.3.1. Oral 12
3.3.2. Inhalation 14
3.4. TOXICANT INTERACTIONS 14
4. CARCINOGENICITY 16
4.1. HUMAN DATA 16
4.2. BIOASSAYS 16
4.3. OTHER RELEVANT DATA 21
4.4. WEIGHT OF EVIDENCE 21
5. REGULATORY STANDARDS AND CRITERIA 23
6. RISK ASSESSMENT 24
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 24
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 24
6.3. CARCINOGENIC POTENCY (q-j*) 24
6.3.1. Oral 24
6.3.2. Inhalation 24
7. REFERENCES 25
APPENDIX A: Summary Table for Llndane 37
APPENDIX B: Cancer Data Sheet for Derivation of q-j* 38
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LIST OF TABLES
No. Title Page
3-1 Design of Llndane Chronic Feeding Studies In Rats 10
3-2 Design of Llndane Chronic Feeding Studies 1n Mice 11
4-1 Investigations of the Carclnogenldty of Llndane 1n
Laboratory Animals by the Oral Route 17
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DNA Deoxyr1bonucle1c add
EEG Electroencephalogram
LDso Median lethal dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
Undane, also known as Y-hexachlorocyclohexane (CAS No. 58-89-9), are as
follows:
Chemical class: pesticide
Molecular weight: 291 (Callahan et al.. 1979)
Vapor pressure: 1.6xlO~* mm Hg (Mabey et al., 1981)
Water solubility: 7.8 mg/8. at 25°C (Horvath, 1982)
Log octanol/water
partition coefficient: 3.85 (Velth et al., 1979)
Log BCF: 2.26-2.67 (Velth et al., 1979)
Half-life 1n
Water: >5-10 days (estimated)
Soil: 56 days 1n clay loam (Callahan et al., 1979)
378 days 1n sandy loam (Callahan et al.,
1979)
The estimation of the half-life for Undane 1n aquatic media Is based on
the anaerobic mlcroblal degradation half-life of this chemical 1n aquatic
sediments as reported 1n Callahan et al. (1979).
No reported value for the half-life of Undane 1n the atmosphere could
be located 1n the literature searched. Based on the reactions for chlori-
nated aliphatic hydrocarbons, Undane may undergo reaction with hydroxyl
radicals 1n the atmosphere (Graedel, 1978). Unfortunately, the rate con-
stant value for this reaction 1s not known. Based on the saturation vapor
pressure data and the predictions of CupHt (1980), Undane may not be
sorbed onto partlculate matter In the air. In air, the demonstrated removal
mechanism for Undane appears to be ralnout (IARC, 1979).
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The average K for Undane was determined to be 735 (McCall et al.,
1980). This suggests that Undane may have a low soil mobility; however,
Undane may leach from soil to groundwater, particularly from soils with low
organic matter content (McCall et al., 1980). Page (1981) detected Undane
1n -2154 of groundwater samples collected from New Jersey during 1977-1979.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS
2.1. ORAL
Llndane (y-HCH) 1s apparently rapidly absorbed from the gastro-
intestinal tract; the rapidity may be enhanced by Incorporation In Upld
vehicles. The fact that Undane 1s unusually water soluble for an organo-
chloMne Insecticide may contribute to the rapidity of Us absorption
(Herbst and Bodenstein, 1972).
Chadwlck et al. (1971, 1978) treated Fischer 344 rats with dally oral
doses (number unspecified) of 2 mg [14C]-labeled Undane. Only 2-5% of
the total dose was recovered 1n the feces, Indicating that -95% of the dose
was absorbed following oral administration.
2.2. INHALATION
Pertinent data regarding absorption of Undane following Inhalation
exposure could not be located 1n the available literature.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Studies of tox1c1ty due to Undane are complicated by the
fact that five Isomers of hexachlorocyclohexane, each with Its own toxic
effects on mammalian species, are often Involved In mixtures of hexachloro-
cyclohexane tested for toxldty 1n laboratory animals. According to Delch-
mann (1981), commercially available hexachlorocyclohexane 1s a mixture of
predominantly four of Its five Isomers. As an Insecticide the y-isomer,
Undane, Is the most effective.
Llndane 1s the most acutely toxic Isomer of hexachlorocyclohexane and
causes (as does the a-lsomer) stimulation of the CNS. The B- and
S-isomers generally cause CNS depression. Because Undane 1s more rapidly
eliminated than other hexachlorocyclohexane Isomers, it 1s the least
chronically toxic Isomer.
It' has been demonstrated that young animals are more sensitive to the
toxic effects of Undane than are adults of the same species (Radaleff and
Bushland, 1960). The increased sensitivity among the young may be related
to the inability of livers of young animals to produce, as rapidly as livers
of adults, the enzymes that detoxify Undane (Pouts and Adamson, 1959).
Diseased and distressed animals also show a similar sensitivity (Chen, 1968).
Although cases of acute toxidty associated with Ingestlon of Undane by
humans have been reported, data regarding subchronic oral exposure of humans
to Undane have not been located in the available literature.
An abstract of a study of the toxldty of technical grade hexachloro-
cyclohexane in rats was located (Barros and Sallba, 1978). Groups of 10,
60-day-old male Wlstar rats were fed diets containing 0, 0.9 or 900 ppm
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technical hexachlorocyclohexane for 90 days. The high-dose group experi-
enced growth rate depression, an Increase 1n relative liver weight and mild
hyaline degeneration of the kidneys. Both treated groups exhibited degener-
ative liver changes Including fatty accumulation.
In a range-finding experiment prior to a major cardnogenlcHy bloassay
(NCI, 1977), groups of five male and five female Osborne-Mendel rats were
fed diets containing 0, 160, 320, 640, 1280 or 2500 ppm Undane for 6 weeks,
followed by a 2-week observation period. Dosage levels >1280 ppm were
associated with Increased mortality when compared with controls. A reduc-
tion 1n weight gain during the first 3 weeks was recorded for both male and
female rats exposed to 320 or 640 ppm Undane. After cessation of exposure,
weight gains of treated males approached those of controls.
Concurrently, groups of five male and five female B6C3F, mice were fed
diets containing 0, 40, 80, 160, 320, 640 or 1280 ppm Undane for 6 weeks,
followed by an observation period of 2 weeks. No effects on weight gain
were recorded and no mortality occurred 1n groups of mice fed diets contain-
ing <160 ppm Undane. Mortality of one male and two females occurred 1n the
320 ppm groups and all mice exposed to the 640 ppm had succumbed by 5 weeks
of treatment. Although these subchronlc studies provide some Information on
mortality, the small group size and limited evaluation of toxlclty criteria
render these studies Inadequate for use In risk assessment.
More recently, the hlstochemlcal and biochemical changes 1n rats fed
diets containing hexachlorocyclohexane (grade and purity not specified) have
been Investigated (Shlvanandappa and KMshnakumarl, 1981). Groups of
28-day-old weanling male rats (number and strain not specified) were fed
diets containing 0, 100, 250, 750, 1500 or 3000 ppm Undane for 90 days.
Dosage levels >250 ppm resulted 1n progressive accumulation of I1p1ds 1n the
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peMportal hepatocytes and adrenal cortex. At dosages of 750 and 1500 ppm,
sucdnlc dehydrogenase activity decreased and alkaline phosphatase activity
Increased In the bile canal1cul1 and kupfer cells of the liver, as deter-
mined hlstochemlcally. At "higher dietary levels," serum glutamlc oxalo-
acetlc transamlnase and 3-glucuron1dase were elevated, and lactate dehydro-
genase and alkaline phosphatase activities were reduced. Hepatic mlcrosomal
protein was markedly elevated at all dietary levels. The authors concluded
that the dietary level of 100 ppm hexachlorocyclohexane resulted 1n no sig-
nificant hlstopathologlcal, hlstochemlcal or biochemical changes when com-
pared with controls. Therefore, 1n this study 100 ppm benzene hexachlorlde
1s designated a NOAEL.
Subsequently, Shlvanandappa et al. (1982) fed diets containing 0, 100,
250, 750 or 1500 ppm hexachlorocyclohexane to groups of ten, 28-day-old male
CFT-W1star rats to Investigate Inhibition of adrenal steroldogenlc activity
associated with hexachlorocyclohexane. The hexachlorocyclohexane used 1n
this experiment was reportedly 99% pure and consisted of 72% a-, 5% B-,
13.5% y-» 8% *- and a trace of the e-1somers. Following the 90-day
treatment period, rats were killed and adrenal glands were collected and
subjected to h1stolog1cal and hlstochemlcal evaluation. No significant
changes associated with treatment were noted In adrenal glands from rats fed
diets containing 100 or 250 ppm hexachlorocyclohexane. At dietary levels of
750 or 1500 ppm of hexachlorocyclohexane, marked hypertrophy of the adrenal
glands was noted with cortical cells enlarged and showing vacuollzatlon.
Hlstochemlcal examination revealed accumulation of cholesterol-positive
I1p1ds and marked reduction 1n the activities of several steroldogenlc
enzymes.
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Oesch et al. (1982) Investigated the effects of llndane on liver weights
and the activities of various hepatic enzymes 1n CF, and B6C3F.J mice and
Osborne-Mendel rats. Groups of three animals of each sex were allocated to
control, low, medium or high dose diets. Diets fed to CF1 mice contained
0 (control), 56 (low), 111 (medium) or 360 (high) ppm Undane. Diets fed to
B6C3F, mice contained 0 (control), 56 (low), 170 (medium) or 270 (high)
ppm Undane. Osborne-Mendel rats received diets containing 0 (control), 56
(low), 111 (medium) or 360 (high) ppm Undane. The Undane used 1n these
studies was reportedly 99% pure. At the end of the 3-month treatment
period, the animals were killed, livers were weighed and the activity of
several hepatic enzymes was determined.
Liver weights were significantly Increased 1n high dose group CF mice
(p<0.01) and Osborne-Mendel rats (p<0.01) when compared to controls. No
high-dose group B6C3F, mice survived to 90 days. Female Osborne-Mendel
rats In the middle dose group experienced a significant (p<0.05) Increase 1n
body weight compared with controls. Significant Induction of several
hepatic enzymes was observed 1n both strains of mice and Osborne-Mendel
rats. The most marked examples were the Induction of glutath1one-S-trans-
ferase 1n all treated groups of female CF, mice (p<0.01) and the Induction
of epoxlde hydrolase 1n all treated groups of Osborne-Mendel rats. Since
minimal enzyme Induction without hepatomegaly occurred at the lowest dose
tested 1n both species of animal, this dietary concentration (56 ppm) 1s a
NOAEL 1n this study. Assuming that rats and mice consume food equivalent to
5 and 13% of their body weight, respectively, dally Intakes of 2.8 and 7.3
mg/kg/day, respectively, can be estimated.
3.1.2. Inhalation. Repeated Inhalation of Undane by humans 1s most
Hkely to result from occupational exposure and will be discussed 1n Section
3.2.2.
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Rats exposed to 0.78 mg Undane/m3 for 7 hours/day, 5 days/week for
180 days showed "some hepatocellular enlargement." No other clinical
symptoms of toxldty were noted (Heyroth, 1952).
3.2. CHRONIC
3.2.1. Oral. Reports of toxldty 1n humans associated with chronic oral
exposure to Undane could not be located 1n the available literature.
According to Delchmann (1981), Lehman (1954) Indicated that the highest
tolerated no-effect dose of Undane In rats consume for >2 years Is -50 ppm
1n the diet, or 5 mg/kg bw, assuming that rats eat food equivalent to 10% of
their body weight per day. FHzhugh et al. (1950) suggested that rats can
tolerate "long term" feeding of diets containing 50 ppm Undane, but
experienced "changes of questionable significance" at that level. No
changes were observed 1n rats exposed to diets containing 0.15, 10 or 30 ppm
Undane (ACGIH, 1980).
Administration of 10 ppm Undane to the diets of rats for 1-2 years
resulted 1n noxious effects to them and their offspring. Body weights were
decreased after treatment for 5 months; Increased urinary ascorbic acid and
changes (unspecified) 1n blood levels of ascorbic add were noted. Ascorbic
add content 1n both Hver and adrenals was reduced (Petrescu et al., 1974).
Administration of 100 ppm Undane 1n the diet to male and female beagle
dogs resulted In slightly enlarged livers without h1stopatholog1cal change
(Rlvett et al., 1978). In this study, dogs were fed diets containing 25, 50
or 100 ppm Undane for 104 weeks. Rlvett et al. (1978) reported that the 50
ppm diet was a no-effect level.
An NCI (1977) cardnogenldty bloassay of Undane was performed using
Osborne-Mendel rats and B6C3F, mice. Groups of 50 male and 50 female rats
were allocated to high- and low-dose groups. Matched controls consisted of
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10 rats of each sex. The dosage schedule for rats In this experiment 1s
detailed 1n Table 3-1. Similar numbers of mice were allocated to matched
control, low and high dose groups as Indicated 1n Table 3-2.
Groups of treated rats exhibited no changes 1n body weights when com-
pared with those of matched controls. Individual rats, however, did
exhibit decreases 1n body weight occasionally. Applying the Tarone test for
positive dose-related trends 1n mortality to the Kaplan and Meier probabil-
ity of survival curves Indicated no significant effect of treatment on sur-
vival. Clinical signs In all groups of treated rats Included rough and dis-
colored hair coats, pale mucous membranes and vaginal bleeding, particularly
during the second year of the study.
Groups of treated mice exhibited no statistically significant changes 1n
body weight when compared with that of matched controls. Low-dose female
mice, however, consistently had body weights less than that of matched
control, or high-dose group female mice. Clinical signs In all groups of
treated mice Included rough hair coats, alopecia and abdominal dlstentlon
(particularly 1n males) during the second year. Female mice appeared to be
more excitable when handled and Increased fighting was observed among male
mice.
3.2.2. Inhalation. Toxldty to Undane by Inhalation 1n the workplace
has been reported by Sas1nov1ch et al. (1974), who observed pathological
changes 1n the livers of 55% of 59 female and 29 male workers exposed to
hexachlorocyclohexane (composition not characterized) for 11-23 years.
Chronic pancreatitis was observed In 5% of the workers; "biochemical abnor-
malities" were noted in 60% of these workers. No exposure data were
reported 1n this study.
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TABLE 3-1
Design of Llndane Chronic Feeding Studies 1n Ratsa
Sex and
Treatment
Group
Male
Matched control
Low-dose
High-dose
Initial
No. of
Animals'5
10
50
50
Llndane
1n D1etc
(ppm)
0
320
160
0
640
320
0
Time
Treatedd
(weeks)
NA
38
42
NA
38
42
NA
on Study
Untreated6
(weeks)
109
NA
NA
30
NA
NA
30
TWA
Average Dose^
(ppm)
NA
236
NA
NA
472
NA
NA
F ema 1 e
Matched control 10
Low-dose 50
High-dose 50
0
320
160
80
0
640
320
160
0
NA
2
49
29
NA
2
49
29
NA
108-109
NA
NA
NA
29-30
NA
NA
NA
30
NA
135
NA
NA
NA
270
NA
NA
NA
Source: NCI, 1977
All animals were 35 days of age when placed on study.
cDoses of Undane were lowered during the study, as Indicated, due to
deaths among the treated animals.
All animals were started on study on the same day.
eWhen diets containing Undane were discontinued, treated rats and their
matched controls were fed diets without corn oil for 15 weeks, then control
diets (2% corn oil added) for an additional 15 weeks.
fTWA = £(dose 1n ppm x no. of weeks at that dose)
Z(no. of weeks receiving each dose)
NA = Not applicable
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TABLE 3-2
Design of Lindane Chronic Feeding Studies In M1cea
Sex and
Treatment
Group
Male
Matched control
Low-dose
High-dose
Female
Matched control
Low-dose
High-dose
Initial
No. of
An1malsb
10
50
50
10
50
50
Lindane
1n Diet
(ppm)
0
80
0
160
0
0
80
0
160
0
Time
Treated0
(weeks)
NA
80
NA
80
NA
NA
80
NA
80
NA
on Study
Untreatedd
(weeks)
90
NA
10
NA
10
90
NA
10
NA
10-11
aSource: NCI, 1977
^All animals were 35 days of age when placed on study.
CA11 animals were started on study on the same day.
dWhen diets containing Undane were discontinued, treated mice and their
matched controls were fed control diets (2% corn oil added).
NA = Not applicable
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The ACGIH (1980) reported that minor symptoms and signs (unspecified) of
neurological disturbances were noted in 14/37 workers exposed to lindane
over a 2-year period (Czegledl-Janko and Avar, 1970). Of these workers,
three had "serious EEG disturbances." Blood levels of lindane ranged from
0.002-0.340 ppm; levels >0.02 ppm correlated with more severe evidence of
neurological dysfunction. No exposure data from this study were reported.
Treon et al. (1951) reported "minimal pathology in several species of
laboratory animals exposed 7 hours/day, 5 days/week for ~1 year at an aver-
age of 0.7 mg/m3 lindane." Rats exposed continuously for 655 days to 0.19
mg lindane/m3 exhibited no pathological lesions (Spear, 1952). No other
toxiclty parameters were reported.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. The teratogenic and fetotoxic effects of Undane were
studied in four groups of rats (number and strain not reported)
(Mametkullev, 1978). Group 1 received 25 mg lindane/kg bw/day on days 1-20
of gestation. Group 2 received 25 mg lindane/kg bw/day on days 7-15 of
gestation. Group 3 received 25 mg Undane/kg bw/day on days 1-7 of gesta-
tion. Group 4 received 12 mg Undane/kg bw/day on days 1-20 of gestation.
A group of untreated controls was maintained; no vehicle control group was
mentioned. Lindane was dissolved 1n corn oil (strength of solution not
reported) and administered by gavage. All dams were killed and examined on
day 20 of gestation. Terata were not reported in the offspring from any
treated dams. Post1mplantat1on fetal death was reported to be 13.2, 25.6,
11.2, 7.6 and 9.5% 1n the control group and groups 1-4, respectively. Sta-
tistical significance of the apparently high Incidence of postlmplantatlon
fetal mortality in Group 1 rats was not reported. Palmer et al. (1978)
obtained similar results with white rabbits.
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A 4-generation study of the effects of Undane on reproductive per-
formance of rats (strain not specified) was performed by Petrescu et al.
(1974). According to the U.S. EPA (1980a), these authors reported that 5,
10 or 15 mg Undane/kg bw/day administered 1n the diet resulted In an
Increase 1n the average length of gestation from 21-22 days 1n control rats
and 21-24 days 1n treated animals. A dose of 15 mg/kg/day was associated
with a decrease 1n the number of births compared with the number of animals
1n the parental generation. Delayed sexual maturation and longer estrous
cycle length were noted 1n F? and F_ females from all treated dams. An
Increase 1n the number of stillbirths was also reported. Additionally, F,
and F? offspring from all exposed dams exhibited a high Incidence of
spastic paraplegia.
Disturbed estrous cycles, lowered embryonic viability, reduced fertility
and delayed sexual maturation were reported In female rats treated with 0.5
mg Undane/kg bw/day- for 4 months. Rats treated with 0.05 mg/kg bw/day
showed none of these effects (Shtenberg and MametkuHev, 1976).
In beagle dogs, Earl et al. (1973) reported that oral doses of 7.5 and
15 mg Undane/kg bw/day from day 5 of gestation to delivery resulted 1n an
Increase In stillbirths.
Some parameters of reproductive performance 1n male rats exposed to
Undane were Investigated by Shlvanandappa and KMshnakumarl (1983). Groups
of 10 male 28-day-old CFT Wlstar rats were fed diets containing 0, 100, 750
or 1500 ppm technical hexachlorocyclohexane for 90 days. The technical
hexachlorocyclohexane reportedly contained 72% a-, 5% B-, 13.6% y-, 8%
6- and a trace of the e-1somers. The dietary concentration of 1500 ppm
was associated with decreased food consumption (p<0.01) and decreased growth
rate (p<0.05) beginning at week 7. Also at this dietary level, a marked
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decrease 1n testlcular weight (p<0.001), diameter of the seminiferous tubule
(p<0.001) and diameter of the nuclei of the Leydlg cells (p<0.001) was
noted. Total testlcular Upld (p<0.05) and cholesterol (p<0.02) levels were
Increased. A marked decrease 1n the activity of several enzymes related to
steroldogenesls was also seen (no statistical analysis). These Investi-
gators concluded that exposure to 1500 ppm Undane 1n the diet markedly
reduced normal testlcular maturation and function.
3.3.2. Inhalation. Pertinent data regarding teratogenldty, fetotoxldty
or Impaired reproductive performance associated with Inhalation exposure to
Undane In humans or animals could not be located In the available liter-
ature.
3.4. TOXICANT INTERACTIONS
LHterst and Miller (1975) determined that the dally treatment of beagle
dogs with phenobarbltal for 60 days prior to the Intravenous administration
of Undane resulted 1n reduced Undane concentrations 1n the brain compared
with controls. The Intravenous administration of 7.5 mg Undane/mlnute
resulted 1n convulsions 1n nonphenobarbltal-pretreated dogs within 27
minutes; Infusion of Undane at this rate failed to trigger convulsions In
phenobarbltal-pretreated dogs after 60-70 mlntues. These Investigators con-
cluded that phenobarbltal may be protective against the ability of Undane
to cause convulsions.
Pretreatment of Wlstar rats with Undane was associated with a reduction
of the teratogenlc effects of a carbamate Insecticide and of sodium acetyl-
sallcylate (Shtenberg and Torch1nsk1i, 1977).
The chloMnatlon of water containing hexachlorocyclohexane (not further
characterized) has been shown to decrease the subsequent LD5-s 1n mice and
rats, presumably by conversion of these compounds to more toxic products
(Shtannlkov et al., 1977).
-14-
-------
Llndane has been shown to Increase the sensitivity of mice to the
convulsion-producing effects of pentylenetetrazol (Hulth et al., 1976).
Ulmann (1972) reported that the toxic effects of Undane have been
antagonized by various tranqulHzers.
--15-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
No ep1dem1olog1ca1 studies of cancer 1n humans associated with exposure
to Undane have been reported. Several case histories link the development
of aplastlc anemia with exposure to hexachlorocyclohexane or Undane alone
(Hans, 1976; Loge, 1965; West, 1967; WoodUff et al., 1966) or 1n combina-
tion with other compounds, particularly DDT (Hans, 1976; WoodUff et al.,
1966). The concurrent development of acute paramyeloblastlc leukemia 1n two
cousins simultaneously exposed to Undane was reported by JedUcka et al.
(1958). Barthel (1976) reported an Increased Incidence of lung cancer 1n
workers who had applied various pesticides. Including Undane. These
reports do not constitute sufficient weight of evidence to conclude that
Undane 1s a human carcinogen.
4.2. BIOASSAYS
Several Investigators have examined the potential cardnogenldty of
Undane 1n laboratory animals. These studies are summarized 1n Table 4-1.
In male and female Wlstar rats, FHzhugh et al. (1950) observed no
tumors following lifetime exposures of doses up to 800 ppm Undane 1n dry
diet or 1600 ppm Undane 1n oil solution added to the diet. Dietary concen-
trations of 500 ppm Undane for 24 weeks failed to result 1n liver tumors 1n
male dd mice (Nagasaki et al., 1972a; Ito et al., 1973a,b), but 660 ppm
technical hexachlorocyclohexane for 24 weeks resulted 1n hepatomas 1n 20/20
mice (Nagasaki et al., 1971, 1972b). Hanada et al. (1973) produced hepa-
tomas In both male and female dd mice fed diets containing 600 ppm Undane
for 32 weeks. In male Wlstar rats exposed to a dietary concentration of 500
ppm Undane, no hepatocellular carcinomas were observed after 24 or 48 weeks
(Ito et al., 1975).
-16-
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TABLE 4-1
Investigations of the Carclnogenlctty of Llndane In Laboratory Animals by the Oral Route
Species/
Strain Sex
Rat/ M.F
Ulstar
Nice/dd N
Mlce/dd N
Mlce/dd M
Nice/dd N
Nice/dd F
Dose of
Exposure
(ppm)
1600
800
400
100
50
10
5
800
100
10
0
660
66.0
6.6
0
500
250
100
0
SOO
250
100
0
600
300
100
0
600
300
1 100
0
Duration
of
Treatment
(weeks)
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
24
24
24
NA
24
24
24
NA
24
24
24
NA
32
32
32
NA
32
32
32
NA
Duration
of
Study
(weeks)
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
llfespan
24
24
24
24
24
24
24
24
24
24
24
24
37-38
37-38
37-38
37-38
37-38
37-38
37-38
37-38
Purity
of
Compound
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
>98X
NA
technical
technical
technical
NA
NR
NR
NR
NA
>99X
>99X
>99X
NA
NR
NR
NR
NA
NR
NR
NR
NA
Vehicle or
Physical
State
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
10X oil In diet
dry diet
dry diet
dry diet
dry diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
diet
Target
Organ
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
all organs
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
liver
Tumor
Type
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatocellular
carcinoma
hepatocellular
carcinoma
hepatocellular
carcinoma
hepatocellular
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
Tumor
Incidence
(p value)
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
0/10
20/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
0/20
3/4
0/9
0/10
0/14
1/3
0/7
0/8
0/15
Reference
Fltzhugh
et al..
1950
Nagasaki
et al.,
1971.1972b
Nagasaki
et al.,
1972a
Ito
et al..
1973a,b
Hanada
et al.,
1973
Hanada
et a-1..
1973
-------
TABLE 4-1 (cent.)
oo
i
Species/
Strain
Rat/
Hlstar
Hlce/
Chbl
NNRI
Nice/
Rats/
Osborne-
Nendel
Sex
N
H.F
N
F
M
F
N
N
N
F
F
F
Dose of
Exposure
(ppm)
500
500
0
50
25
12.5
0
400
400
0
0
472C
236C
0
(matched
controls)
270d
135
-------
TABLE 4-1 (cont.)
Species/
Strain
Nice/
B6C3F!
Sex
N
H
N
F
F
F
Dose of
Exposure
(ppm)
160
80
0
(matched
controls)
160
80
0
(matched
controls)
Duration
of
Treatment
(weeks)
80
80
NA
80
80
NA
Duration
of
Study
(weeks)
90
90
90
90-91
90
90
Purity
of
Compound
100X
100X
NA
100X
100X
NA
Vehicle or
Physical
State
diet
diet
diet
diet
diet
diet
Target
Organ
liver
liver
liver
all organs
all organs
all organs
Tumor
Type
hepatocellular
carcinomas
hepatocellular
carcinomas
hepatocellular
carcinomas
NA
NA
NA
Tumor
Incidence Reference
(p value)
9/46
(NS)
19/49
(p=0.001)
2/10
(NS)
NS
NS
NS
Includes neoplasla and hyperplastlc nodules
DBased on numbers of animals alive subsequent to first tumor
CTUA dose reflecting 38 weeks of treatment at 640 or 320 ppm and 42 weeks of treatment at 320 or 160 ppm for the high dose-group or the low-
dose group, respectively (dose lowered due to death among the treated rats).
dTWA dose reflecting 2 weeks of treatment at 640 or 320 ppm. 49 weeks of treatment at 320 or 160 ppm, and 29 weeks of treatment at 160 or 80
ppm for the high-dose group or the low-dose group, respectively (dose lowered due to death among the treated animals).
NA = Not applicable
NS . Not significant
NR = Not reported
-------
Welsse and Herbst (1977) fed diets containing 12.5, 25 or 50 ppm Undane
to groups of 100 male and female Chb1 NMRI mice. Groups of 200 males and
females were maintained as controls. The Incidence of liver cell adenomas,
after 80 weeks of treatment, was 5/200, 2/100, 0/100 and 2/100 1n control,
low-, mid- and high-dose groups, respectively. Tumor Incidence was not
reported by sex. The Incidence of tumors 1n other organ sites was 41/200,
22/100, 13/100 and 22/100 1n control, low-, mid- and high-dose groups,
respectively.
The NCI (1977) published the results of an extensive bloassay 1n
Osborne-Mendel rats and B6C3F.. mice. The protocol of this study was
described 1n Section 3.2.1. After 80 weeks of exposure and an additional
29-30 weeks of observation, no significantly exposure-related Increase 1n
the Incidence of tumors was found 1n rats of either sex. Only 1n low-dose
male B6C3F, mice was a significantly Increased Incidence of tumors
(hepatocellular carcinomas) found (p=0.001, Fisher exact test). The Inci-
dence 1n the high-dose group was not significant and the Cochran-Armltage
test for dose-related trend was not significant. Combining the Incidence of
neoplastlc nodules with hepatocellular carcinomas did not Increase the sig-
nificance of the findings. No hepatic hyperplasla was observed In mice of
either sex. These factors, coupled with a relatively high (23%) Incidence
of hepatocellular carcinoma combined with neoplastlc nodules 1n control
mice, led the NCI (1977) to conclude that "under the conditions of this bio-
assay llndane was not carcinogenic for Osborne-Mendel rats or B6C3F, mice."
Thorpe and Walker (1973) demonstrated a substantial Increase 1n the
Incidence of malignant liver tumors 1n both male and female CF, mice fed
-20-
-------
diets containing 400 ppm Undane for 110 weeks. Malignancies were observed
1n 16/29 treated males and 10/29 treated females compared to Incidences of
2/45 and 0/44 1n control male and female mice, respectively.
4.3. OTHER RELEVANT DATA
Mutagenldty of llndane has been studied by several Investigators, pre-
dominantly with negative results. Buselmaler et al. (1972) reported that
Undane had no effect on the reversion of Salmonella typhlmurlum G46 or
Serratla marcescens a21 1n a host-mediated assay. Schubert (1969) found no
Increased Incidence of respiratory-deficient mutants In yeast (species
unspecified) associated with Undane. Negative results In dominant lethal
assays were reported 1n mice (U.S. EPA, 1973; NAS, 1977). No sex-Hnked
recessive mutants were found In Drosophlla melanogaster exposed to Undane
(Benes and Sram, 1969). No unscheduled DNA synthesis was reported by Ahmed
et al. (1977) 1n SV-40 transformed human flbroblasts (VA-4) exposed to
llndane.
Chromosomal breaks and gaps 1n Chinese hamster flbroblasts were related
to Undane exposure (Ishldate and Odashima, 1977), and alterations 1n
mltotlc activity were reported by Tsoneva-Maneva et al. (1971). A positive
dominant lethal response 1n D. melanogaster related to Undane was observed
only 1n the third and subsequent generations from adults fed food containing
20 ppm Undane (S1nha and S1nha, 1983). Technical grade hexachlorocyclo-
hexane was also associated with a dominant lethal effect 1n Swiss mice when
fed continuously to males at 500 ppm diet for 4, 6 or 8 months (Lakkad et
al., 1982).
4.4. WEIGHT OF EVIDENCE
Although Undane has been associated with aplastlc anemia, possibly a
preneoplastlc lesion (Hans, 1976; Loge, 1965; West, 1967; WoodUff et al..
-21-
-------
1966) and paramyeloblastlc leukemia (JedUcka et al., 1958), Insufficient
evidence exists to classify Undane as a human carcinogen. The carclnogenl-
city of Undane 1n the mouse has been clearly demonstrated by Thorpe and
Walker (1973), who reported liver cancers 1n 55 and 34% of male and female
mice, respectively, fed diets containing 400 ppm Undane for 110 weeks. The
Incidence 1n control males and females was 4 and 0%, respectively. Applying
the criteria for weight of evidence proposed by the Carcinogen Assessment
Group of the U.S. EPA, Undane 1s most appropriately classified a Group B2 -
Probable Human Carcinogen (Federal Register, 1984).
-22-
-------
5. REGULATORY STANDARDS AND CRITERIA
Based primarily on the work of Treon et al. (1951), who found minimal
pathology In several species (unspecified) exposed to 0.7 mg Undane/m3
for 7 hours/day, 5 days/week for ~1 year, and the work of Spear (1952), who
reported "no pathology" 1n rats continuously exposed to 0.19 mg llndane/m3
for 655 days, the ACGIH (1980) has recommended a TWA-TLV of 0.5 mg/m3 and
a STEL of 1.5 mg/m3.
The FAO/WHO Interim ADI 1s 1 yg/kg/day, which was revised downward
from an original recommendation of 12.5 mg/kg/day made In 1972 (NAS, 1977).
The U.S. EPA (1980a) reported a tolerance for Undane 1n animal fats of 7
ppm, and In milk of 0.3 ppm. The tolerance for most fruits and vegetables
1s 1 ppm. Finished drinking water should contain no more than 0.004 ppm
(U.S. EPA, 1980a).
Based on the carcinogenic potency derived from the cardnogenlcHy assay
data of Thorpe and Walker (1973), the U.S. EPA (1980a) has determined that
an ambient water quality criteria of 186 and 625 ng/a, should be protective
for the consumption of 2 8. water and 6.5 g fish and shellfish/day, or the
consumption of fish and shellfish alone, respectively.
-23-
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Llndane Is a chemical that 1s a known carcinogen 1n mice, and for which
data are sufficient for computing a q^. It 1s, therefore, Inappropriate
to calculate an oral or Inhalation AIS for llndane.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Llndane Is a chemical that Is a known carcinogen In mice, and for which
data are sufficient for computing a q *. It 1s, therefore, Inappropriate
to calculate an oral or Inhalation AIC for llndane.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The U.S. EPA (1980a) derived a q^ of 1.326 (mg/kg/
day)"1 for human exposure to Undane based on the Incidence of liver
tumors that occurred 1n male CF, mice 1n the Thorpe and Walker (1973)
study. This risk estimate reflects the lack of additional data between 1980
and the present. A q * of 1.326 (mg/kg/day)'1 was also presented 1n
U.S. EPA (1985). The complete data base from which this computation Is made
1s presented In Appendix B.
6.3.2. Inhalation. Since no reports of cancers In either humans or
animals exposed to Undane by Inhalation have been found In the available
literature, no q * for Inhalation of Undane can be calculated.
-24-
-------
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APPENDIX A
Summary Table for Llndane
Experimental
Species Dose/Exposure Effect q-|*
Inhalation
AIS
AIC
Carcinogenic
potency
Oral
AIS
AIC
Carcinogenic mice Hver 1.326
potency malignancies (mg/kg/day) 1
Reference
NO
ND
ND
ND
ND
Thorpe
Walker
and
, 1973
ND = Not derived
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APPENDIX B
Cancer Data Sheet for
Derivation of q-|*
Compound: Undane
Reference: Thorpe and Walker (1973); U.S. EPA (1980a)
Species, Strain, Sex: mice, CF, male
Body weight: 0.03 kg (assumed)
Length of exposure (le) = 770 days
Length of experiment (Le) = 770 days
Llfespan of animal (L) = 770 days
Tumor site and type: liver, "malignant"
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(ppm)
Transformed Dose
(mg/kg/day)
Incidence
No. Responding/No. Tested
or Examined
0
400
0
52
11/45
27/28
Unadjusted q-|* from study = 1.0x10 * (mg/kg/day) 1
Human q-j* = 1.326 (mg/kg/day)'1
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