-------
*
lA
^
&
|
«
"5
i
IM
?
G
»
wt
^
«
2
^"
1
1
k
^
a*
O
«_
e
* .
^
<«
^
e
*-
u
1
_J
A
i
^
5
^
w
<«
"3
A
g
^*
k
g
1
w
,.?
55
n
tM
^
S
>
^^
«* e
««
Sc
k
1
&
A
s « »
ui » Cw
Ut f» O
r_ fm
1 g f
*" » «
«~
I * g
^ *O ~ ^»
^ « tn
*
S * 5
5 5
F» ^n
<
W tfl
K S
Cm f»
O tfl
p- ^-
s i
4 m
F- n
ft O
* v»
>
«
^
f
*
tn .j
O«
1*.
O*
t
1
*
s-
^M
*
I
«
S i
g i
e i
? ^
V*
8
«*
r
<*
j
f
I
v»
s 1
1 :
g e
« !
i * f
S 2
S» 0
? *
a
e
ei
«
«*
I
₯
i
^g
s
*
k
*»
<*
*
'«*
«tf
o
«
i
e
""" *
r»*3
*I k
** ^
*l
m 2
IM
.«
tailsili
oopared
r«
00670
V-53
-------
that when endMn was added to the dally diet of CS7B1/6J Inbred nice and
C302F1/J hybrid mice In the amounts of 3.0 and 0.3 ppn, the pesticide was
not carcinogenic to the animals. Reuber in his Independent analysis of the
slides of this study came to the opposite conclusion for the 0.3 ppn dose
{Reuber, 1979).
In an NCI study (1979), female B6C3F1 mice 35 days of age Ingested
endMn admixed with the diet for 80 weeks at concentrations of 0, 2.5 or 5.0
ppn and 0, 1.6 and 3.2 ppn for males. All surviving nice were killed at 90
or 91 weeks. .Each treated group contained 50 animals and each control group
10 animals. In male mice, two or more animals per'treated group had hepato-
cellular carcinoma (16X at the high dose) compared with one (10%) in the
control group. A corresponding number of mice with malignancies was not
observed In females. Significant Incidences for any site In either sex were
not observed. Because of the high mortality 1n the treated groups, hlsto-
loglcal examination was limited to only one section of the liver and since
the numbers of control animals were only 10, an Independent reviewer stated
(Reuber, 1979) that no conclusions could be reached from this study.
four bloassays for cardnogenldty were done In rats and three were on
mice. These bloassays were done at different Institutions, namely Food and
Drug Administration (FDA) during 1955-1957 as Devaluated by Reuber (1978),
the National Cancer Institute (NCI, 1979), the University of Cincinnati
(Ketterlng Laboratory) (UUherup et al.. 1970), and the University of Miami
(Delchmann et al., 1970). All the bloassays on rats and mice were reported
as negative by those authors. There were, however, deficiencies in the
studies which is explained below, which render the findings Inadequate to
properly assess the carcinogenic potential 1n animal test systems.
00670 V-54
-------
In the FDA rat (Osborne-Mendel) study the animals at highest dose (25
ppm) did not survive well and additional animals were started In that dose.
The remainder of the groups lived For the programmed two year study. It
also appeared that every animal came to autopsy and not all sections From
grossly observed animals were studied microscopically. In spite of some
deficiencies there were a sufficient number of animals In the studies
particularly In the aspect of liver and kidney. In all experimental and
control groups (Reuber, 1978). This study was originally reported as
negative. It was reevaluated by- a panel of pathologist whose report was
referenced In a CAG document (U.S. EPA, 1978). One pathologist considered
the finding positive (Table V-11 and V-12) but did not provide slide by
slide tabulation of his findings and did not distinguish between primary
and/or metastatlc tumors In the liver. A second pathologist whose original
finding Indicated that the study was negative, provided slide by slide
tabulation of diagnosis which was confirmed by the panel review. In the FDA
mice (C3HF1) study the survival was very poor 1n both control and
experimental group.
The lettering study used two strains of mice (C5781/6J and C302FI/J).
The C57B1/6J strain exhibited mainly leukemia and liver tumors with low
Incidence. These tumors appeared equally 1n the experimental and control
groups and the latent period of tumor formation was similar. But In the
C302F1/J strain, the Incidence of liver tumors In the dose group (3 pom) was
slightly higher In the female than In controls and the latent period of
tumor formation was decreased than other groups (Hitherup et al.. .1970).
00670
-------
The NCI bloassay was done In Osborne-Mendel rats and B6C3F1 mice. These
studies were reported as negative. A primary reviewer for NCI noted that
the negative findings could be a reflection of the high toxldty of endrln,
which only permitted the administration of relatively low chronic dosages.
Furthermore, the reviewer observed that an accidental overdose among low
dose male nice resulted In early death of several animals In this treatment
group and the study was marred by a small (10) 1f matched controls; however,
this deficiency was compensated by the use of pooled controls (see Table
V-17). There were significant Increases 1n hemangloma In low dose male
rats, adrenal adenoma and/or carcinoma In high: dose In males, pituitary
adenomas In the high dose female, adrenal adenoma and/or carcinoma In low
dose female rats as compared to the pooled controls. Although, the
Islet-cell carcinoma 1n male rats had a significant trend but no
statistical significance at either dose group, the NCI concluded that these
tumors could not be clearly considered related to the adralnstratlon of
endrln (NCI, 1979). Although NCI concluded that the bloassays of endrln
were not carcinogenic, the responses noted above can not be totally Ignored.
Endrln was not mutagenlc In any bacterial strains but exhibited
chromosomal aberration In germinal tissues. Endrln 1s also structurally
related to aldMn. dleldrln, chlordane, chlorendlc acid and heptachlor which
are known to carcinogenic In animals. The available cancer epldemlologlc
data Involving several studies 1s Inadequate to demonstrate or rcfut. a
carcinogenic hazard because of study design .limitations and/or mixed
exposures. Using the criteria In the U.S. EPA (1986) guidelines for
classification of carcinogens, endrln Is most appropriately classified in
Group D; I.e. a chemical for which there 1s Inadequate evidence to assess
the potential carclnogenlclty for humans. This classification Is based on
00670 V-56 .. :}
-------
TABLE V-17
Analysis of Incidence of Primary Tumors In Osborne-Mendel
rats fed EndMn In the diet
Sex Site
Male Hemangloma
P Values*
Adrenal
Carcinoma
P Values*
Adrenal -
Adenoma or
Carcinoma
P Values*
Pancreatic
Islet Cell
Carcinoma
Female Pituitary-
Adenoma
P Values*
Ad renal -
Carcinoma
P Values*
Adrenal:
Adenoma or
Carcinoma
P Values
Pooled
Control
0/49(0}
NS
0/44(0}
NS
2/44(5)
P- 0.028
0/46(0)
P.Values
0.039
4/44(9)
P.O. 015
2/46(4)
NS
4/46/(9)
NS
Matched
Control
0/10(0)
NS
0/9(0)
NS
2/9(22}
NS
0/10
2/7(29)
NS
1/9(11)
NS
3/9(33)
P.O. 041
Low
Dose
5/46(11}
P.O. 024*
2/46(4}
NS
4/46(9}
NS
0/45
11/47(23)
NS
7/49(14)
NS
14/49(33)
P.O. 004*
High
Dose
3/47(6)
NS
0/44(0}
NS
8/44(18}
P.O. 045*
3/47(6)
13/45(29)
P.O. 016*
3/47(6}
NS
7/47(15)
NS
Source: NCI, 1979
NS . Non significant
* - Significant with respect to pooled control
* « Beneath the Incidence of tumors In the control groups Is the
probability level for the Cochran AmUage test when P <0.05, otherwise
not significant (NS) 1s Indicated.
00670
V-57
-------
the nonposltive but suggestive results In some of the animal studies. The
negative conclusions as reported by the study authors of the four bloassays
do not support a Group E classification, because of the Inadequacies of the
studies. A Group 0 weight-of-evidence Is thought to be the best classifi-
cation until additional studies can be done to clarify the situation.
Later studies suggested that endrln or Its rapidly-produced metabolites
might act as .promoters, although some have produced conflicting evidence.
Ito et a1. (1980) showed that endrln (25 ppm In diet) promotes the develop-
ment of preneoplastlc changes In rat liver after Initiation with N-nltroso-
dlethylamlne or N-2-fluorenylacetam1de. Kaslansky and Williams (1981)
showed that endrln (10** to 10"* N) was not genotoxic In the hepatocyte
primary culture (HPC)/ONA repair assay utilizing hepatocytes from male
Fischer F344 rats, male CD-I mice and male Syrian hamsters. ONA repair was
observed In response to a positive control In all three systems. Thus, the
mechanism of the weak hepatocardnogenlclty of endrln may reflect an epl-
genetlc mechanism, probably Involving a promotional rather than a genotoxlc
effect. Kurata et al. (1982) demonstrated that endrln above 5 rog/i In the
HGPRT system using wild-type 6-thloguanlne-sensltlve V79 Chinese hamster
cells and mutant 6-th1oguan1ne-res1stant cells Inhibited metabolic coopera-
tion (reciprocal exchange of material between cells In contact), as do
recognized *.unor promoters. A concentration of 20 mg endrln/i caused 80%
Inhibition whereas 10 mg endr1n/l elicited -25X Inhibition. On the other
hand, Miller et al. (1981). In an abstract, reported that endrln (0-40 uN)
did not change the frequency of transformation of C3H 10T1/2 cells by
3-methylcholanthrene or benzo(a)pyrene (0-10 mg/i) after a 3-hour incu-
bation.
00670 V-58
-------
Summary
The acute oral LD5Q of endrln given to manuals by oral gavage ranged
from 2.3 mg/kg to 43.4 mg/kg bw (see Table' V-l). The LD50 following
dermal exposures ranged from 10.9-92 rag/kg bw and was vehicle-dependent. A
.lone Inhalation study Indicated that 130 seven-hour exposures to 0.36 ppm
endMn 'vapor" were not fatal to rats, hamsters and guinea pigs; however,
two of four rabbits died after 188 exposures and one of three mice died
after 10? exposures (see Table V-5). Young animals appeared to be more
sensitive to dietary endMn than older animals (see Table V-3). Metabolites
of endrln were more acutely toxic In rats than the parent compound {see
Table V-2), with 12-ketoendrln being the most toxic In both male and female
rats and having acute oral L05Qs of 1.1 and 0.8 mg/kg bw, respectively.
The acute oral LD$Q values for endrln Itself were S.6 and S.3 mg/kg bw,
respectively. In this same study.
Short-term endrln exposures reportedly elicit CMS effects, Including
convulsions (Emerson et al., 1964). reduced locomotor activity (Kavlock et
al., 1981), and altered EEG recordings (Revzln, 1968). Reported hepatic
effects Include elevated liver weight, Uplds and trlgycerldes. and changes
In cytochrome P-4SO content and P-450-mediated enzyme activities {Hartgrove
et al., 1977; Pawar and Kachole, 1978; Borady et al., 1983; Hostafa et al.,
1983). Endrln also elicits changes 1n cardiac output, blood pressure.
hemolysls and other hematologlcal parameters (Emerson et al., 1964; Hlnshaw
et al., 1966; Reins et al.. 1966).
Longer exposure to endrln elicits mortality, depressed weight gain or
weight loss, and elevated organ-to-body weight ratios (Treon et al., 1955;
Nelson et al., 1956; Chernoff et al.. 1979; Kavlock et al., 1981). Abnormal
00670 V-59 :.
-------
EEG patterns, elevated serum alkaline phosphatase, reduced plasma specific
gravity and Intermittent blindness have also been reported, as well as
altered hepatoblllary function, following endrln exposure ranging from 2
weeks to several months (Nelson et al., 1956; Speck and Haaske, 1958; Young
and Hehendale, 1986).
Chronic endrln exposure causes mortality or early appearance of clinical
signs associated with aging (Treon et al., 1955; Delchmann et al., 1970;
(
NCI, 1979). Organ-specific effects reported Include elevated organ-to-body
weight ratios, lung congestion and hemmorhage, swelling of renal tubules,
and chronic Interstitial nephritis (Treon et al.,. 19S5; (Mechmann et al.,
1970; Reuber, 1978). Prenatal exposure to endrln elicited terata. mortality
and/or reduced neonatal weight or weight gain In offspring of hamsters and
mice. These outcomes were not consistently observed 1n rats. However,
evidence of .altered behavioral development, measured by maze locomotor
activity, was observed 1n offspring of rats, mice and hamsters following
prenatal endrln exposure.
Endrln was not mutagenk In mlcroblal systems with or without metabolic
activation, and endrln exposure did not significantly affect
sister-chromatld exchange frequencies In a human lymphold cell line.
However, a significant elevation of slster-chromatld exchange frequency was
observed In minnows following endrln exposure.
Conclusions concerning endrln carclnogenlclty have not been entirely
consistent. Endrln was determined to lack carclnogenlclty In Osborne-Hendel
rats and 86C3F1 mice under the conditions of an NCI (1979) bloassay. This
conclusion Is consistent with those of three previously reported studies
00670 V-60 ''V17/88
-------
concerning endrln carclnogenlclty 1n rats and mice. In contrast, Reuoer
(1979) has concluded that an increased tumor Incidence Is elicited by
chronic endrln exposure, based on Ms Independent evaluation of the NCI
(1979) bloassay tissue sections, and on a separate study (Reuber, 1978).
00670 V-61
-------
VI. HEALTH EFFECTS IN HUMANS
Acute Tox1dt₯
In September 1978, the U.S. Department of Health and Human Services
Issued an occupational health guideline for endrln (U.S. OHHS, 1978).
Symptoms of overexposure were described as follows:
Exposure to endrln may cause sudden convulsions which may occur
from 30 minutes to 10 hours after exposure. Headache, dizziness,
sleepiness, weakness and loss of appetite may. be present for 2-4
weeks following this exposure. A number of deaths have occurred
from swallowing endrln. In less severe cases of endrln poisoning,
the complaints Include headache, dizziness, abdominal discomfort,
nausea, vomiting. Insomnia, agitation and mental confusion.
Electroencephalograms may show dysrhythmlc changes which frequently
precede convulsions; withdrawal from exposure usually results 1n a
normal, electroencephalogram within 1-6 months. In most cases,
recovery 1s rapid, but headache, dizziness, lethargy, weakness and
anorexia may persist for 2-4 weeks.
Accidental and Intentional Poisonings. Several Incidents of endrln
poisoning from contaminated flour have been reported In the literature. In
Hales, bread made from flour contaminated with endrln during shipment In a
railway car resulted In 59 poisoning cases with no deaths In 1956. The
bread contained up to 150 mg endrln/kg bread and the smallest acute dosage
to elicit serious effects was calculated to be 0.2 mg/kg bw (Oavles and
Lewis, 1956).
In 1967, explosive outbreaks of acute endrln poisoning occurred In Doha,
Qatar and Hofuf In Saudla Arabia as a result of the ingestlon of food
prepared with endrIn-contaminated flour (Weeks. 1967; Curley et al.. 1970).
Twenty-six persons died and 874 were hospitalized, Hany others were prob-
ably poisoned to a lesser degree but did not seek medical aid. The concen-
tration of endrln 1n bread eaten by patients ranged from 48-1807 mg/kg
00680 VI-1 JC/2^7
-------
bread. Hour used to made the bread contained 2153-3367 mg endrIn/kg flour.
Coble et al. 41967) reported acute endrIn poisoning with sudden convulsions
In three Egyptians, following ingestlon of'bread made with contaminated
flour. In these cases, recovery was spontaneous. A serum endrIn concentra-
tion of 0.053 ppm was reported for one of these patients 5 hours after Us
apparent consumption In contaminated bread, and 30 minutes after a convul-
sion was observed.
In the Punjab province of Pakistan between July 14 and September 26,
1984 there were 194 cases of probable endrIn poisoning (Anonymous, 1984;
Rowley et al.. 1987}. Of the 194 cases, 19 (70%) deaths occurred among
persons between 1 and 9 years of age. Hales and females were equally
affected. Symptoms Included sudden collapse, "bilateral jerking of the.
upper extremities followed by general tonic, clonlc contractions and
frothing and vomiting1. Older patients reported headaches and/or nausea and
minor muscular spasms about one-half hour before collapsing. Repeated
attacks were associated with hypoxla. pulmonary congestion and death. Serum
levels from 12 of 18 patients with convulsions had measurable levels of
endrln. Values from the 12 patients ranged from 0.3-254 ppb with a mean of
30.10 ppb. No endrln was detected In the urine of these 12 patients (Rowley
et al., 1987). A case-control study did not Implicate causative food or
environmental factors. However, a common food product, sugar, nay have been
contaminated. One composite sugar sample taken from the homes of three
patients had endrln levels of 0.04 ppn (Rowley et al.. 1987). The presence
of endrln In 57% of patients with seizures tested In Pakistan suggests that
endrln was the cause of this outbreak (Anonymous, 1984; Rowley et al., 1987).
00680 vi-2
-------
Cases of fatal endrln poisoning have been reported from Intentional
IngestIon and-accidental Ingest Ion. Tewarl and Sharma (1978) reported 11
!
fatal poisonings; the time periods from administration of the pesticide
(route not known In seven cases) to death ranged from 1-6 Murs. Endrln
Ingestlon with milk or alcohol appeared to Increase toxldty as death
occurred within an hour or two. Increased toxldty was attributed by the
authors to more rapid absorption through the GI tract.
A pedlatrlc hospital In Mexico- reported endrln intoxication In 33
patients ranging 1n age from 1*16 years (Hontoya Cabrera et al., 1982).
Accidental Ingestlon accounted for 22 cases. 7 were suicides and 4 were
attributed to criminal Intent. The accidental poisonings resulted from the
uncontrolled use of endrln In the home as a rodentlclde.
A 19-year-old male who attempted suicide by Ingestlon of endrln devel-
oped severe pulmonary edema as well as CMS Involvement. Pulmonary edema was
thought to be due to chemical pneumonltls and aspiration pneumonia. The
authors believed that the use of PEEP (positive end-expiratory pressure) up
i
to 28 cm H^O In treatment of the pulmonary edema contributed to the
patient's complete recovery (Jedelkln et al.. 1979).
Effects of Occupational Exposures. No Illnesses were noted In
seasonal workers dusting potatoes with 1% endrln dust at a calculated dermal
exposure of 2.0 mg/kg bw/day In combination with a calculated respiratory
exposure of 0.044 mg/kg bw/day (Wolfe et al.. 1963). Also, no Illnesses
were noted when endrln was applied at 544-634 kg/acre as an emulslflable
00680 VI-3
-------
concentrate for mice control at a calculated dermal dose of 0.28 lag/kg/day
In combination with a calculated respiratory exposure of 0.0011 dig/kg bw/day
(Wolfe et al., 1963).
Immunology. Thirteen pesticides Including endrln were tested for
their In vitro effects on human lymphocyte mltogenlc responses to phyto-
hemaglutlnln and neutrophll chemotaxls (Lee et al.. 1979; Park and Lee,
1980). This study was undertaken In an effort to clarify the Immunosuppres-
slve effects of many pesticides. Endrln Inhibited the lymphocyte response
In whole blood 11.5% and 14.2% In mononuclear cells. Neutrophll chemotaxls
was Inhibited 27X (77*4 vs. 105*10 cells per high power field 1n control
cultures). In each case. Inhibition was not reported to be statistically
significant. All pesticides tested Inhibited lymphocyte responses to some
degree, and the authors suggested that the Immunosuppresslve effect of
pesticides could be a direct effect of those chemicals on leukocytes.
Eo1dem1olog1ca1 Studies. Jager (1970) reported an epldemlologlcal
-study conducted on 826 male workers at the Insecticide plant of Shell Neder-
land Chemle located at Pernls. Netherlands. A unit for the production of
endrln was begun In February 1957. During the first 2 years of plant opera-
tion seven cases of endrln Intoxication had occurred and were accompanied by
convulsive seizures. All were due to acute overexposure either following an
accident or to obvious neglect of precautions. Normal recovery was rapid,
usually within 1-3 days.
Concentrations of endrln In the blood of 45 operators from the endrln
plant were determined at least once a year from 1964-1968. The threshold
00680 VI-4 ««/--.<».>
-------
level of endrln 1n the blood below which no sign or symptoms of Intoxication
were seen was 0.050-0.100 tig/ml. The half.life of endrln In the blood,
and thus 1n the body, was estimated to be -24 hours. Medical files and
routine medical examinations revealed no abnormalities other than those that
would be expected In any group of 233 long-term workers (4-13.3 years expo-
sure). Results of determination of alkaline phosphatase, SGOT, SGPT, LDH,
total serum proteins, and the spectra of serum proteins did not show any
changes that could be correlated with the Influence of the degree or dura-
tion of exposure to these Insecticides on these parameters. In all cases of
Intoxication characterized by typical EEG changes, EEG patterns returned to.
normal. In the study of the parameters of enzyme Induction, the data showed
that occupational exposure In endrln manufacturing may cause enzyme Induc-
tion 1n hydroxylatlng enzyme systems although this response appeared not to
affect the health of the workers. It was not known whether endrln or Its
manufacturing precursors were the causative agents (Jager, 1970).
t
A follow-up mortality study on 233 of these workers having at least 4
years of exposure by 1970 has recently been reported (Rlbbens, 1915). Of
these 233 workers who were occupationally exposed to aldMn, dleldrln,
endrln and/or TelodMn, 232 were accounted for. The mean and range of expo-
sure durations were .11 and 4-27 years, respectively. These periods, as well
as the exposure levels, were considered sufficient for meaningful mortality
evaluation. The total mortality of this population was 25, significantly
lower than the expected mortality of 38 based on death statistics of Dutch
men. Nine of 25 deaths were caused by neoplasms, versus 12 expected cancer
deaths; 3/9 neoplasms were lung tumors. The remaining six cases were
comprised of six different neoplasms, none of which were liver tumors.
00680 VI-5
-------
These results were concluded to reveal no evidence for specific cardnogen-
Iclty of endrln. aldMn or dleldrln In this exposed population.
Hoogendam et al. (1962, 1965) conducted a parallel study at the same
plant. Of the 122 men exposed to all pesticides at the plant, 25 workers
had EEG abnormalities (Hoogendam et al., 1962). A worker was accidentally
covered with a 50% Isodrln solution in. xylene. He experienced dizziness and
headache and profusely perspired 2 hours later. This worker suffered a
typical eplleptlform convulsion 6 hours after the exposure, regained con-
sciousness within 10 minutes and rapidly recovered. There Is some evidence
to suggest that Isodrln was partially converted to endrln In the liver of
this patient (Brooks, 1969). The EEGs of patients with endrln Intoxication
showed paroxysms of predominantly bilateral synchronous theta-waves. In the
other report (Hoogendam et al., 1965) three endrln workers suffered convul-
sive Intoxications, two being examined for recovery of abnormal EEGs. One
was exposed for 1.5 years and the other for 3 years. One recovered In 1
month, and the other In <6 months. The authors suggested that the prevail-
ing exposure in the manufacture of aldMn, dleldrln and endrln did not
disturb liver function since the levels of SGOT and SGPT returned to normal
1n the four workers who Initially showed Increases.
Ottevanger and Van Sittert (1979) continued the enzyme Induction studies
of Jager (1970) on 29 endrln workers at the endrln manufacturing plant In
Pernls. The D-glucarlc acid concentration In urine was considered to be a
useful test for enzyme Induction. After 7 days of exposure, levels of the
metabolite, antl.-12-hydroxyendrln. Increased (up to 0.360 mg/g creatlnlne)
accompanied by a sharp rise In D-glucarlc acid levels. After the long week-
end, the antl-12-hydroxyendrln levels decreased, but D-g1ucar1c acid levels
00680 VI-6
-------
remained above normal. The normal values obtained after a 6-week shutdown
and maintenance period Indicated that enzyme Induction In endMn workers 1s
reversible. A urinary antl-12-hvdroxvendrln level of 0.130 mg/g creatlnlne
was considered the threshold level below which enzyme Inductlo- does not
occur, although exceptions were noted.
VMJ-Standhardt et al. (1979) examined urinary excretion of D-g1ucar1c
acid and total porphyrln In endMn workers. The excretion of D-glucaMc
add after working was significantly Increased compared with excretion after
a long weekend and with a control group. The results Indicated that
D-glucaMc acid was a useful test for exposure to endMn, but porphyrln
excretion was not.
An epldemlologlcal study was made of 216 patients with contact dermati-
tis In rural regions of Japan from 1968-1970 (Matsushita et al., 1980). All
participants except three were farmers. Exposure occurred mainly from
spraying operations. Chlorinated hydrocarbons (8HC and endMn) were thought
to be responsible for 9.7% of the cases. Inadequate protection of the spray
personnel, poor health conditions and carelessness were largely responsible
for the dermatitis.
Hang and Grufferman (1981) performed a case control study of the associ-
ation between fatal aplastlc anemia and occupations entailing pesticide
exposure. They found no correlation between use of chlorinated hydrocarbon
pesticides. Including endMn, and aplastlc anemia mortality In the United
States from 1950 through 1975.
00680 VI-7
-------
Dltraglla et al. (1981) conducted a retrospective cohort study to
examine the mortality of workers employed In the manufacture of chlordane,
heptachlor, DOT and aldrln/dleldMn/endrln. The four plants selected for
study, are described In Table VI-1. Workers '.elected for the study had been
employed at least 6 months; the personnel In contact with endrln were
located at plants 2 and 3, and numbered 305 and 1155, respectively.
The only major category where observed deaths were greater than expected
was Bnonmal1gnant respiratory system disease1 at Plant 3 (22 observed vs.
10.4 expected: SHR-212) and for 'other respiratory diseases' (11 observed
vs. 5.2 expected: SMR.213, p<0.05). No statistically significant excesses
or deficits 1n mortality for any specific cancer site were noted. In Plant
3 there was a slight excess of cancer of the esophagus (2 observed vs. 0.85
expected), cancer of the rectum (3 observed vs. 1.24 expected), cancer of
the liver (2 observed, vs. 0.57 expected), and cancer of the lymphatic and
hematopoletlc system (6 observed vs. 4.09 expected). There was a deficit
for respiratory cancer (7 observed vs. 12.64 expected) at Plant 3. Addi-
tional analyses are necessary to determine 1f an excess In nonmallgnant
respiratory disease observed at Plant 3 was associated with specific occupa-
tional exposure. Since malignant respiratory disease was not reported at
Plant 2, which also manufactured endrln, endrln alone probably did. not
Induce the lethal respiratory disease reported at Plant 3 unless exposures
were much higher than those at Plant 2. However, OltragUa et al. (1981)
did not report exposure data.
00680 VI-8 GS/18/3&
-------
TABLE VI-1
Description of Plants Included In the Study of Manufacturers
of Organochlorlne (OC) Pesticides*
Starting date for OC
pesticide production
OC pesticides
produced
Other pesticides
produced
Other chemicals
at plant
Location
Plant 1
1946
Chlordane
None
Chlorine,
dlcyclo-
pentadlene
Illinois
Plant 2
1951
Heptachlor,
endrln
None
Chlorine,
chlorendlc
anhydride,
hexachloro-
cyclopenta-
dlene, vinyl
chloride
Tennessee
Plant 3
1946
Aldrln,
dleldrln,
endrln
Organo-
bronlnes;
organo-
phosphates
Numerous
precursors
Colorado
Plant 4
1947
Olchloro-
dlphenyl-trl-
chloroethane
(DOT)
None
Trl-chloro-
acetaldehyde,
sulfurlc acid,
nonce hi or o-
benzene
California
Source: Dltraglla et al., 1981
00660
Vl-9
-------
Summary
Exposure to endrln U reported to cause CNS effects, convulsions and
death. In less severe poisoning, recovery 1s usually rapid and there are no
permanent effects.
A number of cases of acute poisoning resulting from accidental or Inten-
tional Ingestlon of endrln have been reported. The approximate oral dose
producing convulsions Is between 0.2 and 0.2S rug/kg bw.
No potential hazard existed during typical dermal or respiratory expo-
sures encountered by seasonal agricultural workers exposed to endrln through
dusting and spraying operations.
V
t.
No fatalities or permanent abnormalities were recorded In a 1970 eplde-
mlologlcal study of 233 workers engaged 1n the manufacture of chlorinated
hydrocarbon Insecticides Including endrln for more than 4 years. Convul-
sions and CNS effects were observed 1n some workers. Exposure did not
elicit an elevation In total mortality of these workers through 1985.
Occupational exposure In endrln manufacturing may cause enzyme Induction In
hydroxylatlng enzyme systems, but this response appeared to be reversible
and to have no effect on the health of workers. Ant1-12-hvdroxyendr1n
levels excreted 1n the urine of endrIn-exposed workers were correlated with
excretion of D-glucaMc acid.
No correlation was found between mortality from aplastlc anemia and the
use of chlorinated pesticides Including endrln In the United States from
1950 through 1975, although no exposure data were provided to allow assess-
ment of the Importance of endrln In this study.
00680 VI-10 v«
-------
A mortality study of workers engaged In the manufacture of organochlo-
rlne pesticides did not Identify a specific cancer risk but further studies
were recommended.
00680
VI-11
-------
VII. HECHANISMS OF TOXICITY
Acute ToxIcUv
The order of acute oral toxldty to endrln 1n various adult male species
Is monkey > rabbit > pheasant » quail > chicken » cattle « dog > hamster >
guinea pig - rat. Young animals and female animals are more susceptible
than adult males, at least In rats (Treon and Cleveland, 1955). Endrln and
Us metabolites are quickly eliminated except at grossly high doses, and the
total half life varies between 1 and 4 days (see Chapter IV). Doses of >0.2
rag endMn/kg bw can cause convulsions (Jager, 1970); lethality to humans may
occur at doses >6 g/person (Reddy et al., 1966).
The unsubstUuted methylene group 1n endrln Is rapidly attacked to
produce mostly antl- and some vyjl-12-hydroxyendrln, the former being elimi-
nated as the sulfate In the urine of rabbits, female rats and hens, as the
aglycone In the feces of male rats, as the glucuronlde In the urine and the
feces of humans, and as the free metabolite In the urine of the cow (see
Chapter IV). The iyji-alcohol Is quickly transformed to 12-ketoendrln, which
1s the most acutely toxic to rats of all endrln derivatives Including endrln
Itself (Bedford et al., 1975a). In fact, associations between lethality and
the presence of !2-ketoendr1n residues In the brain have been made for rats
(Hutson et al.. 1975). rat fetuses (Kavlock et al.. 1981) and hamster
fetuses (Chernoff et al., 1979) but not for birds (StUkel et al., 197Si,b);
12-ketoendrln has been postulated as the ultimate toxicant, at least In rats
(Bedford et al., 1975a). hamster fetuses (Chernoff et al.. 1979) and rat
fetuses (Kavlock et al., 1981).
00690 VII-1
-------
The CNS Is the major target system for acutely administered endrln.
Emerson et al. (1964) suggested that endrIn-Induced hyperexcltabllHy and
convulsions were caused by a direct action of endrln on the motor cortex
and/or spinal cord; It was further suggested that endrln acted directly on
t
the medulla since the bradycardla that followed endrln exposure preceded
pressure Increases 1n the cerebrosplnal fluid and sagltal venous sinus,
which were also elicited by endrln exposure. Walsh and Fink (1972) suggested
that the mechanism of acute endrln toxlclty Involved Induction of a bio-
chemical lesion In the CNS, followed by a time-dependent process culminating
1n toxic manifestations. It was postulated that Interference with plasma
membrane or mltochondrlal ATPase may be Involved In the mechanism. However,
Hehrotra et al. (1982) reported that although some ATPase activities of rat
brain and beef heart were Inhibited by cyclodlene pesticides (Including
endrln) In vitro, these Inhibitions could not be easily related to the
toxlclty of the compounds. For example, endrln was more toxic to rats than
aldrln, but ATPase activities were Inhibited to a greater extent by aldrln
relative to endrln.
A series of more recent studies suggests that mechanism of CNS disturb-
ance and toxlclty for endrln are related to Interference with gamma-ami no -
butyric add (GABA)-medlated functions. The toxic and convulsant potencies
In mice of a series of U polychlorocycloalkane (PCAA) Insecticides.
Including endrln, were determined and related to their .In vivo potencies for
Inhibiting the mouse brain t-butylb1cyclophosphoroth1onate (TBPS) binding
site, which Is associated with GABA-regulated chloride transport (Cole and
Caslda, 1986). Following LD5Q estimations, male Swiss-Webster mice were
administered ID, U>50/2 or ln5Q/4 doses of: each compound by Intra-
perltoneal Injection. Nice were sacrificed 30 minutes later, brains were
00690 VII-2
-------
removed and binding of [»»S]TBPS to brain membranes was determined. For
endMn specifically, the L05Q was 8 mg/kg bw, and the percent Inhibitions
for LQ50, LDsn/2 and LD50/4 doses were 77-7* 39-6 and °** resPec-
Uvely. These data were consistent with two previous reports suggesting
binding of cyclodlene Insecticides (Including endMn) to the GABA receptor
(Lawrence and Caslda, 1984; Tanaka et al., 1984; Aballs et al., 1985). It
was concluded that the toxlclty or convulsant activities of PCAA
Insecticides were correlated with in vivo disruption of the mouse brain TBPS
binding site.
Aballs et al. (1986) also reported that a GABA-lnducted "d" Influx
Into rat brain mlcrosacs Is reduced by in vitro exposure to cyclodlene
Insecticides. Hlcrosacs exposed to endrln (1 vH) exhibited an 82% reduc-
tion In »*C1~ Influx relative to control. These data were Interpreted
as supportive of previous suggestions that cyclodlene Insecticides (Includ-
ing endrln} Inhibit functions mediated by the GABA receptor.
Peripheral vascular effects of acute endrln exposure were examined in
partially Isolated forclimbs of 10 mongrel dogs (Emerson and Hlnshaw, 1965).
Following the surgical forellmb separation and. In 5/10 dogs, denervatlon of
the forellmb, endrln (10 mg/kg) was Intravenously Infused. After about 10
minutes of Infusion, Innervated 11mb vascular resistance Increased "80%;
this Increased resistance was accompanied by a decrease In 11mb blood flow.
Similar results were observed In the denervated forellmbs after about 10
minutes of Infusion. However, In contrast to the Innervated limbs, vascular
resistance subsequently Increased steeply to high levels, and 11mb blood
flow virtually ceased. It was concluded that sympathetic 1nnervat1on was
not necessary for vascular resistance Increases following endrln exposure.
00690 VI1-3 ' 1
-------
and U was suggested that the vascular effects of endHn may be due to
circulating catecholamlnes.
t
Endrln toxlclty may also be mediated through effects on membrance
permeability, since hemolysls has been observed for postendrln hematocrHs
In dogs (Emerson et al., 1964), and 'hemorrhagU'enteritis* has been noted
1n rats and birds (Stlckel et al., 1979b).
Subchronlc studies in human workers are consistent with a reversible
Induction of liver mlcrosomal activity, as denoted by urinary levels of
D-glucarlc acid, which Is dependent on the level of cytochrome P-450
(Ottevanger and Van Slttert, 1979). D-glucarlc acid was not detected In
urine when antl-12-hvdroxyendrln urine levels were <0.13 mg/g of creatlnlne.
In rats {Treon et al., 1955), the only long-term degenerative changes In
the organs from fatally-poisoned animals studied occurred In the liver and
kidneys. The mechanisms responsible for such changes are not known.
Endrln was reported to lack cardnogeniclty In several studies (Treon et
al., 1955; Belchmann et al., 1970; Wltherup et al., 1970; MCI, 1979), but
Reuben (1978, 1979) has concluded that endrln Is a carcinogen. It Is note-
worthy that endrln lacks genotoxlclty In bacterial assays (Ames et al.,
1975; HoMya et al., 1983), and like other organochlorlne pesticides. In
rat, mouse and hamster hepatocytes (Haslansky and! Williams, 1981). In view
of these results, Haslansky and Mllllaras (1981) proposed that the cardno-
geniclty of organochlorlne pesticides reflects an eplgenetlc rather than a
genotoxlc mechanism^ This proposal Is consistent with the observations of
00690 - VII-4
-------
Kurata et al. (1982), which Indicated that organochlorlne pesticides
(Including endrin) inhibited metabolic cooperation 1n Chinese hamster
cells. It was suggested that the pesticides that Inhibited metabolic
cooperation might be tumor promoters. Further, Ho et al. (1980) reported
that dietary endrin exposure (25 ppm for 6 weeks) elicited an Increase In
the area of hyperplastlc liver nodules In hepatectomlzed Fischer F344 rats
previously treated with dlethylnltrosamlne. although the number of nodules
was not affected by endrin. A classification system was also proposed;
endrin would be classified by this system as a weak promoter.
It 1s emphasized that the discussion In the above paragraph should not
be construed as positive evidence for endrin tumorlgendlty, but rather, as
evidence of a possible eplgenetlc action of endrin. Conclusions concerning
endrin carc1nogen1dty are presented In the following chapter.
Interactions
Ludke (1976) demonstrated that prior treatment with a closely-related
Insecticide can Increase bird mortality. Fourteen-week-old male and female
white quail (Collnus vlrglnlanusl were divided Into four groups; four birds
constituted the control group. All groups were fed turkey maintenance mash
with IX (w/w) propylene glycol mixed In the diet. Pesticides were dissolved
In propylene glycol and mixed Into the diet. Twenty-eight birds received 10
pom technical chlordane In the diet for 10 weeks and 20 of these were i.*er>
fed 10 ppm 98% pure endrin 1n the diet for 6-10 days. A fourth group (N.20)
was fed 10 ppm endrin 1n the diet. No mortality occurred 1n the control
group nor in the group fed chlordane alone. For endrIn-fed birds, mortality
occurred on days 1 (1 bird), 6 (7), 9 (S) and 10 (2). For the chlordane-
endrIn-treated groups, mortality occurred on days 3 and 6-10 (14 birds) of
00690 VII-S
-------
endrln exposure, and survivors were sacrificed on days 9 and 10 of endrln
exposure. All surviving birds treated with endrln alone or chlordane-endrln
lost weight and showed depleted llpld content In the carcasses (Table
VII-1). Control and chlordane-treated birds showed no significant
decreases. Birds that survived exposure to chlordane-endMn or endrln alone
had lower brain residues of endrln than the dead birds. Birds dying of
endrln poisoning alone had brain residues ranging from 0.34-1.84 mg
endr1n/kg ww (survivors 0.28-0.62 mg endr1n/kg ww). In chlordane-endrIn-
treated birds, the dead birds contained 0.17-1.25 mg endrln/kg brain,
whereas the survivors had 0.14-0.56 mg/kg brain. The latter two groups
differed at p<0.10. Dead or moribund birds treated with the two pesticides
contained significantly lower (p<0.025) endrln brain residues than the
corresponding birds treated with endrln alone. Thus, birds nay be more
vulnerable to a toxicant if the bird already carries a body burden of one or
more closely related chemicals. In this study, mortality from endrln alone
t
was associated with as little as 0.34 mg endr1n/kg brain.
Meena et al. (1978) Investigated endrln-Induced toxldty In normal rats
and rats Irradiated with gamma radiation by dividing 128 male albino rats
(150-200 g) Into four equal groups. The control group received groundnut
oil l.p.; group 2 received a single l.p. Injection of 10 mg endrln/kg bw In
groundnut oil; group 3 served as Irradiated controls (900 rads); group 4
received 10 mg endrln/kg bw 0.5 hours after Irradiation. In both normal and
Irradiated rats, endrln caused a significant Increase In SCOT, SGPT and
ATPase; add and alkaline phosphatase, sucdnlc dehydrogenase and glucose-6-
phosphatase decreased significantly during varying periods of 2-48 hours
after treatment. In Irradiated rats given endrln. the changes appeared
earlier and were more pronounced than In normal rats given endrln alone.
00690 VII-6
,
-------
TABLE VI LI
Height Loss and Llpld Content (Mean X + S.E.) of Quail Carcasses After
Technical Chlordane, 98X-Pure Endrln, and Chlordane-Endrln Treatments*
Treatment
Chlordane
Endrtn
Condition No. % Llpld % Height Loss
None
10 ppm diet:
10 weeks
None
10 ppm diet:
10+ weeks
none
none
10 ppm diet:
6-10 days
10 ppm diet:
6-10 days
S
s
0
H
S
0
H
S
4
4
13
1
3
12
3
3
4.69+0.77
3.45+0.56
0.43+0.14
0.73~
2.73+0.97
0.39+0.06
0.27+0.04
2.78+1.29
0
0
32.2+2.4
68.6"
14.7.+1.1
31.4+3.0
37.2711.7
19.U3.5
'Source: Ludke. 1976
S * Sacrificed, no apparent signs of toxklty; 0
(reduced activity and lowered appetite}
dead; N moribund or sick
00690
VII-7
-------
except 1n the case of ATPase where.endrln appeared to neutralize the effect
of radiation-on the nUochondrlal membrane. The study Indicated that endrln
leads to Injury of liver and kidney tissues, and 'that this may occur sooner
after gamma Irradiation of rats.
Following 2 weeks of dietary exposure to 0, 5 or 100 pprn endrln, rats
were administered a single dose of CC1. (0.1 ml/kg) by Intraperltoneal
V
Injection, and hepatotoxldty was assessed the following day by determina-
tion of serum enzyme activities (Young and Nehendale, 1986). No signifi-
cant elevations 1n enzyme activities were observed following exposure to
endrln alone. Following exposure to CC1. alone, modest but significant
elevations In serum of male rats was reported for SGPT, SGOT and Isocltrate
dehydrogerase (ICD) activities. In females, CCl^ exposure elicited
significant but modest elevations In SGOT and ICO activities and a more
substantial elevation 1n ornUMne-carbanyl transferase (OCT) activity.
However, exposure to CC1. plus endrln elicited marked elevation In SGPT
and ICO activities In females relative to the untreated controls. Further.
these activities were statistically significantly higher than those of
animals exposed to CC14 alone. It was concluded that dietary endrln
pretreatment potentiated CC1. hepatotoxUHy.
Summary
Acute exposure to endrln causes death, which Is preceded by convulsions
and other CMS disturbances. Acute toxlclty Is associated with the presence
of 12-ketoendMn, and this metabolite has been postulated to be the ultimate
t
toxicant. Evidence suggests that endrln (and other polychlorocycloalkene
Insecticides) may Induce convulsions and death by Interfering with GABA-
regulated functions In the CMS, particularly chloride transport. Increased
00690 VII-8 ^ ,
-------
vascular resistance that follows endrln exposure may be Mediated through
effects of circulating catecholamlnes. Studies of human workers exposed
subchronkally to endrln suggest Induction of liver mlcrosomal enzymes.
Mechanisms of chronic endrln toxlclty are not known.
As with other organochlorlne pesticides, endrln lacks genotoxlclty In
bacterial systems and In rodent hepatocytes, but can Inhibit metabolic
cooperation In Chinese hamster cells. These observations are consistent
with, but do not necessarily Indicate, a capability of endrln to Influence
tumor development by eplgenetlc mechanisms.
Evidence for Interactions augmenting endrln toxldty exists for birds
carrying a body burden of closely related chemicals, and for rats pretreated
with gamma Irradiation. Pretreatment with endrln potentiated CCl4-1nduced
hepatic Injury In rats.
00690 VII-9
-------
. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
Introduction
The quantification of lexicological effects of, a chemical consists of
separate assessments of noncarclnogenlc and carcinogenic health effects.
Chemicals that do not produce carcinogenic effects are believed to have a
threshold dose below which no adverse, noncarclnogenlc health effects occur.
while carcinogens are assumed to act without a threshold.
In the quantification of noncarclnogenlc effects, a Reference Dose
(RfD). [formerly termed the Acceptable Dally Intake (ADI)] Is calculated.
The RfD Is an estimate (with uncertainty spanning perhaps an order magni-
tude) of a dally exposure to the human population (Including sensitive
subgroups) that 1s likely to be without an appreciable risk of deleterious
health effects during a lifetime. The RfO Is derived from a no-observed-
adverse-effect level (MOAEl), or lowest-observed-adverse-effect level
(LOAEL), Identified from a subchronlc or chronic study, and divided by an
uncertainty factor{s) times a modifying factor. The RfO is calculated as
follows:
Rf0 . : {MOAEL or LOAEL) . /fc
[Uncertainty Factor(s) x Modifying Factor]
Selection of the uncertainty factor to be employed 1n the calculation of
the RfO 1s based upon professional judgment, while considering the entire
data base of toxlcologlcal effects for the chemical. In order to ensure
that uncertainty factors are selected and applied,In a consistent manner,
00700 VII1-1
.
-------
the U.S. EPA (1988*) employs a modification to the guidelines proposed by
the National Academy of Sciences (MAS, 1977, 1980) as follows:
Standard Uncertainty Factors (UFs)
Use a 10-fold factor when extrapolating from valid experimental
results from studies using prolonged exposure to average healthy
humans. This factor 1s Intended to account for the variation
In sensitivity among the members of the human population. [10HJ
Use an additional 10-fold factor when extrapolating from valid
results of long-term studies on experimental animals when
results of studies of human exposure are not available or are
Inadequate. This factor Is Intended to account for the uncer-
tainty in extrapolating animal data to the case of humans.
[10A]
Use an additional 10-fold factor when extrapolating from less
than chronic results on experimental animals when there 1s no
useful long-term human data. This factor Is Intended to
account for the uncertainty 1n extrapolating from less than
chronic NOAELs to chronic NOAELs. [10S]
Use an additional 10-fold factor when deriving an RfD from a
LOAEL Instead of a NOAEL. This factor 1s Intended to account
for the uncertainty In extrapolating from LOAELs to NOAELs.
[101J
Modifying Factor (NF)
Use professional Judgment to determine another uncertainty
factor (NF) that 1s greater than zero and less than or equal to
10. The magnitude of the MF depends upon the professional
assessment of scientific uncertainties of the study and data
base not explicitly treated above, e.g., the completeness of
the overall data base and the number of species tested. The
default value for the HF Is 1.
The uncertainty factor used for a specific risk assessment Is based
principally t'^on scientific judgment rather than scientific fact and
accounts fur possible 1ntra- and Inter species differences. Additional
considerations not Incorporated In the NAS/ODW guidelines for selection of
an uncertainty factor Include the use of a less than lifetime study for
deriving an RfD, the significance of the adverse health effects and the
counterbalancing of beneficial effects.
00700 VI11-2
-------
From the RfO, a Drinking Water Equivalent Level (DUEL) can be calcu-
lated. The DUEL represents a medium specific (I.e., drinking water)
lifetime exposure at which adverse, noncarclnogenlc health effects are not
anticipated to occur. The DUEL assumes 100% exposure from drinking water.
The DUEL provides the noncarclnogenlc health effects basis for establishing
a drinking water standard. For Ingestlon data, the DUEL Is derived as
follows:
nue. (RfDl x (Body weight In kg) ..
DUEL ~"^~~ mo/l
Drinking Hater Volume in I/day ' ^
where:
Body weight assumed to be 70 kg for an adult
Drinking water volume assumed to be 2 t/day for an adult
In addition to the RfO and the DUEL, Health Advisories (HAs) for expo-
sures of shorter duration (1-day, 10-day and longer-term) are determined.
The HA values are used as Informal guidance to municipalities and other
organizations when emergency spills or contamination situations occur. The
HAs are calculated using an equation similar to the RfD and DUEL; however,
the NOAELs or LOAELs are Identified from acute or subchronlc studies. The
HAs are derived as follows:
HA . (NOAEL or LOAELl x (bw) m /f
(UF) x ( t/day) "~
Using the above equation, the following drinking water HAs are developed
for noncarclnogenlc effects:
1. 1-day HA for a 10 kg child Ingesting 1 i water per day.
2. 10-day HA for a 10 kg child Ingesting 1 t water per day.
3. longer-term HA for a 10 kg child Ingesting l,t water per day.
4. Longer-term HA for a 70 kg adult Ingesting 2 i water per day.
00700 VIII-3 >
-------
The 1-day HA calculated for a 10 kg child assumes a single acute
exposure to the chemical and Is generally derived from a study of <7 days
duration. The 10-day HA assumes a limited exposure period of 1-2 weeks and
Is generally derived from a study of <30 days duration. The longer-term HA
Is derived for both the 10 kg child and a 70 kg adult and assumes an
exposure period of -7 years (or 10% of an Individual's lifetime). The
longer-term HA Is generally derived from a study of subchronlc duration
(exposure for 10% of animal's lifetime).
The U.S. EPA categorizes the carcinogenic potential of a chemical, based
on the overall welght-of-evldence, according to the following scheme:
Group A: Human Carcinogen. Sufficient evidence exists from
epidemiology studies to support a causal association between
exposure to the chemical and human cancer.
Group B: Probable Human Carcinogen. Sufficient evidence of
carclnogenlclty In animals with limited (Group 81) or Inade-
quate (Group 82) evidence 1n humans.
Group C: Possible Human Carcinogen. Limited evidence of
carclnogenlclty 1n animals in the absence of human data.
Group 0: Mot Classified as to Human Carclnogenlclty. Inade-
quate human and animal evidence of carclnogenlclty or for which
no data are available.
Group E: Evidence of Moncarclnogenlclty for Humans. Mo
evidence of carclnogenlclty In at least two adequate animal
tests In different species or In both adequate epldemlologlc
and animal studies.
If toxlcologlcal evidence leads to the classification of the contaminant
as a known, probable or possible human carcinogen, mathematical models are
used to calculate the estimated excess cancer risk associated with the
Ingestlon of the contaminant In drinking water. The data used In these
00700 VII1-4
-------
estimates usually cone from lifetime exposure studies using animals. In
order to predict the risk for humans from animal data, animal doses must be
converted to equivalent human doses. This conversion Includes correction
for noncontlnuous exposure, less than lifetime studies and for differences
In size. The factor that compensates for the size difference 1s the cube
root of the ratio of the animal and human body weights. It Is assumed that
the average adult human body weight Is 70 kg and that the average water
consumption of an adult human Is 2 i of water per day.
For contaminants with a carcinogenic potential, chemical levels are
correlated with a carcinogenic risk estimate by employing a cancer potency
(unit risk) value together with the assumption for lifetime exposure from
Ingestlon of water. The cancer unit risk Is usually derived from a linear-
ized multistage model with a 95% upper confidence limit providing a low dose
estimate; that Is, the true risk to humans, while not Identifiable. Is not
likely to exceed the upper limit estimate and, In fact, may be lower.
Excess cancer risk estimates may also be calculated using other models such
as the one-hit, Helbull. loglt and problt. There 1s Uttle basis In the
current understanding of the biological mechanisms Involved In cancer to
suggest that any one of these models Is able to predict risk more accurately
than any other. Because each model 1s based upon differing assumptions, the
estimates derived fur each model can differ by several orders of magnitude.
The scientific data base used to calculate and support the setting of
cancer risk rate levels has an Inherent uncertainty that Is due to the
systematic and random errors In scientific measurement. In most cases, only
studies using experimental animals have been performed. Thus, there 1s
00700 VIII-5 ---/.-"
-------
uncertainty when the data are extrapolated to humans. When developing
cancer risk rate levels, several other areas of uncertainty exist, such as
the Incomplete knowledge concerning the health effects of contaminants In
drinking wa*er, the Impact of the experimental animal's age, sex and
species, the nature of the target organ system(s) examined and the actual
rate of exposure of the Internal targets in experimental animals or humans.
Dose-response data usually are available only for high levels of exposure
and not for the lower levels of exposure closer to where a standard may be
set. When there Is exposure to more than one contaminant, additional
uncertainty results from a lack of Information about possible synerglstlc or
antagonistic effects.
Moncarc1noaen1c Effects
Although the acute LD$0 for endrln has been determined for a number of
species, the available data for defining short-term health advisories (HAs)
1s more limited. In an abstract, Revzln "(1966) reported an Increase 1n the
amplitude of the EEG and a tendency toward spiking after seven dally doses
of 0.2 mg/kg bw endrln In rats. Mo effects were noted, however, after 1 or
2 days exposure to the same dose level. Speck and Haaske (1958) reported
EEG changes and occasional convulsions after 1 week using dally oral doses
of 3.5 mg/kg bw In rats. It was not reported whether effects occurred at
lower doses (0.8 and 1.7 mg/kg bw}, which were also employed.
Information on acute and subchronlc effects of endrln exposure Is
available from perinatal toxlclty studies. Chernoff et al. (1979.) reported
marked maternal toxlclty 1n Syrian golden hamsters at doses >1.5 mg/kg
*
bw/day for 10 days. Kavlock et al. (1981) reported decreased locomotor
00700 VII1-6
-------
activities In adult female CD-I nice after single oral exposures to 1.5 or
4.5 tag/kg endMn, but not to 0.5 mg/kg endrln. In CO rats, single oral
endrln doses of 0.5. 1.0 or 2.0 mg/kg bw elicited a dose-related decrease In
locomotor activity. Pregnant CD-I nice exposed to endrln doses of 0.5, 1.0,
1.5 or 2.0 mg/kg bw/day by oral gavage on days 7-17' of gestation exhibited
reduced weight gain at the three highest exposure levels and elevated liver-
to-body weight ratios at all exposure levels. Pregnant CO rats exposed to
endrln doses of 0.075, 0.150, 0.300 or 0.450 mg/kg/day by oral gavage on
days 7-20 of gestation exhibited decreased weight gain at the two highest
doses only; llver-to-body weight ratios were unaffected In all exposure
groups. Thus, 0.150 mg/kg/day may be considered las a NOAEL for a 14-day
oral endrln exposure. >
s
Nelson et al. (1956) exposed Sprague-Oawley rats to 1, 5, 25, 50 and 100
ppm endrln In the diet for up to 16 weeks. Body weights and serum alkaline
phosphatase, an Index of liver damage, were measured weekly. Following 4
weeks of exposure, 40X mortality had occurred at exposure levels >5 ppm in
males, and hypersensltWUy to various stimuli and nasal bleeding had
occurred at the 1 and 5 ppm exposure levels. Body weight losses and
elevated serum alkaline phosphatase occurred at all exposure,levels. By 10
weeks of exposure, mortality had occurred at all exposure levels In males
and to females at levels >25 ppm. Mortality within the groups remained the
same at week 16.
s
MCI (1979) 1n a cancer range-finding study found decreases In body
weight gain In rats administered 20 ppm. but not ,10 ppm In the diet for 6
weeks. In the same study decreased body weight gains were also reported In
mice administered 10 ppm, but not 5 ppm 1n the diet.
00700 " VIII-7 v- ;>.'&
-------
Treon si al. (1955) conducted subchronlc and chronic exposure studies on
both rats and dogs. Groups of 20 male and 20 female Carworth rats were
given diets containing 0, 1, 5, 25, 50 or 100 ppro endrln for up to 2 years.
Mortality was high at the 50 and 100 ppm exposure levels. Weight gain was
decreased 1n the males exposed to 5 and 25 ppm, but not 1 ppm, for 20 weeks.
Liver-to-body weight ratios were Increased In male rats In the 5 and 25 ppm
. groups, but not the 1 ppm group, after 2 years of exposure. Liver-to-body
weight ratios 1n the female rats exposed to 1 or 5 ppm endrln for 2 years
did not differ significantly from controls.
x'
Treon et al. (1955) also conducted a study with beagle dogs In which
groups of 1-4 were fed diets containing 0-50 ppm endrln for up to IB months.
All dogs fed 10-50 ppm (0.49-4.00 mg/kg/day) died, and >50% of those fed 5-8
ppm (0.20-0.65 mg/kg/day} died. Actual endrln Intakes were reported by the.
authors. All dogs receiving <4 ppm (0.18 mg/kg/day) survived, but growth
was affected In the 4 ppm groups. The 3 pom (0.19 mg/kg/day} group had
significantly higher relative kidney and heart weights than controls. Dogs
fed 1 ppm endrln were similar to controls 1n all parameters, Including gross
pathology and hlstopathology. According to the authors, the dogs (two males
and two females) on the 1 ppm diet actually consumed 0.083 mg/kg/day.
While other chronic studies have been conducted with the primary Intent
of evaluating carcinogenic response, some toxlclty data have also been
^
reported. Delchmann et al. (1970) administered endrln to rats at concentra-
tions of 2, 6 and 12 ppm 1n the diet for up to 37 months. A moderate
Increase 1n cloudy swelling of the liver and renal tubular epithelium along
00700 VII1-8
-------
with a moderate Increase 1n the Incidence of lung congestion and focal
hemorrhage was reported. Since the authors stated that the effects were not
dose-related. It Is assumed they occurred at the 2 ppm level as well as the
t"
higher doses.
In an NCI (1979) study both mice and rats were chronically exposed to
endrln. The mice were administered a time-weighted-average (TWA) concentra-
tion In the diet of 1.6 and 3.2 ppm, while the rats received 3 and 6 ppm.
Neither mortality nor body weights were affected by either dose. However, a
variety of clinical signs usually associated with aging were observed
earlier 1n the exposed mice and rats. Although a NOAEL was not observed In
the Delchmann et al. (1970) or the NCI (1979) studies, the results of these
Investigations provide strong support for a NOAEL no greater than O.OS mg/kg
bw In rats and 0.13 mg/kg bw In mice (1 ppm In the diet).
In a 2-year dog study, beagle dogs (7/sex/group) received diets
containing 0, 0.1, 0.5, 1.0, 2.0 or 4.0 ppm endrln for >2 years (U.S. EPA,
1987). Interim sacrifices (2 dogs/sex/group} were performed at 6 and 12
months. Parameters monitored Included growth, food consumption, behavior,
serum and urine chemistry, organ weights and hlstopathology of all major
organs. Animals treated at the 2 and 4 ppm dose levels experienced convul-
sions, slight Increase In relative liver weights, and mild hlstopathologlcal
changes In liver cells. Because of the effects observed In the dogs
consuming diets containing 2 ppm endrln (0.05 mg/kg/day), this level was
considered the LOAEL. No adverse effects were observed In dogs receiving
diets containing <1 ppm endrln. Therefore. 1 ppm (0.025 mg/kg/day) was
considered the NOAEL.
00700 VIII-9
-------
Only one chronic nonmaonallan study appears to have been conducted to
u-
date. KreUzer (1980) measured behavioral effects of endrln In adult
bobwhHe quail (Collnus vlrolnlanusl using nonspatlal discrimination
reversal tasks. The birds were fed 0.1 and 1.0 ppra endrln In the diet {0.01
and 0.10 mg/kg bw 1f It Is assumed the birds eat an amount equivalent to 10%
of bw/day) for up to 240 days. Significantly Increased error rates were
detected at both levels of exposure. While the results of this study
suggest a NOAEL lower than values determined from other chronic studies, H
Is uncertain how they relate to those of mammalian exposures. Acute LD5Q
studies on pigeons (Revzln, 1966) suggest that some species of birds may be
more sensitive to endrln exposure than mammals.
Quantification of Moncardnoqenlc Effects
i
Derivation of UOav HA. Previously the study by Revsln (1968) was
selected as the basis for the 1-day HA. In this study. Revsln reported
alterations In the EEG of squirrel monkeys after 7 dally doses of 0.2 mg/kg
endrln. Results of this study were provided as an abstract. Recently the
*
Science Advisory Board of the U.S. EPA {1988c) 1n their meeting discourage
the use of data from an abstract for the derivation of an HA level. Under
the circumstances, the Kavlock et al. (1981) study Is considered for the
1-day HA. In a preliminary range finding study, Kavlock et al. (1981)
reported decreased locomotor activities In adult female CD-I mice following
single oral endrln doses of 1.5 or 4.5. but not 0.5 mg/kg bw. The 0.5
-------
where:
0.5 rag/kg « MOAEL, based on locomotor activities In mice
(Kavlock et al., 1981)
10 kg . weight of protected Individual (child)
j
1 i/day » assumed water consumption by a child
100 ^uncertainty factor, chosen In accordance with
NAS/OOW and Agency guidelines for use with a NOAEL
from a study In animals
Derivation of 10-Day HA. Formerly the 10-day HA value was calculated
based on the results of the Nelson et al. (1956) study on rats. However,
revaluation of the study Indicated certain observations that should not be
Ignored. These observations Included body weight losses, hypersensltlvlty
to various stimuli, nasal bleeding and Increased alkaline phosphatase
activity at the lowest endrln level tested. In view of the noted
observations, U 1s prudent to consider the Kavlock et al. (1981) study for
derivation of the 10-day HA. Kavlock et al. (1981) reported depressed
maternal weight gain In CO. rats exposed to endrVn doses of 0.300 or 0.450
but not 0.150 or 0.075 mg/kg/day for U consecutive days; 0.150 rag/kg/day
can be considered a NOAEL for a 10-day exposure. The 10-day HA for a 10 kg
child Is derived as follows:
10-day HA . 0.150 mq/kq/day x 10 kq m
' 1 i/day x 100
where:
0.150 mg/kg/day - NOAEL, based on weight gain changes In rats
(Kavlock et al.. 1981)
10 kg - weight of protected Individual (child)
1 i/day assumed water consumption by a child
100 - uncertainty factor, chosen 1n accordance with
NAS/OOW and Agency guidelines for use with a
NQAEL from a study 1n animals
00700 VIII-11
-------
Derivation of Longer-Term HA. Subchronlc exposure data appropriate
for deriving longer-term HAs are extremely limited. Nelson et al. (1956)
reported body weight losses, hypersensltlvUy to various stimuli, nasal
bleeding and Increased alkaline phosphatase activity to levels of endrln >1
ppm m Sprague-Dawley rats. The reported LOAEL of 1 ppm endrln In the diet
corresponds to a dose of 0.05 mg/kg/day (assuming an average dally dietary
consumption of 5X of body weight for Sprague-Dawley rats In a subchronlc
study; U.S. EPA. 1987). By 10 weeks of exposure, mortality had occurred at
all exposure levels 1n males and to .females at levels >25 ppm.
Treon et al. (1955) reported elevated kidney and heart-to-body weight
ratios In beagle dogs exposed for up to 18 months to diets containing 3 ppm,
but not 1 ppm endrln. At both doses, organ-to-body weight ratios for liver.
brain and spleen did not differ significantly from controls. Based on
measured food Intake, the dally dose for the 1 ppm dose group varied from
0.045-0.12 mg/kg bw. However, the dally Intake of 1 ppm endrln appears to
be suspect since this range overlaps with the 3 ppm range of exposure as
given 1n the published report. It Is therefore recommended that the DUEL,
which Is based on lifetime exposure (see Assessment of Lifetime Exposure and
Derivation of a DUEL Section), be used as a conservative basis for the
longer-term HA. . This value 1s based on a chronic NOAEL of 0.025 ng/kg/day.
i-
The Nelson et al. (1956) study Is precluded for use since a high rate of
mortality occurred In male rats at >0.05 mg/kg/day after 10 weeks.
The DUEL of 0.009 mg/l 1s based on adult body weight and water
consumption and therefore Is used directly for the longer-term HA for
adults. For the 10 kg child, the RfD upon which the DUEL 1s based Is used
1n the following derivation.
00700 VIII-12
-------
Longer-Term HA . Rfp ' 10 k<* . °-0003 «W««Y * 10 "1
(child) 1 i/day 1 I/day
« 0.003 mg/l
where: '
RfO - 0.0003 mg/kg/day
10 leg assumed weight of exposed: Individual (child)
1 I/day assumed volume of water consumed/day by a 10
kg child
Assessment of Lifetime Exposure and Derivation of a DUEL. A review of
the literature, Including an unpublished study from the CBI files concerning
endrln and the various RfO values that have been promulgated by the
different branches, of the Agency, has Indicated that the CBI study is the
most appropriate basis for an RfD (U.S. EPA, 1988b). In this 2-year dog
study, beagle dogs (7/sex/group) received diets containing 0, 0.1, 0.5, 1.0,
2.0 or 4.0 ppm endrln for >2 years. Animals treated at the 2 and 4 ppm dose
levels experienced convulsions, slight Increase In relative liver weights,
and mild hlstopathologlcal changes 1n liver cells. No adverse effects were
observed at <1 ppm endrln, therefore 1 ppm (0.025 mg/kg/day) was considered
the NOAEL. Using the above study, the derivation of the DUEL Is as follows:
Step 1 - RfD Derivation
RfQ m 0.025 mq/kq/day .
100
where:
0.025 mg/kg/day - NOAEL for oral exposure In dogs (U.S.
EPA,1987)
100 - uncertainty factor appropriate for use with a
NOAEL (from animal data and to protect
sensitive members of the human population
00700 VII1-13
-------
Step 2 - DUEL Derivation
EfD x 70 ko 0.00025 mn/ko/dav x 70 ko . _ ., .
- - * - rc * - ' - » » 0.009 mg/i
2 I/day 2 i/day
where:
RfO . 0.0002S mg/kg/day
*
70 kg assumed weight of protected Individual (adult)
2 ft/day - assumed volume of water consumed by a 70 kg adult
The recommended lifetime DWU for a 70 kg adult Is 0.009 mg/i endrln.
A sunnary of the data used to calculate the HAs and the lifetime DUEL Is
provided 1n Table VI1I-1. The values derived for the HAs and DUEL represent
estimates of the concentration of endrln 1n drinking water that will not
cause adverse effects after 1-day, 10-day, longer-term or lifetime exposures.
Carcinogenic Effects
There are no clinical reports available relating endrln exposure to
Induction of cancer in humans. DUraglla et al. (1981) conducted a retro-
spective cohort study to examine the mortality of workers employed In the
manufacture of chlordane, heptachlor, DDT and aldrln/dleldrln/endrln. No
statistically significant excess for any specific cancer site was noted.
However, since no exposure data are reported, the results of this study are
Inconclusive. While there 1s no evidence linking endrln to cancer Induction
In humans, the amount of data available 1s Insufficient to allow definite
conclusions to be drawn.
Four bloassays for carc1nogen1c1ty were done In rats and three were on
mice. These bloassays were done at different Institutions, namely Food and
Drug Administration (FDA) during 1955-1957 as Devaluated by Reuler (1978),
00700 VII 1-14
-------
I
O
i
>
T o>
a
M e
S
ut
ii
sr
&
a ei
w
>
i » «Q mf
« * 91
VI
Wl
s
rt
S
V* V"
§ §
v C 3 ^
O C O
8S Si
^ >
* U < > <»
w e « * S**y S"" S
« x i- x« >e «^e
(M
i/i
JM
O
2
*
u
I
00700
VIII-15
-------
the national Cancer Institute (MCI, "l979J. the University of Cincinnati
{Ketterlng Laboratory) {yitherup et al.. 197'0). and the University of N1am1
{Oelchmann et al., 1970). All the bloassays on rats and nice were reported
as negative by those authors. There were, however, deficiencies 1n the
studies which 1s explained below, which render the findings Inadequate to
properly assess the carcinogenic potential 1n animal test systems.
In the FDA rat (Osborne-Hendel) study the animals at highest dose (25
ppni) did not survive well and additional animals were started 1n that dose.
The remainder of the groups lived for the programmed two year study. It
also appeared that every animal came to autopsy and not all sections from
grossly observed animals were studied microscopically. In spite of some
deficiencies there were a sufficient number of animals In the studies
particularly In the aspect of liver and kidney. In all experimental and
control groups (Reuber, 1978). This study was originally reported as
negative. It was reevaluated by a panel of pathologist whose report was
referenced 1n a CAG document (U.S. EPA. 1978). One pathologist considered
the finding positive (Table V-ll and V-12) but did not provide slide by
slide tabulation of his findings and did not distinguish between primary
and/or metastatlc tumors In the liver. A second pathologist whose original
finding Indicated, that the study was negative, provided slide by slide
tabulation of diagnosis which was confirmed by the panel review. In the FDA
mice (C3HF1) study the survival was very poor 1n both control and
experimental group.
The Ketterlng study used two strains of mice (CS7B1/6J and C302F1/J).
The C5781/6J strain exhibited mainly leukemia and liver tumors with low
Incidence. These tumors appeared equally 1n the experimental and control
00700 VII1-16
-------
groups and the latent period of tumor formation ,was similar. But In the
C302F1/J strain, the Incidence of liver tumors 1n the dose group (3 ppm) was
slightly higher In the female than in controls and the latent period of
tumor formation was decreased than other groups (WHherup et al., 1970).
The NCI bloassay was done In Osborne-Mendel rats and B6C3F1 mice. These
studies were reported as negative. A primary reviewer for NCI noted that
the negative findings could be a reflection of the high toxlclty of endrln,
which only permitted the administration of relatively low chronic dosages.
Furthermore, the reviewer observed that an accidental overdose among low
dose male mice resulted In early death of several animals In this treatment
group and the study was marred by a small (10) If matched controls; however,
this deficiency was compensated by the use of pooled controls (see Table
V-17). There were significant Increases 1n hemangloma In low dose male
rats, adrenal, adenoma and/or carcinoma In high dose In males, pituitary
adenomas In the high dose female, adrenal adenoma and/or carcinoma 1n low
dose female rats as compared to the pooled controls. Although, the
Islet-cell carcinoma In male rats had a significant trend but no
statistical significance at either dose group, the NCI concluded that these
tumors could not be clearly considered related to the admlnstratlon of
endrln (NCI, 1979). Although NCI concluded that the bloassays of endrln
were not carcinogenic, the responses noted above can not be totally Ignored.
Endrln was not mutagenlc In any bacterial strains but exhibited
chromosomal aberration In germinal tissues. Endrln 1s also strycturally
related to aldrln, dleldrln, chlordane, chlorendlc add and heptachlor which
are known to carcinogenic In animals. The available cancer epldemlologlc
00700 VIII-17
-------
data Involving several studies 1s Inadequate to demonstrate or refute a
carcinogenic hazard because of study design limitations and/or mixed
exposures. Using the criteria 1n the U.S. EPA (198^) guidelines for
classification of carcinogens, endrln 1s most appropriately classified In
Group D; I.e. a chemical for which there 1s Inadequate evidence to assess
the potential cardnogenlclty for humans. This classification Is based on
the nonposUlve but suggestive results In some of the animal studies. The
negative conclusions as reported by the study authors of the four bloassays
do not support a Group E classification, because of the Inadequacies of the
studies. A Group 0 we1ght-of-ev1dence Is thought to be the best classifi-
cation until additional studies can be done to clarify the situation.
Existing Guidelines. Recommendations and Standards
The U.S. EPA (1975) has set an Interim standard for endrln in finished
water of 0.0002 mg/t. The U.S. EPA (1980a) proposed an ambient water
criterion for endrln of 0.001 mg/i. This value was the sane as the
maximum allowable concentration recommended at that time by the Public
Health Service.
The World Health Organization (FAO/UHO, 1973} established as a guideline
a maximum Intake of 2 yg/kg/day, or 138.2 vg/day, for a 69.1 kg person.
The proposed Index Allnentarlus Commission's maximum residue limit In wheat
Is 20 ug/kg (Bailey et al.. 1982).
The threshold limit value {8-hour TLV/TWA) recommended by the American
Conference of Governmental Industrial Hyglenlsts Is 0.10 mg/m» (0.10
00700
VIII-18
-------
wUh a short tine exposure limit (15 minutes} of 0.30 mg/m»
(ACGIH, 1982). The Occupational Safety and Health Administration limits are
the same, 0.10 mg/ra» (29 CFR 1910-1000).
The history of recommendations concerning endrln Is provided In the
Federal Register (1979). The U.S. EPA Issued a notice of rebuttable pre-
sumption against registration and continued registration (RPAR) of endrln-
containing products (e.g., R1d-a-B1rd and SorbUHI} on July 27, 1976. It
Included three supportable risk presumptions risk of significant popula-
tion reductions of nontarget organisms, acute toxlclty to wildlife, and
teratogenlclty. After review, the Agency determined that the offsetting
economic, social or environmental benefits were still not great enough.
Thus, endrln use was cancelled In the following areas: on cotton In all
areas east of Interstate highway 35; on small grains to control all pests
other than army cutworm, the pale western cutworm and grasshoppers; on apple
orchards In the eastern United States to control meadow voles; on sugarcane
to control the sugarcane borer; and on ornamentals. Registration for new
uses of endrln was denied, as well as Us use In unenclosed bird perch
treatments. Limited use was allowed under specific conditions for the
following: on cotton west of Interstate 35; on small grains to control army
cutworms and pale western cutworms; on apple orchards In the eastern United
States to control the pine vole and In the western United States to control
meadow voles; on sugarcane to control the sugarcane beetle; for conifer seed
treatment; and use In enclosed bird perch treatments. New uses and regis-
tration of endrln under specified conditions were allowed as follows: as a
tree paint in. Texas; on alfalfa and clover seed ;crops 1n Colorado; and on
small grains to control grasshoppers (In Montana). These determinations
were originally Issued on October 20. 1978 by the Agency.
00700 VIII-19 :
-------
In response to the endrln RPAR, the Agency determined that endrln was
unlikely to pose an oncogenlc risk to humans, and that the risk presumptions
for acute dermal toxlclty and fatalities to endangered species had been
rebutted.
In the case of fish kills, signs stating "Contaminated: No Fishing* must
be posted for 1 year after a fish kill, or for 6 months after lesser
contamination unless endrln residues In the edible portion of fish are <0.3
ppm ww.
The bird species deemed potentially at risk were the Arctic and American
peregrine falcons, bald eagles and brown pelicans. A NOEL of 1.5 mg/kg bw
was accepted for teratogenlclty In the hamster. The LOEL In the hamster was
5 mg/kg. However, behavioral studies using quail have Indicated that either .
quail are very sensitive to the effects of endrln or the endpolnts measured
are more sensitive than those used In the past.
Special Considerations
Endrln given to the dam at dose levels -10-fold 1n excess of the chronic
NOEL In adult nonpregnant animals has been associated with reduced fetal
weight 1n hamsters and mice. At levels comparable to the chronic NOEL,
endrln exposure resulted 1n Increased locomotor activity of offspring of
rats and hamsters. Thus, unborn children must be considered a potentially
sensitive group.
The general public In the Missouri and Mississippi basins between March
1964 and June 1967 were exposed to endrln In drinking water (Schafer et al.,
00700 V1H-20
-------
1969} and In 1976 in Ottawa, Canada (Williams et al., 1978). These situa-
tions occurred In agricultural areas. Acid drinking waters are more likely
\**-
to contain endrln ketone than endrln Itself (ApSlmon et al., 1982). also
keeping In mind that endrln cannot be analyzed well In acid water, In
»
contrast to endrln ketone (Millar et al., 1981). Thus, people living In
areas of high endrln use have more potential for risk than have the general
population.
Farming communities and workers near areas of endrln application nay be
exposed not only to endrln (Wolfe et al., 1963, 1967; U.S. EPA, 1971, 1979;
Arthur' et "al., 1976; Oeg1er7 1964), but also to the major product of
sunlight degradation, the half-cage ketone Identified also in environmental
samples (Zablk et al., 1971). Exposure to this product may Increase their
risk.
Workers exposed to endrln In occupational environments have been known
to suffer convulsions (Jager, 1970). Such workers are the best study
populations for monitoring signs of cancer. Poisoning episodes have also
been reported for endrIn-contaminated flour (Coble et al., 1967; Weeks.
1967; Curley et al., 1970).
Previous exposure to related compounds can Increase susceptibility to
the toxic effects of endrln. Pretreatment of quail with chlordane at
dosages less than the MOAEL (10 ppm 1n the diet for 10 weeks) resulted In
greater mortality In birds subsequently administered 10 ppm endrln In the
diet than 1n those administered endrln alone (Ludke, 1976). Of the birds
that died, the ones treated with endrln alone had lower brain endrln concen-
trations than In those pretreated with chlordane.
00700 VI11-21 '""" -
-------
Radiation may increase the response to endrln. Irradiation of rats with
gamma particles (900 rads} before Injection of 10 mo/kg bw endrln to rats
resulted In a greater increase In SGOT, SGPT, and a greater decrease in acid
and alkaline phosphatase, succlnlc dehydrogenase and glucose-6-phosphatase
^ s
than In rats treated with endrln alone (Meena et al., 1978).
Finally, stress may lower the threshold for the toxic effects of endrln.
The survival times of female field alee fPeromyscus manlculatus) were
shorter during combined cold and starvation* at doses of endrln as low as 1
*_<
ppm 1n the diet, than 1n stressed nice that received no endrln (Morris,
1968).
Summary
The NOAEL for acute exposure to endrln Is determined to be 0.5 mg/kg
bw/day based upon locomotor activities 1n mice. Based upon this NOAEl, a
1-day HA for a 10 kg child of 0.05 mg/t Is proposed.
The NOAEL for 14-day exposure to endrln Is determined to be 0.150 mg/kg
bw/day based upon body weight changes In rats. Utilizing this NOAEL a
10-day HA 1s proposed to be 0.02 mg/l for a 10 kg child.
The NOAEL for a 2-year exposure to endrln Is determined to be 0.025
mg/kg bw/day based upon hlstologlcal liver lesions 1n dogs. Utilizing this
NOAEL, longer-term HAs of 0.003 mg/l for children and 0.009 mg/l for
adults are proposed.
00700 VIII-22
-------
An RfO of 0.00025 mg/kg/day was derived based upon a NQAEl of 1 ppm
endrln In the diets of dogs exposed for 2 years and mild hlstopathologlcal
liver changes in exposed animals. Based on this RfO, a lifetime DUEL of
0.009 mg/l Is proposed.
00700
VIII-23
-------
IX. REFERENCES
Aballs, I.N., N.E. EldefrawV and A.T. Eldefrawl. 1985. High-affinity
stereospedflc binding of cyclodlene Insecticides and yhexachlorocyclo-
hexane to y-amlnobutyrlc acid receptors of rat brain. Pestle. Blochem.
Physlol. 24: 95-102.
Aballs. I.M., M.E. Eldefrawl and A.T. Eldefrawl. 1986. Effects of Insecti-
cides on GABA-lnduced chloride Influx Into rat brain mlcrosacs. 3. Toxlcol.
Environ. Health. 18: 13-23.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1982.
Threshold Unit Values for Chemical Substances and Physical Agents In the
Workroom Environment with Intended Changes for 1984. Cincinnati, OH. p. 17.
Ames, B.N., J. HcCarm and E. Yamasakl. 1975. Methods for detecting car-
cinogens and mutagens with the Salmonella/naimallan-nlcrosome nutagenldty
test. Hutat. Res. 31: 347-364.
Anonymous. 1979. Beginning of the end for use of endrln. J. Am. fled.
Assoc. 241: 353.
Anonymous. 1984. Acute convulsions associated with endrln poisoning -
Pakistan. J. An. Ned. Assoc. 253(3): 334-335.
00710
IX-1
-------
ApSlmon, J.W.. K. Yamasakl, A. Fruchler, A.S. Chau and C.P. Huber. 1S82.
Apparent carbon-carbon bond cleavage In an epoxlde. 2,3,4,4,5,6-hexachloro-
12-pxopentacyc1o[5.4.1.1.«,ll.O»,lo.Os,»]tMdecane: A minor product from the
add treatment of endrln. Can. J. Chen. 60: 501-508.
Arthur, R.D., J.O. Cain and 8.F. Barrentlne. 1976. Atmospheric levels of
pesticides 1n the Mississippi delta. Bull. Environ. Contain. Toxlcol. 15:
129-134.
Bailey, S.. G.B. Collins. F.B. F1shw1ck, H.V. Hart, D.F. Horler and K.A.
Scudamore. 1982. Pesticide residues In foodstuffs In Great Britain:
i
QrganochloMne pesticides, organophosphorus pesticides and fumlgant residues
1n home-produced and Inported wheat. Pestle. Scl. 13: 373-378.
Baldwin, H.K. and D.H. Hutson. 1980. Analysis of human urine for a metabo-
lite of endrln by chemical oxidation and gas-liquid chromatography as an
Indicator of exposure to endrln: Analyst. 105: 60-65.
Baldwin, H.K.. J. Robinson and O.V. Parke. 1970. Metabolism of endrln In
the rat. J. Agrlc. Food Chen. 18: 1117-1123.
Baldwin. M.K., J.V. Crayford, D.H. Hutson and O.L. Street. 1976. The
metabolism and residues of "C-endrln In lactatlng cows and laying hens.
PesUc. Sd. 7: 575-594.
Bedford, C.T. and D.H. Hutson. 1976. The comparative metabolism In rodents
of the Isomerlc Insecticides dleldrln and endrln. Chen. Ind. (London).
(10): 440-447.
i
00710 IX-2 :
-------
-------
Bedford, C.T., O.H. Hutson and I.I. Natoff. 1975a. The acute toxlclty of
endrln and Us metabolites to rats. Toxlcol. Appl. Pharmacol. 33: 115-121.
Bedford, C.T.. R.K. Harrod. E.G. Hoadley and O.H. Hutson. 1975b. The
metabolite fate of endrln In the rabbit. Xenoblotlca. 5: 485-500.
Benes, V. 1969. HutagenU activity of some pesticides In OrosophlUa
melanooaster. Ind. Bed. 38: 442-444.
Bird, C.H., R. Khan and A.C. Richardson. 1978. Structure of endrln alde-
hyde. Chem. Ind. (London). (7): 231-232.
Blus, L., E. Cromartle, L. NcNease and T. Joanen. 1979. Brown pelican:
Population status, reproductive success, and organochlorlne residues In
Louisiana, 1971-1976. Bull. Environ. Contain. Toxlcol. 22: 128-134.
i
Blus, L.J. 1978. Short-tailed shrews: Toxldty and residue relationships
of DOT, dleldrln and endrln. Arch. Environ. Contain. Toxlcol. 7: 83-97.
t
Blus, L.J. 1982. Further Interpretation of the relation of organochlorlne
residues in brown pelican eggs to reproductive success. Environ. Pollut.
Series A. 28: 15^33.
Borady, A.H.A., T.H. KUchall, R. Awadallah, K.A. Ibrahim and S.A.R. Karoar.
1983. Effect of some Insecticides on fat metabolism and blood enzymes In
rats. Egypt. J. Anln. Prod. 23: 33-44.
00710 IX-3
-------
Brooks, G.T. 1969. The metabolism of dlene-organochlorlne (cyclodlene)
Insecticides. Residue Rev. 27: 81-138.
Brooks, G.T. 1974a. Chlorinated Insecticides, Vol. 1. Technology and
Applications, CRC Press, Cleveland, OH. p. 164-166.
Brooks, G.T. 1974b. Chlorinated Insecticides, Vol. 1. Technology and
Applications, CRC Press, Cleveland. OH. p. 82-83.
Butler, L.C., D.C. Stalff, G.U. Sovocool, N.K. Wilson and J.A. Magnuson.
1981. Reductive degradation of dleldrln and endrln In the field using
acidified zinc. J. Environ. Sc1. Health. B16: 395-408.
Cabral, J.R.P., F. Raltano, T. Holiner, S. Bronczyk and P. Shub1k. 1979.
Acute toxlclty of pesticides In hamsters. Toxlcol. Appl. Pharmacol. 48:
A192.
Carey, A.E., P. Douglas, H. Tal. W.G. HHchell and G.B. Mlersna. 1979.
Pesticide residue concentrations 1n soils of five United States cities, 1971
urban soils monitoring program. Pestle. NonU. J. 13: 17-22.
CHENLINE Data Base for CAS Indexing Terms and CAS Registry Numbers. 1983:
June.
Chernoff, M. and R.J. Kavlock. 1982. An .In vivo teratology screen utlllz-.
1ng pregnant mice. J. Toxlcol. Environ. Health. 10: 541-550.
00710
IX-4
-------
Chernoff, N.t R.J. Kavlock, R.C. Hanlsch, et al. 1979. Perinatal toxlclty
of endrln In rodents. I. Fetotoxlc effects of prenatal exposure 1n ham-
sters. Toxicology. 13: 155-165.
Coble, Y., P. HlldebramU, J. Davis, F. Raasch and A. Curley. 1967. Acute
endrln poisoning. J. An. Ned. Assoc. 202: 153-157.
Cole. L.H. and J.E. Caslda. 1986. Polychlorocycloalkane Insecticide-Induced
convulsions In mice In relation to disruption of the 6ABA-regulated chloride
lonophore. Life Sc1. 39: 1855-1862.
Cole, J.F., L.M. Klevay and M.R. Zavon. 1970. Endrln and dleldrln: A com-
parison of hepatic excretion rates In the rat. Toxlcol. Appl. Pharmacol.
12: 547-555.
Cox, R.H. and J.D. McKlnney. 1978. Carbon-13 NMR spectra of some chlori-
nated polycyclodlene pesticides. Org. Nagn. Reson. 11: 541-546.
Cunnings, J.G., K.T. Zee, V. Turner, F. Qulnn and R.E. Cook. 1966. Resi-
dues In eggs from low-level feeding of five chlorinated hydrocarbon Insecti-
cides to hens. J. Assoc. Off. Anal. Chem. 49: 354-364.
Curley, A., R.H. Jennings, H.T. Hann and V. Sedlak. 1970. Measurement of
endrln following epidemics of poisoning. Bull. Environ. Contam. Toxlcol.
5: 24-29. [ . '
Davles, G.H. and I. Lewis. 1956. Outbreak of food poisoning from bread
made of chemically contaminated flour. Br. Ned. J. 11: 393-398.
00710 IX-5
-------
Delchraann, W.B., W.E. HacDonald, E. Blum, et al. 1970. TumoMgenlcHy of
aldMn, dleldMn and endrln In the albino rat. Ind, Hed. 39: 426-434.
D1ksh4th, T.S.S. and K.K. Datta. 1973. Endrln Induced cytologlcal changes
In albino rats. Bull. Environ. Contam. Toxlcol. 9: 65-69.
OHraglla, D., O.P. Brown, T. Namekata and N. Iverson. 1981. Mortality
study of workers employed at organochlorlne pesticide manufacturing plants.
Scand. J. Work Environ. Health. 7: 140-146.
EUhers, T.R. 1980. Evaluation of pesticide supplies and demand for 1980.
U.S. Department of Agriculture. Economics. Statistics and Cooperatives
Service. Agrlc. Econ. Rep. 454. p. 8-9.
Emerson, I.E., Jr. and L.B. Hlnshaw. 1965. Peripheral vascular effects of
the Insecticide endMn. Can. J. Physio!. Pharmacol. 43: 531-539.
Emerson, I.E., Jr., C.M. Brake and L.B. Hlnshaw. 1964. Cardiovascular
effects of the Insecticide endrln. Can. J. Physlol. Pharmacol. 42: 41-51.
FAO/HHO {food and Agricultural Organization/World Health Organization).
1973. 1972 evaluation of some pesticide residues In food. FAO Agrlc.
Studies No. 90.
Feare, C.J., O.D.B. Summers and R. Longstaff. 1978. Toxlclty of endrln-
treated pear buds to bullfinches. Exp. Hortlc. 30: 42-45.
00710 IX-6
-------
Federal Register. 1979. EndMn Intent to cancel registrations and denial
of applications for registration of pesticide products containing endrln,
and statement of reasons. 44: 43632-43657.
Frank, R., H.£. Braun, H. HoldMnet, G.J. Slrons, E.H. Smith and D.W. Olxon.
1979. Qrganochlorlne Insecticides and Industrial pollutants In the ra11k
supply of southern Ontario. Canada - 1977. J. Food Prot. 42: 31-37.
Galnes. T.B. 1969. Acute toxlclty of pesticides. Toxlcol. Appl.
Pharmacol. 14: 515-534.
Glatt, H., R. Jung and F. Oesch. 1983. Bacterial mutagenlcUy Investiga-
tion of epoxldes: Drugs, drug metabolites, steroids and pesticides. Nutat.
Res. 11: 99-118.
Good, E.E., and G.U. Ware. 1969. Effects of Insecticides on reproduction 1n
the laboratory mouse. IV.. Endrln and dleldMn. Toxlcol. Appl. Pharmacol.
14: 201-203.
Grant, H.F. 1973. Cytologlcal effects of environmental mutagens-pesti-
cides. Mutat. Res. 21: 221-222.
Graves, J.B. and J.R. Bradley. 1965. Response of Swiss albino mice to
Intraperltoneal Injection of endrln. J. Econ. Entomol. 58: 178-179.
Gray, I.E., Jr., R.J. Kavlock, M. Chernoff. J.A. Gray and J. HcLamb. 1981.
Perinatal toxlclty of endrln In rodents. III. Alterations of behavioral
<
ontogeny. Toxicology. 21: 187-202.
00710 IX-7 :
-------
Gray, I.E.. Jr., R.J. Kavlock, J. Ostby, J. Ferrell, J. Rogers and K. Gray.
1986. An'evaluation of figure-eight naze activity and general behavioral
development following prenatal exposure to forty chemicals: Effects of
cytoslne arablnoslde, dlnocap, nltrofen and vitamin A. Neurotoxlcology. 7:
449-462.
Green, V.A. 1969. Effects of pesticides on rat and chick embryo. .In:
Trace Substances 1n Environmental Health. III. Proc. Univ. Missouri 3rd
Ann. Conf. Trace Subst. Environ. Health, p. 183-209.
Gregory, W.W. 1970. Bloaccumulatlon of endrln from natural food sources In
the eastern bobwhlte quail, Collnus vlrglnlanus v1rq1n1anus L. Olss. Abstr.
Int. 31: 736B-737B.
Gregory, U.W., J.K. Deed and L.G. Webb. 1972. Bloaccumulatlon of endrln
from natural food sources 1n the eastern bobwhlte quail, Collnus vlrqlnlanus
L. In: Proc. Ann. Conf. Southeast Assoc. Game F1sh. 25: 156-164.
Hadler, N.R. 1982. Poisons, economic. l£: Klrk-Othmer Encyclopedia of
Chemical Technology, 3rd ed. Ulley-Intersclence, New York. 18: 317.
Hartgrove. R.M.. Jr.. S.G. Hundley and R.E. Webb. 1977. Characterization
of the hepatic mixed function oxldase system In endrln-reslstant and
-susceptible pine voles. Pestle. Blochem. Physio!. 7: 146-153.
Hayes, W.H. 1963. Clinical Handbook on Economic Poisons. U.S. Pub. Health
Serv.. Publ. 476. (Cited 1n Coble et al.. 1967)
00710 IX_8
-------
Hayes, H.J., Jr. and A. Curley. 1968. Storage and excretion of dleldrln
and related compounds. Effect of occupational exposure. Arch. Environ.
Health. 16: 155-162.
Heinz, G.H. and R.H. Johnson. 1979. Elimination of endrln by mallard
ducks. Toxicology. 12: 189-196.
Hlnshaw, L.B.,.L.A. Solomon, O.A. Reins, V. MoHca and T.E. Emerson. 1966.
Effects of the Insecticide endrln on the cardiovascular system of the dog.
J. Pharraacol. Exp. Ther. 153: 225-236.
Hlrom, P.C.. P. H111burn, R.L. Smith and R.T. Williams. 1972. Species
variations In the threshold molecular-weight factor for the biliary excre-
tion of organic anlons. Blochem. 0. 129: 1071-1077.
Hoffman, O.J. and P.M. Albers. 1984. Evaluation of potential embryotoxlc-,
Uy and teratogenlclty of 42 herbicides, Insecticides and petroleum contami-
nants to mallard eggs. Arch. Environ. Contam. Toxlcol. 13: 15-27.
Hoogendam, I., J.P.J. Versteeg and H. de VHeger. 1962. Electroencephalo-
grams In Insecticide toxlclty. Arch. Environ. Health. 4: 86-94.
Hoogendam, I., J.P.J. Verstseg and M. de VUeger. 1965. Nine years' tox-
lclty control In Insecticide plants. Arch. Environ. Health. 10: 441-448.
Hudson, R.H., H.A. Haegele and R.K. Tucker. 197,9. Acute oral and percu-
i
taneous toxlclty of pesticides to mallards: Correlations with mammal Ian
toxUUy data. Toxlcol. Appl. Pharmacol. 47: 451-460.
00710 IX-9
-------
Hunter, C.G., A. Rosen, R.T. Williams, J.G. Reynolds and A.M. Morten. I960.
Studies on the fate of aldrln. dleldrln and endrln In the manual. Hededcl,
Landbouw. Op. Staat. Sent. 25: 1296-1307.
Hutson. 0.H. 1981. The metabolism of Insecticides In man. Prog. Pestle.
Blochem. 1: 247-285.
Hutson, D.H. and E.G. Hoadley. 1974. The oxidation of a cyclic alcohol
(12-hydroxyendrln) to a ketone (12-keto-endrln) by alcrosomal mono-oxygena-
tlon. Chemosphere. 3: 205-210.
Hutson, D.H.. H.K. Baldwin and E.C. Hoadley. 1975. Detoxification and bio-
activation of endrln In the rat. Xenoblotlca. 5: 697-714.
IARC (International Agency for Research on Cancer). 1979. IARC Hongraphs
on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC,
MHO, Lyon. France. Vol. 1-20.
Ito, N., H. Tatematsu, K. NakanlsM, et al. 1980. The effects of various
chemicals on the development of hyperplastlc liver nodules In hepatectomlzed
rats treated with N-n1trosod1ethylan1ne or N-2-fluorenylacetamlde. Gann.
71: 832-842=
i
Iv1e, G.M. and J.E. Caslda. 1971a. Sensitized photodecomposltlon and
photosensltlzer activity of pesticide chemicals exposed to sunlight on
silica gel chromatoplates. J. Agrlc. Food Chen. 19: 405-409.
00710 IX-10
-------
Iv1e, G.H. and J.E. CasVda. 1971b. Photosensltlzers for the accelerated
degradation of chlorinated cyclodlenes and other Insecticide chemicals
exposed to sunlight on bean leaves. J. Agrlc. Food Chen. 19: 410-416.
aager, K.H. 1970. Aldrln, Oleldrln, Endrln and Telodrln. Elsevler Pub-
lishing Company, New York.
i
iJarvlnen, A.U. and R.H. Tyo. 1978. Toxlclty to fathead minnows of endrln
In food and water. Arch. Environ. Contarn. Toxlcol. 7: 409.
Oedelkln. R., R. Kaplan, A. Shaplra, H. Radwan and S. Hoffman. 1979. The
successful use of "high level" PEEP 1n near fatal endrln poisoning. Crlt.
Care Ned. 7: 168-170.
Jegler, Z. 1964. Health hazards In Insecticide spraying of crops. Arch.
Environ. Health. 8: 670-674.
Kaiser. T.E., H.L. Relchel, L.N. Locke, et al. 1980. Organoch1or1ne pesti-
cide PC8 and PBB residues and necropsy data for bald eagles from 29 states
i
1975-1977. Pestle. Nonlt. J. 13: 145-149. j
Kavlock, R.J., M. Chernoff. B.C. Hanlsch, 3. Sray, E. Rogers and L.E. Gray,
Jr. 1981. Perinatal toxlclty of endrln 1n rodents. II. Fetotoxlc effects
of prenatal exposure In rats and mice. Toxicology. 21: 141-150.
Kavlock, R.J., N. Chernoff and E.H. Rogers. 1985. The effect of acute
maternal toxlclty on fetal development 1n the mouse. Teratog. Cardnog.
Hutagen. 5: 3-13.
00710 ix-n -" -
-------
Kenaga, E.E. 1980. Correlation of blocohcentratlon factors of chemicals In
aquatic and terrestrial organisms with 'their physical and chemical proper-
ties. Environ. Scl. Technol. 14: 553-556.
K11gemag1, V., R.6. Sprowls and L.C. Terrlere. 1958. Endrln content of
milk and body tissues of dairy cows receiving endrln dally 1n their diet.
J. Agrlc. Food Chen. 6: 518-521.
Klein, U.t W. Mueller and F. Korte. 1968. Excretion, distribution, and
metabolism of endr1n~{!4C) In rats. Justus Lleblgs Ann. Chem. 713: 180*185.
Korte, F. 1967. Metabolism of aldrln, dleldrln, and endrln. In: Symp.
Science and Technology of Residual Insecticides In Food Production with
Special Reference to Aldrln and (Meldrln. p. 102-117.
Korte. F., U. Klein, I. Welsgerber, R. Kaul, U. Mueller and A. DJIrsaral.
1970. Recent results 1n studies on the fate of chlorinated Insecticides.
In: Inter-American Conf. on Toxicology and Occupational Medicine; 6th and
7th Pesticide Symp.; Collection of Papers, W.B. Delchmann, J.I. Radomskl and
R.A. Penalver, Ed. Halos and Associates, Coral Gables. FL. p. 51-56.
Kreltzer, J.F. 1980. Effects of toxaphene and endrln at very low dietary
concentrations on discrimination acquisition and reversal In bobwhlte quail,
Collnus vlrglnlanus. Environ. Pollut. A23: 217-230.
Kurata. M., K. Hlrose and M. Umeda. 1982. Inhibition of metabolic coopera-
tion In 'Chinese hamster cells by organochlorlne pesticides. Gann. 73:
217-221.
00710 IX-12 "
-------
Kutz, F.H., S.C. Strassraan and J.F. Sperling. 1979. Survey of selected
organochlorlne pesticides In the general population of the United States:
Fiscal years 1970-1975. Ann. N.Y. Acad. Sc1. 320: 60-68.
Lawrence, L.J. and J.E. Caslda. 1984. Interactions of llndane, toxaphene
and cyclodlenes with brain-specific t,-buty1b1cydophosphoroth1onate receptor.
Life Scl. 35: 171-178.
Lee, T.P., R. Noscatl and 8.H. Park. 1979. Effects of pesticides on human
leukocyte functions. Res. Commun. Chem. Pathol. Pharmacol. 23: 597-609.
Long. U.K., L.D. Newsom and A.M. Hulllns. 1961. Endrln residues In the fat
of lambs grazed on endrln-treated pasture. J. Econ. Entomol. 54: 605-606.
Ludke, J.L. 1976. Organochlorlne pesticide residues associated with mor-
tality: AddUlvlty of chlordane and endrln. Bull. Environ. Con tarn. Toxlcol.
16: 253-260.
MacLeod, K.E., R.C. Hanlsch and R.G. Lewis. 1982. Evaluation of gel per-
meation chromatography for cleanup of human adipose tissue samples for GC/MS
analysis of pesticides and other chemicals. J. Anal. Toxlcol. 6: 38-40.
NcCann, J.A., U. Teeters, O.J. Urban and N. Cook. 1981. A short-term
dietary toxUUy test on small mammals. Am. Soc. Test. Hater. Spec. Tech.
Publ. 757: 132-142.
Main, O.C. 1978. Endrln toxlclty In cageblrds. Aust. Vet. J. 54: 198-199.
00710 IX-13
-------
Manganl, F., B. Crescent1n1 and F. Bruner. 1981. Sample enrichment for
determination of chlorinated pesticides In water and soil by chromatographlc
extraction. Anal. Chen. 53: 1627-1632.
Marlon, H.R. 1976. OrganochloMne pesticide residues 1n plain chachalacas
from south Texas, 1971-72. Pestle. MonH. J. 10: 84-86.
Maslansky, C.J. and 6.M. U1ll1ams. 1981. Evidence for an eplgenetlc mode
of action In organochloHne pesticide hepatocarclnogenlclty: A lack of geno-
toxUHy 1n rat, mouse, and hamster hepatocytes. J. Toxlcol. Environ.
Health. 8: 121-130.
Matsushita, T., S. Nomura and T. Wakatsukl. 1980. Epidemiology of contact
dermatitis from pesticides In Japan. Contact Dermatitis. 6: 255-259.
Meena, K., P.K. Gupta and S.R. Bawa. 1978. Endr1n-1nduced toxldty In
normal and Irradiated rats. Environ. Res. 16: 373-382.
Mehrotra. B.D., S.K. Bansal and D. Oesalah. 1982. Comparative effects of
structurally related cyclodlene pesticides on ATPases. J. Appl. Toxlcol.
2: 278-283.
Merck Index. 1983. An Encyclopedia of Chemicals, Drugs and Biological*,
.10th ed., M. Wlndholz and S. Budavarl, Ed. Published by Merck and Company
Inc., Rahway, NJ. p. 517.
Metcalf. R.L. 1981. Insect control technology. In,: Klrk-Otnmer Encyclo-
pedia of Chemical Technology. 3rd ed. John Wiley & Sons, New York. 13: 435.
00710 IX-14
-------
Millar, J.O., R.E. Thomas and H.J. Schattenberg, III. 1981. Determination
of organochloMne pesticides and polychloMnated ,b1pheny1s In.water by gas
chromatography. Anal. Chem. S3: 214-219.
Miller, C., S. Nesnow and A. Sarrlf. 1981. Qleldrln and related compounds
as modifiers of polycycllc hydrocarbon carclnogenesls 1n cell culture.
Proc. Am. Assoc. Cancer Res. 22: Abstract 466, p.118.
Montoya Cabrera, H.A., M. Escartln Chavez, M. Reynoso Garcia and C.G.
Strecker. 1982. Intoxlcadon por endrln. Informe de 33 casos. Rev. Med.
Inst. Mex Seguro Soc. (Mexico). 20: 79-84. (Spa.)
NoHya. N., T. Ohta. K. Uatanabe, T. Hlyazawa, K. Kato and Y. Shlrasu.
1983. Further mutagenlcUy studies on pesticides In bacterial reversion
assay systems. Mutat. Res. 116: 185-216.
Morris, R.D. 1968. Effects of endrln feeding on survival and reproduction
In the deer mouse, Peromvscus manlculatus. Can. J. Zool. 46: 951-958.
Mostafa, M.H., E.A. E1-Bass1oun1. S.M. E1-Sewedy, T. Taw1f1c and A.M.
El-Sebae. 1983. Influence of pretreatment with various Insecticides on the
N-demethy1at1on of d1methy1nUrosam1ne. Environ. Res. 32:57-61.
Mulr, C.M.C. 1968. No title provided. (Cited In Jager, 1970)
00710
IX-15
-------
Nagelsmlt, A., P.H. Van V11et, H.A.H. van der HUl-Wetzels, et al. 1979.
Porphyrlns as possible parameters for exposure to hexachlorocyclopentadlene,
allylchloMde, epkhlorohydMn and endrln. In: Chemical Porphyrla 1n Han,
J.O.T.H.A. StMk and J.H. Koeman, Ed. Elsevler/North Holland B1oraed1ca1
Press. New York. p. 55-61.
NAS (National Academy of Sciences). 1977. Drinking Water and Health.
Vol. 1, p. 19-63.
NAS (National Academy of Sciences). 1980. Drinking Hater and Health.
Vol! 3. p. 25-67.
NCI (National Cancer Institute). 1979. Bloassay of endrln for possible
carclnogenlclty. Carclnogenesls Tech. Rep. Ser. 12, NCR-CG-TR-12. DHEH
Publ. No. (NIH) 79-812.
Nelson. S.C., T.L. Bahler, M.V. Hartuell, D.A. Greenwood and I.E. Harris.
1956. Serum alkaline phosphatase levels; weight changes, and mortality
rates of rats fed endrln. J. Agrlc. Food. Chem. 4: 696-700.
N10SH (National Institute for Occupational Safety and Health). 1978.
Pocket Guide to Chemical Hazards. 191 p.
Oh 1 end or f, H.H., D.H. Swine ford and L.N. Locke. 1981. OrganochloMne
residues and mortality of herons. Pestle. Monlt. J. U: 125-135.
00710
IX-16
-------
Ottevanger,; C.F. and N.J. Van SUtert. 1979. Relation between antl-12-
hydroxyendrln excretion and enzyme Induction 1n workers Involved 1n the
manufacture of endrln. ln_: Chemical Porphyrla In Nan, J.J.T.H.A. StMk and
J.H. Koeman, Ed. Elsevler/North Holland B1omed1cal Press, New York.
p. 123-129.
Ottolenghl, A.D., J.K. Haseman and F. Suggs. 1974. Teratogenlc effects of
aldrln, dleldrln, and endrln In hamsters and nice. Teratology. 9: 11-16.
Pandey, B.B. 1978. A note on endrln poisoning In bullocks. Indian Vet.
J. 55: 253.
Park, B.H. and T.P. Lee. 1980. Effects of pesticides on human leukocyte
function. HHS Publ. (FDA). FDA-80-1074. p. 273-274.
Pawar, S.S. and M.S. Kachole. 1978. Hepatic and renal mlcrosomal electron
transport reactions In endrln treated female guinea pigs. Bull. Environ.
Contam. Toxlcol. 20: 199-205.
Peterson, S.R. and R.S. EHerson. 1978. p.p'-OOE, polychlorlnated
blphenyls and endrln In old squaws In North America, 1969-1973. Pestle.
Honlt. 3. 11: 170-181.
Phillips, O.D., 6.E. Pollard and S.B. Soloway. 1962. Thermal 1somer1zat1on
of endrln and Us behavior 1n gas chromatography. J. Agrlc. Food Chem. 10:
217-221.
00710
IX-17
-------
Probst, G.S., K.E. HcNahon, L.E. H111, et al. 1981.. Chemically-Induced
unscheduled DNA synthesis In primary rat hepatocyte cultures: A comparison
with bacterial nutagenUHy using 218 compounds. Environ. Nutagen. 3:
11-32. .
Radeleff, R.D. 1956. Hazards to livestock of Insecticides used In mosquito
control. Mosquito News. 16: 79-80.
Rapaport, E., E. Farjoun, S. Shlosberg and H.N. Egyed. 1979. Endrln poi-
soning In a herd of goats. Refu. Vet. 36: 142-143.
Reddy. O.B., V.O. Edward, G.J.S. Abraham and R.K. Venkallswara. 1966. No
title provided. (Cited In Jager, 1970)
Rees, G.A.V. and L. Au. 1979. Use of XAD-2 macroretlcular resin for the
recovery of ambient trace levels of pesticides and Industrial organic pollu-
tants from water. Bull. Environ. Contain. Toxlcol. 22: 561-566.
Relchel, H.L., E. Cromartle, T.6. Lament, 8.H. Bulhern and R.H. Prouty.
1969. Pesticide residues 1n eagles. Pestle. Honlt. 3. 3: 142-144.
Reins, O.A., 0.0. Holmes and L.B. Hlnshaw. 1964. Acute and chronic effects
of the Insecticide endrln on renal function and renal heaodynamlcs. Can. J.
Physlol. Pharnacol. 42: 599-608.
Reins, O.A., J.A. Rleger. Jr.. U.B. Stavlnoha and L.B. Hlnshaw. 1966.
Effect of endrln on venous return and catecholamlne release In the dog.
Can. 3. Physlol. Pharmacol. 44: 59-67.
00710
IX-18
-------
Reuber, H.D. 1978. Carcinomas, sarcomas and other lesions in Osborne-
Mendel rats Ingesting endrln. Exp. Cell. 81ol. 46: 129-145.
Reuber, H.D. 1979. CarclnogenlcHy of endrln. Scl. Total Environ. 12:
101-135.
Revzln. A.M. 1966. The effects of endrln on telencephallc function In the
pigeon. Toxlcol. Appl. Pharmacol. 9: 75-83.
Revzln, A.M. 1968. Effects of chronic endrln administration on brain
electrical activity In the squirrel monkey. Fed. Proc. 27: 597.
Rlbbens, P.M. 1985. Mortality study of Industrial workers exposed to
aldrln, dleldrln and endrln. Int. Arch. Occup. Environ. Health. 56: 75-79.
Richardson, L.A.. J.R. Lane, W.S. Gardner, J.T. Peeler and J.E. Campbell.
1967. Relationship of dietary Intake to concentration of dleldrln and
endrln 1n dogs. Bull. Environ. Contara. Toxlcol. 2: 207-219.
Robinson, 0, 1962. Shell Research Ltd. Private communication to K.W.
Jager. (Cited In Jager, 1970}
t
t
Rowley, O.L., H.A. Rab, U. Hardjotanojo. et al. 1987. Convulsions caused
by endrln poisoning In Pakistan. Pediatrics. 79(6): 928-934.
00710 IX-19 08/19/88
-------
Roylance, K.J., C.D. Jorgenson, G.M. Booth and M.W. Carter. 1985. Effects
of dietary endrln on reproduction of mallard ducks. Arch. Environ, Contam.
Toxlcol. 14: 705-711.
Safe. S. and 0. Hutzlnger. 1973a. Mass Spectrometry of Pesticides and
Pollutants. CRC Press, Cleveland, OH. p. 124.
Safe, S. and 0. Hutzlnger. 19735. Mass Spectrometry of Pesticides and
Pollutants. CRC Press, Cleveland, 044. p. 23.
SANSS Data Base. 1963. .Endrln nomenclature. Indexing terms and synonyms,
June.
Seldenberg, J.N., D.6. Anderson and R.A. Becker. 1986. Validation of an jn.
vivo developmental toxldty screen In the mouse. Teratog. Carclnog. Mutagen.
6: 361-374.
Schafer, M.L., J.T. Peeler, U.S. Gardner and J.E. Campbell. 1969.
Pesticides In drinking water. Waters from the Mississippi and Missouri
Rivers. Environ. Scl. Technol. 3: 1261-1269.
Sharma, R.O. and O.P. Gautam. 1971. Experimental endrln poisoning 1n
calves. J. Res. (Punjab AgMc. Univ.) 8: 394-403.
Sherman, M. and H.M. Rosenberg. 1954. Subchronlc toxldty of four chlori-
nated dlmethanonaphthalene Insecticides to chicks. J. Econ. Entomol. 47:
1082-1083.
00710 IX-20
-------
SHtlg, M. 1977. Pesticide Process Encyclopedia. Noyes Data Corp., Park
Ridge, NJ. p. 226.229.
Sobtl, R.C., A. KMshan and J. Oavles. 1983. Cytotc1net1c and cytogenetU
effect of agricultural chemicals on human lymphold cells In vitro. II.
QrganochloMne pesticides. Arch. Toxlcol. 52: 221-231.
Spann, J.H., G.H. Heinz and C.S. Hulse. 1986. Reproduction and health of
mallards fed endrln. Environ. Toxlcol. Chew. 5: 755-759.
E '
Spauldlng, J.E. 1972. Pesticide and heavy metal residues. Proc. Meat
Industry Res. Conf., Am. Heat Inst. Foundation, Chicago, IL.
Speck, L.B. and C.A. Haaske. 1958. The effects of chronic and acute expo-
sure of rats to endrln. Am. Ned. Assoc. Arch. Ind. Health. 18: 268-272.
Stlckel, W.H., T.E. Kaiser and W.I. Relchel. 1979a. Endrln versus
12-keto-endrln 1n birds and rodents. Am. Soc. Test. Hater. Tech. Publ.
693: 61-68.
Stlckel, U.H., W.L. Relchel and O.L. Hughes. 1979b. Endrln 1n birds:
Lethal residues and secondary poisoning. Oev. Toxlcol. Environ. Sc1. 4:
397-406.
Tanaka, K.. J.G. Scott and F. Matsumura. 1984. PUrotoxVnln receptor In
the central nervous system of the American cockroach: Its role In the action
of cyclodlene-type Insecticides. Pest. Blochem. Physlol. 22: 117-127.
00710 IX-21
-------
Taylor, O.G. 1980. NIOSH Manual of Analytical Methods, U.S. DHHS, Vol. 6,
Method S-284. p. 80-125.
Telang, $., C. Tong and G.M. Williams. 1981. Induction of rautagenesis by
carcinogenic polycycllc aromatic hydrocarbons but not by organochlorlne
pesticides In the ARL/HGPRT mutagenesls assay. 12th Ann. Meet. Environ.
Mutagen Soc. Environ. Nutagen. 3: 359. (Abst.)
Terrlere, L.C., U. K11gemag1 and O.C. England. 1958. Endrln content of
body tissues of steers, lambs, and hogs receiving endrln In their dally
diet. J. Agrlc. Food Chem. 6: 516-518.
Terrlere, L.C., G.H. Arscott and U. K11gemag1. 1959. The endrln content of
eggs and body tissue of poultry receiving endrln In their dally diet. J.
Agrlc. Food Chem. 7: 502-504.
Tessarl, J.O., L. Griffin and H.J. Aaronson. 1980. Comparison of two
cleanup procedures (Mills, Onley, Galther versus automated gel permeation)
for residues of organochlorlne pesticides and polychloMnated blphenyls In
human adipose tissue. Bull. Environ. Contarn. Toxlcol. 25: 59-64.
Tevarl, S.N. and I.C. Sharma. 1978. Study of the distribution of chlori-
nated organic pesticides 1n different autopsy materials of human poisoning
cases using TLC and UV spectrophotometrlc techniques. Chen. Era. 14:
215-218.
00710
IX-22
-------
Treon, J.f. and P.P. Cleveland. 1955. Toxldty of certain chlorinated
hydrocarbon Insecticides for laboratory animals, with special reference to
aldrln and dleldMn. J. Agrlc, Food Chem. 3: 402-408.
Treon, J.F., F.P. Cleveland and J. Cappel. 1955. Toxldty of endrln for
laboratory animals. J. Agrlc. Food Chem. 3: 842-848.
U.S. OHHS (U.S. Department of Health and Human Services). 1978. Occupa-
tional health guideline For endrln. £n: Occupational Health Guidelines for
Chemical Hazards, F.W. Macklson, R.S. Strlcoff and L.J. Partridge. Jr. Ed.
OHHS (NIOSH) Publ. No. 81-123.
U.S. DHHS (U.S. Department of Health and Human Services). 1982. National
Toxicology Program Annual Plan Fiscal Year 1982. NTP-81-94. p. 53.
U.S. EPA. 1971. Pesticide residues In ambient' air. Dlv. Pestle. Comm.
Studies, Chamblee, GA.
U.S. EPA. 1975. National Interim primary drinking water regulations.
December 24. Federal Register. 40(248): 59566-59588.
U.S. EPA. 1978. Carcinogen Assessment Groups Risk Assessment for Endrln.
June 19. (Unpublished study)
U.S. EPA. 1979. Reviews of the Environmental Effects of Pollutants: XIII
Endrln. Health Effect Research Laboratory, ORD. Cincinnati, OH. EPA
600/1-79-005.
00710 IX-23 «"
-------
U.S. EPA. 1980s. Ambient Water Quality Criteria for EndMn. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Water Regulations
and Standards, Washington, DC. EPA 440/5-80-047. NTIS PB 81-117582.
U.S. EPA. 1980b. Carbon adsorption Isotherms for toxic organic*. EPA
600/8-80-023. p. 194-195.
U.S. EPA. 1985. National Primary Drinking Water Regulations; Synthetic
Organic Chemicals, Inorganic Chemicals, and Microorganisms; Proposed Rule 40
CfR Part 141. Federal Register. 50(219): 46396-47025.
U.S. EPA. 1986, Guidelines for Carcinogen Risk Assessment. Federal.
Register. 51(185): 33992-34003.
U.S. EPA. 1987. Health Effects Assessment for Endrln. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
U.S. EPA. 1988a. Reference Dose (RfD): Description and Use In Health Risk
Assessments. Integrated Risk Information System (IRIS). Online.
Intra-Agency Reference Dose {RfD) Work Group, Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH. February.
00710 IX-24
-------
U.S. EPA. 1988D. Integrated Risk Information .System (IRIS). Reference
Dose (RfD) for Oral Exposure for EndMn. Online. (Verification date
04/20/88). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1988c. Memorandum from Richard Cothern (Science Advisory Board)
to Office of Health and Environmental Assessment and Office of Drinking
Water participants of the Karen IS, 1988 meeting.
Vlgfusson, N.V., E.R. Vyse, C.A. Pernstelner and R.J. Oawson. 1983. in.
vivo Induction of sister-chromatld exchange In Umbra 11ml by the Insecti-
cides endrln, chlordane, dlazlnon and gutMon. Nutat. Res. 118: 61-66.
VHJ-Standhardt, W.G.. J.J.T.W.A. StrU, C.F. Ottevanger and N.J. Van
SHtert. 1979. Urinary 0-g1ucar1c acid and urinary total porphyrln excre-
tion 1n workers exposed to endrln. In.: Chemical Porphyrla 1n Han,
J.J.T.H.A. Strlk and J.H. Ko.eman, Ed. Elsevler/North Holland Blomedlcal
Press, New York, p. 113-121.
Walsh, G.N. and G.B. F1nk. 1972. Comparative toxldty and distribution of
endrln and dleldrln after Intravenous administration 1n nice. Toxlcol.
Appl. Pharmacol. 23: 408-416.
Wang, H.H. and S. Grufferman. 1981. Aplastlc anemia and occupational
pesticide exposure: A case-control study. J. Occup. Ned. 23: 364-366.
00710 IX-25
-------
Weeks, 0,E. 1967. EndMn food-poisoning. A report on four outbreaks
caused by two separate shipments of endMn-contamlnated flour. Bull. UNO.
37: 499-512.
Unite, D.H. 1979. Nationwide residues of organochloHne compounds In wings ^
of adult mallards and black ducks, 1976-77. Pestle. Monlt. J. 13: 12-16.
Williams, G.H. 1980. Classification of genotoxlc and eplgenetlc hepatocar-
clnogens using liver culture assays.. Ann. N.Y. Acad. Scl. 349: 273-282.
Williams, O.T., P.M. Benolt, E.E. McNeil and R. Otson. 1978. Organo-
chlorlne pesticide levels In Ottawa drinking water, 1976. Pestle. MonH. J.
12: 163.
WUherup, S., K.t. Stenmer, P. Taylor and P. Bletsch. 1970. The Incidence
of neoplasms In two strains, of nice sustained on diets containing endrln.
KetteHng Lab., Univ. Cincinnati. Cincinnati, OH.
Wolfe, H.R., W.F. Durham and J.F. Armstrong. 1963. Health hazards of the
pesticides endrln and dleldrln. Arch. Environ. Health. 6: 458-464.
Wolfe, H.R., W.F. Durham and J.F. Armstrong. 1967. Exposure of workers to
pesticides. Arch. Environ. Health. 14: 622-633.
Young, R.A. and H.N. Nehendale. 1986. Effect of endrln and endrln deriva-
tives on hepatoblHary function and carbon tetrachlorlde-lnduced hepato-
toxldty In male and female rats. Food Chem. Toxlcol. 24: 863-868.
00710 IX-26
-------
*
fc
Zaotk, H.J., R.O- Schuetz, y.L. Burton and 8.E. Pape. 1971. Photochemistry
of bloactlve compounds: Studies of a major photolyilc product of endrln. J.
AgrU. Food Che«. 19: 308-313.
00710
IX-27
-------
-------