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Chronic studies have been conducted with several species of fish
including goldfish, bluegill, channel catfish, trout, sunfish, salmon,
and fathead minnow. These studies show that high residues of mirex
are accumulated and retained, and that there are indications of
effects on survival, growth, and/or reproduction. (U.S. EPA, 1981;
Buckler, et al, 1981). In a chronic study using two species of warm-
water fishes, bluegills were fed 0, 1, 3 or 5 mg/kg of mirex for 168
days (Van Valen et al., 1968). No mortality or tissue pathology
resulted from the mirex exposure; however, growth of the bluegills in
the highest treatment groups was adversely affected. Goldfish in
ponds treated with 1.0 ppm mirex showed gill edema, kidney lesions,
and distended gall bladders. Studies with channel catfish reported
similar results. A three-acre pond and surrounding drainage area were
treated with 1.7 g mirex bait acre. After 6 months exposure, catfish
showed residues of 0.65 ppm; however, no significant increase in
mortality or adverse effects were noted (Collins et al., 1973). Cat-
fish in ponds treated three times in 8 months with 1.25 Ibs mirex
bait/acre showed no adverse effects (Hyde et al., 1974). A study with
fathead minnows estimated an EC50 of 34 ug/L after 120 days exposure
when possible signs of reproductive impairment were noted (Buckler et
al., 1981).
Mirex is retained for long periods of time in fish with little or
no elimination. Brook trout fed a mirex contaminated diet (0.7 mg/kg)
for 104 days showed no significant reduction in mirex residues after
385 days of uncontaminated feed (Skea et al., 1981). Substantial
bioconcentration of mirex was reported in goldfish and bluegills
exposed in ponds treated with mirex bait (Van Valen et al., 1968).
Whole body residues in goldfish exposed at 0.1 and 1.0 ppm increased
throughout the experiment. On Day 224 of the experiment goldfish
taken from the 1.0 ppm group contained 61.0 ppm mirex in muscle and
150 ppm mirex in whole body. In the 0.1 ppm treatment group, 11.6 ppm
in muscle and 45 ppm mirex in the whole body were found. Bluegills
exposed to mirex in ponds treated with 100.2 kg or 0.13 kg mirex bait
(theoretical concentrations of 1.0 or 0.0013 ppm, respecitvely, in
water) accumulated throughout the first 84 days at the 1.0 ppm treat-
ment level; residues were detected up to Day 56.
Three applications of mirex bait (1.25 Ibs/acre) to ponds contain-
ing channel catfish resulted in residues in fish averaging 0.015 ppm
in filets and 0.255 ppm in fat (Hyde et al., 1974). In a large scale
study, adult fathead minnows (Pimephales promelas) were exposed to
mirex in water for 32 days at an average concentration of 1.2 ug/L
(Veith et al., 1979). The resulting bioconcentration factor, based on
a sample of 5 whole fishes, was determined to be 18,100. Fathead
minnows exposed to 34 ug/L mirex for 120 days have accumulation fac-
tors in a range of 12,000 to 28,000 with tissue residues continuing to
increase through the 120-day exposure period (Buckler et al., 1981).
In general, mirex concentrations increase with individual fish
weight and appear to parallel reported lipid concentrations for
similar tissues (Insalaco et al., 1982). The highest tissue concen-
10
-------
trations have been found in the liver and viscera, followed by the
skin and muscle.
Freshwater invertebrates are sensitive to mirex with acute LD50
values for several species ranging from 40 to 1000 ppb. (Naqvi and de
la Cruz, 1983). Other invertebrates including the water flea (Daphnia
magna, D. pulex), midge larvae (Chironomus plumosus), and amphipod
(Gammaris pseudolimaeus) showed 48-hr ECSOs of >1 ppm (Sanders et al.,
1981; Johnson and Finley, 1980). Mosquito larvae exposed to 1.0 and
0.1 ppm mirex in water showed a 48-hr LC50 of 0.489 ppm (Alexander and
Norment, 1974). Muncy and Oliver (1963) found no effect of mirex on
red crayfish (Procambaris clarki) at 0.1 ppm during a 72-hr static
exposure. Acute studies (48-hr) with juvenile crayfish Procambaris
blandingi exposed to 0.1 and 0.5 ppb mirex for 48 hours showed that
mortality was delayed for up to 4 days following treatment, but that
65% and 71% respectively of the exposed populations died.
Hydra, a freshwater cnidarian, treated with 1.0, 0.1 and 0.01 ppm
mirex in acetone solution for 6 days exhibited behavioral changes such
as retracting their body tubes and tentacles after 2 days exposure
(Lue and de la Cruz, 1978). Peak mortality occurred on Day 4 at 1.0
ppm, with a time lag between behavioral changes and death. The 96-hr
LC50 was predicted to be 4.1 ppm.
Lue and de la Cruz (1977) studied the toxicity of mirex on two
soil macroarthropods: the land isopod Armadil 1 idium vulgare and the
soil millipede Oxidus gracilus. Feeding a diet ranging from 25 to 3000
ppm mirex, KD50 (knockdown dose for 50 percent of the exposed popula-
tion) and LD50 values for A. vulgare at 10 days exposure were 11.6
ppm and 35.2 ppm, respectively; and for 0. gracilus, 5.4 ppm and 198.7
ppm, respectively.
The earthworm Eisenia foetida, exposed to deposits of mirex on
filter paper for 48 hours was relatively resistant to mirex within
LC50 >l,000/pg/cm2 (Roberts and Borough, 1984).
Some chronic effects data for invertebrates were located. Studies
with several species including daphnids, midge larvae, and amphipods
estimated a maximum acceptable toxicant concentration of <2.4 ug/L for
Gammarus after 120 days of exposure (Sanders et al., 1981). Tests
performed on Hyallela azteca, an amphipod, by Naqvi and de la Cruz
(1973) and Jessimen and Quashi (1983) report 25 day (600 hours) and 13
day LCSOs at concentrations of 1 ug/L and 100 ug/L respectively.
Other tests showed effects ranging up to 1000 ug/L (Table 1).
Freshwater invertebrates have been found to bioconcentrate mirex
following exposure at levels used in the fire ant control program.
Laboratory studies utilizing concentrations much higher (1 and 5 ppb)
have confirmed this (Ludke et al., 1971). Invertebrates have been
found to accumulate mirex residues in lipid bodies with varying rates
of elimination depending on the species, p. magna exposed to 34 ug/L
mirex for 21 days accumulated 8,025 times the concentration in the
water (Sanders et al., 1981). Species of crayfish accumulated a
11
-------
residue 16,860 fold greater than that in the exposure water (Ludke et
al., 1971).
Two studies analyzed the effect of mirex on freshwater algae.
Kricher et al. (1975) exposed the unicellular green algae Chlorella
pyrenoidosa to 1.0 ppm mirex dissolved in acetone. The 1 percent
acetone concentration was found to be somewhat toxic to Chlorella.
When comparisons were made between the mirex sample and the acetone
control, the mean mirex-exposed density was found to be 19 percent
lower than the acetone control after 164 hours.
In another study, exposure of another uncellular green alga,
Chiamydomonas to 1.0 ppm mirex for 168 hours reduced photosynthesis 55
percent and reduced the respiration rate 28 percent (de la Cruz and
Naqvi, 1973).
Health Effects
Reported single oral dose LDSO's for rats range from 365 to 740
mg/kg (U.S. EPA, 1981) (Table 2). LDSO's for dogs range from 1,000 to
15,000 mg/kg (Larson et al., 1979) (Figure 1). The toxicity rating
for mirex is 4 (very toxic) with a probable oral lethal dose (human)
of 50-500 mg/kg, between I tsp. and 1 ounce for a 70 kg (150 Ib)
person (U.S. EPA, 1981). No studies of mirex effects or toxicity in
humans were found in this investigation. Animal studies indicate that
mirex is not metabolized or detoxified in mammals. Mirex is stored in
adipose tissue and excreted at low rates in the feces and in only
trace amounts in the urine (Chambers et al., 1982). Studies with
mice, rats, dogs, and monkeys have shown that mirex is rapidly
absorbed from the digestive tract and is quickly and readily stored in
adipose and other tissues. Mirex is readily transmitted to offspring
through both placental and lactogenic routes (Chu et al., 1981b;
Rogers and Grabowski, 1983; Grabowski and Payne, 1983a and 1983b).
Effects of mirex include reduced food and water consumption,
decrease in body weight, induced cytochrome P-450, and increased liver
weight. Male mice fed 10 mg/kg mirex for 15 days showed induced
cytochrome P-450, decreased blood glucose levels, and a significant
decrease in body weight (Fujimori et al., 1983). The chronicity
factor for mirex (i.e., the ratio of the single dose LD50 to the 90
dose LD50) is 60.8, the highest value reported for any pesticide (U.S.
EPA, 1981).
Few truly chronic studies of mirex have been published, but sub-
chronic studies report hepatotoxic, enzymatic, reproductive, carcino-
genic, and teratogenic effects. The teratogenicity of mirex has been
shown in numerous studies (Grabowski and Payne, 1980b; Rogers and
Grabowski, 1983; Chu et al., 1981b). Teratogenic effects include
edema, heart defects, and cataracts. Rats and mice treated with mirex
have produced smaller litters with reduced survival in the offspring.
Carcinogenic effects have also been reported (Innes et al., 1969;
Ulland et al., 1977; U.S. DHEW, 1980). Mirex administered in the diet
12
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of 26 rats of each sex for 18 months produced statistically signifi-
cant incidences of liver tumors in test animals (Innes et al., 1977).
Forty percent of the treated mice exhibited hepatomas compared to only
4 percent in the control. In a second study, rats receiving 50 or 100
ppm mirex for 18 months showed an increase in liver tumors and lesions
(Ulland et al., 1977). The incidence of these tumors was shown to be
statistically significant. In an unpublished study by the Frederick
Cancer Research Center under contract with the National Cancer Insti-
tute (U.S. DHEW, 1980), preliminary results showed a high and
apparently dose-related incidence of neoplastic nodules of the liver,
hepatocellular carcinoma, and monocytic leukemia in rats at dietary
doses of 25, 50 and 100 ppm for 2 years.
Studies have been conducted with the major photodegredation
products of mirex: chlordectone, photomirex (8-monohydromirex) and
dihydromirex (2.8-dihydromirex). Photomirex and chlordectone have
been found to be very similar to mirex in that they both exhibit
strong lipophilicity (bioaccumulate in fatty tissue), are not readily
eliminated, and are highly persistent in the environment. Though
studies on mirex have been well documented, there is little informa-
tion available on the toxicity of dihydromirex, photomirex and
chlordectone. Chlordectone and photomirex have been shown to cause
similar effects as mirex: increased liver weights, induction of the
microsomal mixed function oxidases, and dose related histological
abnormalities in the thyroid and liver (Fujimori et al., 1983;
Yarbrough et al., 1981; Chu et al., 1981a; Hallett et al., 1978). In
these studies, the toxicities of mirex, photomirex and chlordectone
were compared. Fujimori et al. (1983) treated male mice with 10, 25
or 50 mg/kg chlordectone, mirex and photomirex. Acute test results
showed that clearly distinguishable differences exist between these
three compounds in terms of biological effects. Both daily food and
water intake were significantly decreased in mice treatment with
mirex. In contrast, treatment with chlordectone or photomirex
increased food and water consumption. Chloraectone caused significant
motor incoordination, where mirex and photomirex did not. Mirex and
photomirex caused a significant increase in liver weight, whereas
chlordectone treatment resulted in only a slight increase. Mirex and
photomirex were similar in inducing hepatic MFO (mixed-function
oxidase system).
In a 28-day study by Yarbrough et al., (1981) there did not appear
to be any consistently significant differences between the qualitative
or quantitative toxic effects of mirex and photomirex in rats. These
results suggest that mirex and its degredation products may differ
substantially in their short-term effects, but not in long-term
toxicity.
Tolerances for residues of mirex in food products were set by the
U.S. EPA as follows: 0.1 ppm in fat or meat from cattle, goats, hogs,
horses, poultry, and sheep; 0.1 ppm in eggs; 0.1 ppm in milk fat; 0.01
ppm in or on all other raw agricultural commodities, exclusive of
eggs, milk fat, and animal fat (U.S. EPA, 1981).
16
-------
RECOMMENDATIONS
Aquatic
An Aquatic Life Criterion consists of a Criterion Maximum Concen-
tration (CMC) and a Criterion Continuous Concentration (CCC).
According to EPA guidelines (Stephan et al., 1985), effects data for
eight species including two fish and six invertebrates are required
for establishing criteria (Table 3). Insufficient data on acute
toxicity of mirex precludes the calculation of the FAV and, therefore,
of the CMC.
The Criterion Continuous Concentration (CCC) is equal to the
lowest of three values, the Final Chronic Value, the Final Plant
Value, and the Final Residue Value. Insufficient data on chronic
toxicity of mirex precludes the calculation of a CCC.
A Final Residue Value for freshwater biota was calculated using a
method by EPA (1983) using data discussed above.
The Final Residue Value was calculated as follows:
FinalResidue Value = S. EPA action level for fish
bioconcentration factor
where:
U.S. EPA action level for fish =0.1 ppm
Bioconcentrationfactor (geometric mean) =15,240
therefore:
Final Residue Value = _.__! ppm
15,240
= .007 ug/L
17
-------
TABLE 3. DATA REQUIREMENTS FOR CALCULATION OF AQUATIC LIFE INTERIM
CRITERIA--MIREX
Criterion Requirements
Aquatic Toxicity
Available Data
Acceptability of
Available Data
Acute Test Results from tests on:
A salmonid (class Osteichthyes)
YES
YES
A warm water species commercially
or recreational ly important
important (class Osteichthyes)
Another family in the phylum YES
Chordata(fish,amphibian,etc.)
A planktonic crustacean (cladoceran, YES
copepod, etc.)
Benthic crustacean (ostracod, YES
isopod,scud,crayfish,etc.)
Insect (mayfly, dragonfly, damselfly, YES
stonefly, mosquito, etc.)
Phylum other than Arthropoda/Chordata YES
(Rotifera, Annelida, Mollusca)
Another family of insect YES
NO
(no LC50)
NO
(no LC50)
NO
(no LC50)
YES
(controls; replicates)
NO
(no LC50)
YES
(controls; replicates)
NO
(not aquatic species)
YES
(controls; replicates)
Acute-chronic ratios with species from
three different families:
One fish
One invertebrate
Acutely sensitive freshwater
animal species
NO
NO
NO
Acceptable test results from a test with:
Freshwater algae YES
A vascular plant NO
Bioaccumulation factor with a freshwater YES
species (if a maximum permissible tissue
concentration is available)
NO
(no LC50)
YES
(controls, replicates)
18
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This concentration is, lower than 0.1 ppb where delayed mortality
was noted in Procambans blandingi, but higher than the criterion of
0.001 ug/L given in Quality Criteria for Water (1976). The advisory
concentration for mirex will remain 0.001 ug/L, the same as that given
in the 1976 publication, based on the toxicity information above and
incorporating a safety factor at .01.
Health
No epidemiological studies of the effects of mirex on human health
have been found which could contribute data useful to the derivation
of a criterion (Table 4). However, mirex has been determined to be
carcinogenic in three separate studies with mice and rats (Innes, et
al., 1969; Ulland et al., 1977, NIOSH, 1978). Although data generated
by all three studies show statistically significant increases in
heptocellular carcinomas, the U.S. DHEW (1980) study represents the
best candidate for use in calculating a water concentration of mirex
that results in a cancer risk of 10-5. The water quality criterion
for mirex is based on the induction of hepatocellular carcinomas in
male Fischer (F344/N) rats. The results of the unpublished 2-yr
feeding study by the Frederick Cancer Institute show dose-related
incidence with the unadjusted incidence of the low dose group
significantly different from the control group. Because this study
was not available for our review, the criterion estimate for mirex was
determined from data reported by the U.S. EPA (1983). Using the data
from U.S. DHEW (1980), the slope estimate from the multi stage model
is adjusted to give a human carcinogenic potency estimate of 7.15
(mg/kg/day)-l (U.S. EPA, 1983).
The intake of the mirex from ambient water is assumed from two
sources: (1) drinking an average volume of 2 liters of water per day;
(2) ingesting an average of 6.5 grams of fish per day. Because of
accumulation of residues in fish, the amount of mirex in fish is equal
to a factor R times the water concentration (mg/kg/water). Using
methodology reported by EPA (1983), the water concentration in mg/L
corresponding to a life time cancer risk of 10~5 for a 70 kg person is
calculated by the formula:
C = 7_0 kg x 10
qI (2 + 0.0065R)
where:
q±= 7.15 (mg/kg/day)-1
R = 15,240
For a lifetime cancer risk below 10-6 the criteria for mirex in water
are: 4.9 ng/L if exposure is through water only without consumption
of contaminated aquatic organisms; 0.097 ng/L if exposure is through
aquatic organisms only without ingestion of contaminated water; 0.093
ng/L if exposure is through consumption of both contaminated water and
aquatic organisms.
19
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Sufficient data were not provided in the EPA (1983) report of the
DHEW (1980) study, to derive a threshold effect water quality
criterion. A threshold effect criterion is derived from a no-
observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect
level (LOAEL), or lowest-observed-effect level (LOEL) from a chronic
toxicity assay of at least 90 days duration. None of these values
were reported in the EPA (1983) document, nor were they found in
studies reviewed as part of this investigation.
20
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TABLE 4. DATA REQUIREMENTS FOR CALCULATIONOF HUMAN HEALTH INTERIM
CRITERIA--MIREX
Criterion Requirements
Human Health Effects
Available Data
Acceptability of
Available Data
Non-Threshold:
Carcinogen YES
Tumor incidence tests (Incidence of YES
tumor formation significantly more
than the control for at least one
dose level), or
Data set which gives estimate of YES
carcinogenetic risk, or
Lifetime average exposure tests, or YES
Human epidemiology studies NO
(if available, not required)
Threshold:
Non-carcinogens NO
No observed adverse effect level NO
(at least 90-day), or
Lowest observed effect level NO
Acceptable Daily Intake: NO
Daily water consumption YES
Daily fish consumption YES
Bioconcentration factor NO
Non-fish dietary intake YES
Daily intake by inhalation NO
Threshold Limit Value:
(Based on 8-hour time-weighted NO
average concentrations in air)
Inhalation Studies:
Available pharmacokinetic data NO
Measurements of absorption efficiency NO
Comparative excretion data NO
YES
(EPA approved)
YES
(3 studies with
valid data., EPA
approved)
YES
(EPA approved)
YES
(EPA approved)
YES
(EPA assumptions)
YES
(EPA assumptions)
YES
(EPA assumptions)
21
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