IPCS INCHEM Home

    ETHION

    EXPLANATION

         Ethion was evaluated for acceptable daily intake by the Joint
    Meeting in 1968, and reviewed in 1972, 1982, and 1985 (Annex 1,
    FAO/WHO, 1969a, 1973a, 1983a, and 1986a). A toxicological monograph
    was prepared by the Joint Meeting in 1968 (Annex 1, FAO/WHO, 1969b)
    and monograph addenda were prepared in 1972 and 1982 (Annex 1,
    FAO/WHO, 1973b and 1983b). The ADI allocated in 1968 (0.00125 mg/kg
    b.w.) was revised in 1972 (0.005 mg/kg b.w.) based upon additional
    data. The 1982 Joint Meeting noted that a substantial amount of data
    used in support of the ADI was generated by Industrial Bio-Test
    Laboratories (IBT). In the light of information that IBT studies were
    going to be replaced by appropriate studies, the 1982 Meeting
    withdrew the ADI and replaced it with a temporary ADI at a lower
    level (0.001 mg/kg b.w.), requiring the replacement studies and
    additional data on absorption, distribution, and metabolism in
    mammals. The 1985 Joint Meeting, in the absence of the required data,
    reduced further the temporary ADI (0.0005 mg/kg b.w.) and recommended
    that if the appropriate data were not submitted by 1986, the Meeting
    should consider withdrawing it. The required data and some additional
    data have been provided, which are summarised in this monograph
    addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         Groups of 5 male and 5 female Sprague-Dawley rats were treated
    orally with either low single doses of 2 mg/kg b.w. or high single
    doses of 105 mg/kg b.w. (males) or 10 mg/kg b.w. (females) of
    14C-ethion (98.4% pure, labelled in the methylene position). Five
    additional male and female rats were dosed orally for 14 days with
    2 mg/kg b.w./day of non-labelled ethion before the administration on
    day 15 of an equal single dose of 14C-ethion.

         Seven days after the low single or low multiple doses, both male
    and female rats had eliminated at least 93 - 94% of the administered
    radioactivity in urine (85%) and faeces (4 - 7%); 3 - 4% was
    eliminated in expired air in 3 days. Similar values were obtained for
    females after the high single dose. In males, 7 days after the high
    single dose, 75% of the administered radioactivity had been excreted
    in urine, 15% in faeces; 4% was eliminated in expired air after 3
    days. Multiple pre-treatment of both male and female rats with
    non-labelled ethion slightly increased the percent of radioactivity
    eliminated in the urine during the first 24 hours after a low dose
    of 14C-ethion; the percentages of radioactivity eliminated in the
    urine of males and females were 71 and 65%, respectively, without
    pre-treatment, and 78 and 75%, respectively, after pre-treatment with
    "cold" ethion. Detectable levels of 14C-radiolabelled residues were
    found in all tissues examined from all the animals in all treatment
    groups. The total radioactivity recovered from the 20 tissues examined
    3 days after the administration of 14C-ethion was 0.36% in the
    high-dose males and 0.26-0.29% in all other groups. The highest
    concentrations of radioactivity were found in the liver (0.1-7.0 ppm),
    kidney (0.04-3.9 ppm), adipose tissue (0.02-7.5 ppm) and, occasionally
    markedly, in the hair (0.02-11.2 ppm) of both male and female animals
    (Selim, 1985a).

         The pharmacokinetics of ethion were studied in 5 male and 5
    female Sprague-Dawley rats starved for 18 hours and treated with
    single oral doses of approximately 0.38 mg/kg b.w. 14C-ethion (98.4%
    pure, labelled in the methylene position) in corn oil. Peak blood
    levels of radioactivity were reached after about 6 hours in both male
    and female rats, indicating that ethion was slowly absorbed. The
    decline of radioactivity was slow, with detectable levels of
    radioactivity present in the blood of all animals 72 hours after
    dosing (Selim, 1985b).

    Metabolism

    Rats

         Analysis of male and female rat urine after single or multiple
    doses of 14C-ethion (for details on treatment regimens, see study
    summarized under "Absorption, distribution and excretion") by solvent
    partitioning with ethyl acetate, and by subsequent HPLC of the aqueous
    and organic phases so obtained, indicated the presence of 4 to 6
    distinct radioactive products. The percent distribution of radio-
    activity among the various HPLC bands was the same from high-dose
    male and female rats as from low-dose males. However, a different
    percent distribution was observed in the urine from both male and
    female rats after multiple dosing and from low-dose female animals.
    After solvent partitioning of urine, over 99% of the radioactivity
    was found in the aqueous phase in all cases, indicating that
    non-significant levels (< 1%) of organo-soluble ethion or ethion
    metabolites, such as ethion monooxon or ethion dioxon, were likely to
    be present in rat urine. In addition, HPLC analysis of aqueous and
    organic phases after acidification showed no radioactivity in those
    fractions which were known to correspond to these three compounds. It
    was concluded that, following absorption after the oral administration
    of 14C-ethion by male and female Sprague-Dawley rats, the compound
    is readily metabolized to 4 - 6 polar, water-soluble products, which
    are excreted in the urine (Selim 1985c).

    Chickens

         The levels of 14C-residues were measured in the eggs from and
    the tissues of white leghorn laying hens after the daily oral
    administration of gelatin capsules containing 2.0 mg/kg b.w.
    14C-ethion (99.0% pure, labelled in the methylene position) in
    hexane, equivalent to an estimated (food consumption data) dietary
    intake of 17 ppm, for 10 days. In this study, 1 vehicle control and 3
    test groups of 5 hens/group were used. All animals were sacrificed
    approximately 4 hours after the last dose, and tissue samples from
    liver, adductor muscle, pectoral muscle, and fat were collected.

         Body weights (with the exception of 1 animal), food consumption,
    and egg production in test animals were considered by the authors of
    the study to be normal and were not statistically evaluated. The
    average daily feed consumption of treated hens was 5 to 8% lower than
    that of controls. In dosed animals, 14C-residues were detected
    in all tissues examined and amounted to 3.2, 0.2, and 0.1 ppm
    ethion equivalents in liver, muscle, and fat, respectively. Peak
    14C-residue values in both egg yolk and egg white were recorded
    on day 10 of treatment and amounted to 1.3 and 0.3 ppm ethion
    equivalents, respectively. However, the egg white residues reached a
    plateau after 4 days, while the yolk residues were still increasing
    after 10 days of treatment.

         Non-detectable levels (< 0.004 to 0.008 ppm ethion equivalents)
    of 14C-residues were recorded in the eggs and tissues of control
    animals (Bodden & Zietlow, 1985).

         In a parallel study, TLC and GLC analysis of 14C-residues in
    eggs (egg yolk and egg white) and tissues (liver, muscle, and fat)
    collected from the hens described in the previous paragraph showed
    non-detectable levels (< 0.01 ppm ethion equivalents) of ethion,
    ethion monooxon, and ethion dioxon in eggs and tissues from
    14C-ethion-treated hens, with the only exception being one fat
    sample which was shown by GLC analysis to contain 0.012 ppm ethion.
    Extraction of egg and tissue samples with acetone released only 10 to
    30% of the 14C-residues in all samples examined, except for fat and
    egg yolk, which were approximately 55 and 40% extractable (mainly in
    the hexane phase), respectively. After methanol extraction and
    protease digestion, recovery of 14C-residues as soluble or volatile
    products from liver, muscle, and egg was about 90%, ranging from 97%
    for liver to 88% for egg yolk. The solubilised residues were largely
    found in polar (water-soluble) fractions, except for egg yolk.
    Fractionation of egg and tissue samples by column chromatography
    showed the presence of about 6 metabolites, most of which were polar
    and were able, in some cases, to form volatile radioactive products.
    In liver, evidence was obtained indicating that the major volatile
    component was 14C-formaldehyde (Zietlow, 1985).

    Goats

         Two lactating goats of about 40 kg b.w. were orally administered
    gelatin capsules containing 14C-ethion (99.0% pure, labelled in the
    methylene position) in hexane at the calculated dose of 1.12 mg/kg
    b.w./day, equivalent to an estimated dietary intake for the 2 animals
    of 45 and 70 ppm, for 7 consecutive days. A third control goat was
    given an equivalent volume of hexane. Milk samples were assayed daily
    for 14C-residues. Approximately 4 hours after the final dose the 3
    animals were sacrificed and several tissues were collected and assayed
    for 14C-residues.

         Decreases in food consumption, body weight, and milk production
    observed during the test period in both test animals were attributed
    by the authors of the study to housing in metabolism stalls.
    Detectable 14C-residues were found in all tissues examined from the
    treated goats (fat, kidneys, heart, liver, and muscle), the highest
    values being found in the liver (13.3 and 14.7 ppm ethion equivalents)
    and the kidneys (7.6 and 9.7 ppm), and the lowest in fat (0.2 ppm).
    Peak milk 14C-residue values of 1.27 and 1.51 ppm were recorded at
    day 6 of dosing. 14C-Ethion residues in milk reached a plateau at
    about day 4 of dosing in both animals. The percent butterfat of milk
    samples from the 3 goats in the test period ranged from 3.3 to 10.0%
    (Jobsis & Zietlow, 1985).

         In a parallel study, characterisation of 14C-residues in the
    liver, kidneys, heart, muscle, fat, and milk of these 2 goats after
    oral administration of 14C-ethion indicated the presence of 0.03 ppm
    or less of non-metabolised compound. The metabolites ethion monooxon
    and ethion dioxon were not detected in any samples by TLC or GC
    analysis at sensitivity levels of 0.005 to 0.01 ppm. Forty-six to 75%
    of the 14C-residues from the tissues were soluble in metanol and an
    additional 17 to 32% were solubilised after treatment with protease.
    At least 4 different radioactive products were identified in the
    water-soluble fractions. Attempts to further characterise these polar
    metabolites were largely unsuccessful due to their volatility.
    However, a volatile component was trapped, from kidney tissue, which
    was tentatively identified as formaldehyde. Approximately 49% of the
    14C-residues in milk precipitated with casein and another 10%
    co-crystallised with lactose, leading the authors to suggest that
    14C was incorporated into natural products (Bosh, 1985).

    Toxicological studies

    Special studies on carcinogenicity

    Mice

         Groups of 80 male and 80 female CF1 albino mice were given
    diets containing 0, 0.75, 1.5, or 8 ppm ethion technical (92.1% pure)
    for 105 weeks. For all animals, mortality, morbidity, overt toxic
    signs, body weight, and food consumption were recorded throughout the
    study. Clinical blood and cholinesterase determinations were conducted
    on 10 males and 10 females randomly selected from those purchased
    for the study (baseline determinations) and on 10 mice/sex/group
    prior to interim sacrifices at 6, 12, and 18 months and prior to
    final sacrifice at 24 months. All animals, except those used for
    baseline determinations, were subjected to gross necropsy and to
    histopathological examination of about 30 tissues.

         Survival was 20 to 30% in male groups and 42 to 60% in female
    groups. There was a slight increase in the number of mice observed
    with palpable tissue mass(es) during the study in males, but not in
    females, at 1.5 and 8 ppm (14/80 and 15/80, respectively), as compared
    to controls (11/80). There was a treatment-related decrease of serum
    cholinesterease values in mice of both sexes at 8 ppm, as compared to
    controls. The decrease was statistically significant at 6, 12, and 18
    months for females (29, 25, and 33%, respectively) and at 12 months
    for males (44%), although a high variability was noted in the
    cholinesterase values of control animals. No effects on body weight,
    food consumption, incidence of mortality, haematology (including
    erythrocyte count, total and differential leukocyte count,
    haematocrit, haemoglobin, MCV, MCH, MCHC, and platelet count), blood

    biochemistry (GPT and GOT), or erythrocyte or brain cholinesterase
    were attributable to the administration of ethion. Necropsy at
    termination showed high incidences of eye opacities, kidney and ovary
    cysts, liver tissue masses, and thickened uteri in mice of both
    treated and control groups. None of these findings were related to
    treatment. Histopathology showed low incidences of tumours, apparently
    without statistically-significant differences, in both treated and
    control groups of both male and female mice. The most frequent tumours
    in this study were those found in the liver and lung. In male mice,
    but not in females, the total combined incidence of tumour-bearing
    animals with hepatocellular adenomas and carcinomas was higher in all
    treated groups than in controls (13/80, 14/80, 19/80, and 18/80 in the
    0, 0.75, 1.5, and 8 ppm groups, respectively). In females, the total
    combined incidence of alveolar/bronchiolar adenomas and carcinomas was
    higher in the high-dose group than in control animals (12/80 and 5/80,
    respectively). The author of the study considered the incidences of
    both hepatocellular and alveolar/bronchiolar neoplasms found in
    treated animals of this study to be inside "the ranges normally seen
    in aged mice" and did not regard these neoplasms as treatment related.
    A large variety of non-neoplastic lesions found in various tissues
    from both male and female mice of all groups were either of similar
    incidence in treated and control animals or considered by the authors
    of the study to be within the ranges normally seen for spontaneously-
    occurring lesions in CF1 mice. The author concluded that the
    exposure of CF1 mice to ethion technical for up to 24 months
    "did not appear to produce any neoplastic or non-neoplastic treatment-
    related changes".

         Based on the decreased values of serum cholinesterase activity
    observed at the interim sacrifices, the no-effect level for ethion in
    CF1 albino mice in this study was 1.5 ppm, equal to 0.22 and 0.24
    mg/kg b.w./day for males and females, respectively (Morrow, 1985).

    Rats

    	Groups of 80 male and 80 female Sprague-Dawley CD albino rats were
    given diets containing 0, 2, 4, or 40 ppm ethion technical (92.1%
    pure) for 24 months. All animals were studied for mortality,
    morbidity, overt toxic signs, body weight, and food consumption
    throughout the study. Clinical blood and cholinesterase determinations
    were conducted on 10 male and 10 female rats randomly selected from
    those purchased for the study (baseline animals) and on 10
    animals/sex/group prior to interim sacrifices at 6, 12, and 18 months
    and prior to final sacrifice at 24 months. All surviving animals were
    subjected to ophthalmological examination at 0, 12, and 24 months. All
    animals found dead, sacrificed moribund, or sacrificed on schedule
    were subjected to gross necropsy and to histopathological examination
    of about 30 tissues.

         Survival at termination was 40 to 62% in male groups and 48 to
    58% in female groups. Differences in the incidence of mortality
    between groups were not dose-related and were not considered to be
    treatment-related. The numbers of females presenting palpable tissue
    mass(es) were greater at 4 and 40 ppm (36/80 and 38/80, respectively)
    than in control rats (30/80). The total number of occurrences of
    palpable tissue mass(es) in these females were also increased (844 and
    1159, respectively) as compared to controls (534). According to the
    authors of the study "histopathologic evaluation of these masses,
    however, did not confirm a relationship between the increase in
    palpable mass(es) and neoplasia". There was a treatment-related
    decrease of serum cholinesterase values in both male and female rats
    at 40 ppm. Values were statistically-significantly lower than those of
    control animals at 12 and 18 months for males (-37% and -38%,
    respectively) and at 6, 12, 18, and 24 months for females (-49%, -55%,
    -57%, and -46%, respectively). Statistically non-significant but
    greater than 10% decreases in serum cholinesterase values were noted
    in the 4 ppm females at 6 (-12%), 12 (-19%), and 18 (-12%) months, and
    in the 2 ppm males at 12 months (-13%) when compared to controls. A
    high variability was noted in serum cholinesterase values of control
    animals. Haematological examination (RBC count, haematocrit,
    haemoglobin, total and differential WBC count, platelet count, MCV,
    MCH, and MCHC), blood biochemistry (GPT, GOT, lactate dehydrogenase,
    alkaline phosphatase, total bilirubin, glucose, urea nitrogen, total
    protein, albumin, globulin, cholesterol, Ca+ Na+, and K+),
    ophthalmological examination, and erythrocyte and brain cholinesterase
    determinations indicated no effect attributable to the administration
    of ethion at any dose level. An increase in body weight was observed
    in the 2 ppm males at 12 months and a decrease in testes weight was
    found in the 4 ppm males at 18 months, as compared to controls;
    although statistically significant, these differences were not
    consistent over the treatment period and were not dose-dependent, and
    therefore they were not considered to be treatment-related.

         Histopathological examination at interim and final sacrifices
    indicated no neoplastic treatment-related changes. At termination
    there were several non-neoplastic lesions in both male and female rats
    which apparently occurred at a higher incidence in treated animals
    than in controls. The incidences of these non-neoplastic changes did
    not show a dose-response relationship and were considered to fall
    within ranges encountered in long-term studies with Sprague-Dawley
    rats. These changes, which were judged not to be treatment-related,
    included C-cell hyperplasia of the thyroid in both sexes, vacuolation
    of the adrenal gland in males, and uterine hydrometra in females.

         Based on the results of serum cholinesterase determinations, the
    no-effect level for ethion technical in CD albino rats after 24 months
    of administration in this study was 4 ppm, equal to 0.18 and
    0.22 mg/kg b.w./day for males and females, respectively (Morrow &
    Mayhew, 1985).

    Special study on embryotoxicity/teratogenicity

    Rats

         Groups of 25 mated female rats (Charles River Crl:COBS CD(SD)BR
    strain, 17 weeks old) were administered ethion technical (92.1% pure)
    in corn oil by gavage at doses of 0, 0.2, 0.6, or 2.5 mg/kg b.w./day
    on days 6 through 15 of presumed (observation of vaginal plug
    in situ or in the cage pan) gestation. The female rats were
    sacrificed on day 20 of gestation and, after caesarian section,
    examined for the number of pregnancies, implantations, early and late
    resorptions, live and dead fetuses, and corpora lutea. Fetuses were
    weighed, sexed, and examined for visceral (approximately 1/3 of the
    fetuses in each litter) and skeletal (approximately 2/3 of the fetuses
    in each litter) variations. Water consumption and uterine weights were
    not recorded in this study.

         No rats died during the study. A treatment-related, statistically-
    significant, increase in the incidence of rats with hyperactivity was
    found in the high-dose group. A slight statistically, but not toxico-
    logically, significant decrease in fetal body weight was observed in
    the litters at 0.6 (-0.9%) and 2.5 (-2.1%) mg/kg b.w./day. Slight
    statistically non-significant increases in the incidence of fetuses
    with variations, of litters with fetuses with variations, and of the
    percent of fetuses per litter with one or more variations, were
    observed in the high-dose group. Treatment-related skeletal variations
    were observed in fetuses in the 0.6 and 2.5 mg/kg b.w./day groups.
    These changes consisted of delays in ossification of the ischium and
    pubes of the pelvis in the mid- and high-dose group foetuses and of
    the hyoid and manubrium in the high-dose group fetuses. None of these
    variations occurred in any control or low-dose group fetuses. Only the
    higher incidence of incomplete or absent ossification of the pubes
    observed in the high-dose group achieved statistical significance as
    compared to controls (p < 0.01). These skeletal variations were
    considered by the authors of the study to represent reversible
    developmental delays due to fetal toxicity at 0.6 and 2.5 mg/kg
    b.w./day. Gross external, soft tissue, and skeletal examination
    indicated no other effects attributable to the administration of
    ethion. There were no statistically-significant differences between
    treated and control groups in maternal body-weight gain or food
    consumption nor in the incidence of pregnancies, corpora lutea,
    implantations, live and dead fetuses, early and late resorptions, nor
    in litter size, viability, or sex ratio.

         The authors of the study concluded that "no unique hazard to the
    conceptus occurred as a result of maternal treatment with ethion
    administration under the conditions of the study". Based on skeletal
    observations the no-effect level with respect to embryotoxicity for
    ethion technical in CR1 rats in this study was 0.2 mg/kg b.w./day
    (Hoberman et al., 1983).

    Special studies on mutagenicity

         The mutagenic potential of ethion was studied by the Ames test
    using Salmonella typhimurium strains TA98, TA100, TA1535, TA1537,
    and TA1538, both with and without the addition of a mammalian
    metabolic activation preparation (S-9 mix from liver of male rats
    pre-treated i.p. with a single injection of 500 mg/kg b.w. Aroclor
    1254 in corn oil). A preliminary toxicity determination indicated no
    appreciable toxicity due to ethion at any dose level tested up to
    10,000 g/plate. In the mutagenicity assay ethion was non-mutagenic to
    all strains tested at all the concentrations used (100-10,000 g/
    plate) both with and without metabolic activation. Several positive
    controls were also used in this study both with and without metabolic
    activation (Haworth et al., 1984).

         The ability of ethion to incude unscheduled DNA synthesis (UDS)
    in primary rat hepatocytes from normal adult male Sprague-Dawley rats
    was tested by autoradiographic methods. Based on the results of a
    preliminary cytotoxicity test, 5 concentrations of ethion ranging from
    0.625 to 10 nl/ml were tested in the UDS assay. 2-Acetylaminofluorene
    (2-AAF) was used as a positive control at 2 and 20 g/ml. No
    significant increase in average net nuclear counts over the control
    was observed at any concentration tested. 2-AAF induced a significant
    increase in nuclear counts at both concentrations used. It was
    concluded that under the conditions of the assay ethion did not induce
    unscheduled DNA synthesis at concentrations up to 10 nl/ml, equal to
    12.2 g/ml (Thilagar et al., 1984a).

         The ability of ethion to induce forward mutations at the
    hypoxanthineguanine phosphoribosyl transferase (HGPRT) locus of
    Chinese hamster ovary (CHO) cells in vitro was investigated both in
    the presence and absence of a metabolic activation preparation (S-9
    mix from the liver of Fischer-344 rats pre-treated with Aroclor 1254).
    Based on the results of a preliminary toxicity test, 4 concentrations
    of ethion, ranging from 40 to 100 nl/ml, were tested in the activated
    and non-activated systems. Ethyl methanesulfonate and benzo(a)pyrene
    were used as positive controls in the test without and with metabolic
    activation, respectively. Statistically-significant increases in the
    frequency of mutants were not induced by ethion, either with or
    without metabolic activation. Both positive controls induced
    statistically-significant increases in the frequency of mutants
    (Thilagar et al., 1984b).

         In an in vivo cytogenetics assay the ability of ethion to
    induce numerical or structural chromosome aberrations in rat bone
    marrow cells was investigated. Groups of 5 male Sprague-Dawley rats
    were dosed by gavage with single doses of 0, 4.7, 14, 47, or 140 mg/kg
    b.w./day ethion (92.1% pure) in corn oil for 5 consecutive days, or
    with a single i.p. injection of 5 mg/kg b.w. triethylenemelamine (TEM)
    1 day prior to sacrifice (positive controls). All animals receiving

    140 mg/kg b.w./day and 1 animal receiving 47 mg/kg b.w./day ethion
    died following administration of the second dose. Clinical signs of
    toxicity were reported in the animals in the top 2 dose groups, but
    not in the animals receiving lower doses of ethion or in control rats.
    Bone marrow cells were collected from each surviving animal 6 hours
    after the last dose, arrested in metaphase, and examined for numerical
    or structural chromosomal aberrations. The mitotic index (percent of
    cells in mitosis) and the number of aberrations (gaps, breaks,
    fragments, and rearrangements) were not significantly different in
    treated rats when compared to controls. Excluding gaps, the only
    aberration observed in treated rats was a chromatid break in 1 rat in
    the low-dose group. There was a statistically-significant increase in
    the number of chromosomal aberrations in positive control rats. It was
    concluded that under the conditions of the assay ethion did not induce
    chromosome aberrations in male rats (Putman & Melhorn, 1984).

    Special study on delayed neurotoxicity

    Chickens

         Forty adult white leghorn hens (14 months old) were given ethion
    technical (92.1% pure) in corn oil at a single oral dose of
    1900 mg/kg b.w. (equivalent to the LD75, as calculated from
    preliminary studies). Fifteen minutes before ethion administration the
    hens were given an oral dose of 25 mg/kg b.w. atropine sulfate in
    water. Two control groups of 10 hens/group received either corn oil
    (4 mg/kg b.w.) or tri-ortho-cresyl phosphate (TOCP, 750 mg/kg b.w. in
    corn oil) as the negative and positive control groups, respectively.

         Six ethion-treated animals died of acute anticholinesterase
    effects during the first 6 days of the study. Each animal was
    subjected to daily neurologic evaluation from day 6 onward. One
    positive control animal developed complete motor paralysis of the hind
    limbs and was sacrificed on day 19. All surviving hens were sacrificed
    at 23 - 25 days from the initiation of the study and were subjected to
    gross necropsy and to microscopic examination of the spinal cord and
    peripheral nerves. No hen in either the ethion-treated or the negative
    control group had any neurological score after day 8 of the study.
    Early neurological scores recorded during the first 8 days after
    dosing were considered by the authors of the study to be acute effects
    of cholinesterase inhibition. In the positive control group 2/10
    animals showed late neurological scores starting from days 12 - 18
    after TOCP administration. During histopathological examination the
    group mean frequencies of axonal swellings per transverse section of
    cervical spinal cord were 7/100, 15/100, and 187/100 in the negative
    control, ethion-treated, and positive control animals, respectively.
    The higher frequencies of axonal swellings per transverse section
    observed in TOCP- and ethion-treated hens, when compared to controls,

    were statistically significant (p < 0.01, non-parametric test) for
    positive control animals, but not for ethion-treated hens. The
    frequencies of axonal swellings per number of transverse sections
    below the cervical spinal cord were statistically-significantly
    increased both in positive control and ethion-treated hens (78/61 and
    32/268, respectively) when compared to control animals (1/55). Based
    on the sporadic distribution and low frequency of these changes in the
    spinocellular tract, the statistically-significant increase in axonal
    swellings observed below the cervical spinal cord was not considered
    by the authors of the study to be evidence of delayed neuropathy.
    During peripheral nerve examination the following observations were
    made which were not treatment-related: minimal foci of axonal
    degeneration in 1/34, 2/10, and 5/9 hens and 1 or 2 axonal swellings
    in 5/34, 2/10, and 4/9 hens in ethion-treated, negative control, and
    positive control animals, respectively.

         Based on the historically good correlation between the hen's
    neurological score and the frequency of axonal swellings in transverse
    sections of the cervical spinal cord, as noted in previous delayed
    neurotoxicity studies conducted in the authors' laboratory, the
    authors of the study concluded that ethion technical "displayed no
    potential for development of clinical or morphologic changes
    associated with organophosphorus-induced delayed neurotoxicity" in
    white leghorn hens at the LD75 (1900 mg/kg b.w.) (Davidson et al.,
    1982).

    Special study on reproduction

    Rats

         In a 3-generation reproduction study (2 litters/generation)
    groups of 15 male and 30 female albino rats (Charles River CD strain)
    were designated as F0 parental animals and given diets containing
    0, 2, 4, or 25 ppm ethion technical (92.1% pure) in corn oil from day
    30 of age until completion of their second lactation period (lactation
    of F1b litters). To obtain the following generations, 15 males and
    30 females from each treatment group were randomly selected from the
    second litters of each generation (F1b and F2b litters) and
    designated as F1 and F2 parental animals, respectively. Both F1
    and F2 parental animals were 21 to 35 days old at the start of the
    F1 and F2 generations, respectively. All animals were observed for
    mortality, morbidity, and overt signs of toxicity. All surviving
    parental animals were subjected to gross necropsy. Five rats/sex/group
    from the F1b, F2b, and F3b litters were subjected to gross
    pathology study. Serum, erythrocyte, and brain cholinesterase
    determinations were conducted at final sacrifice of 10 rats/sex/group
    from the F1 and F2 parental generations. Pre-mating serum and
    erythrocyte cholinesterase determinations were made on 10
    rats/sex/group.

         Survival was good in all groups of the 3 generations. Small
    (< 10%) but statistically-significant reductions in body weight were
    noted during the F2a lactation period of F1 females at 25 ppm.
    These reductions were considered by the authors not to be treatment-
    related. Scattered statistically-significant differences in food
    consumption between treated and control animals were observed
    which were not considered by the authors of the study to be
    attributable to ethion administration. No effects attributable to
    ethion administration were noted on antemortem observations,
    reproductive performance (including mating index, male and female
    fertility index, and gestation index), progeny survival (including
    mean numbers of pups delivered, delivered viable, still-born, found
    partially cannibalised, and surviving at 1, 4, 7, 14, and 21 days of
    the lactation period), or progeny body weight and development. In the
    F1 generation, statistically-significant reductions of serum
    cholinesterase values were recorded in the 25 ppm females when
    compared to controls at both the pre-mating (-43.2%) and final
    (-44.8%) sacrifices. A statistically-significant increase of
    erythrocyte cholinesterase values was noted in the 25 ppm F1 males
    at final sacrifice when compared to controls. There were no
    statistically-significant treatment-related decreases in serum,
    erythrocyte, or brain cholinesterase values in males, nor in
    erythrocyte or brain cholinesterase values in females of the F1
    generation when compared to controls. In the F2 generation, a
    statistically-significant reduction in serum cholinesterase values
    (-52.7%) was noted in the 25 ppm females at final sacrifice when
    compared to controls. A 22% reduction of serum cholinesterase values
    as compared with controls was also noted in the 4 ppm F2 females,
    but the difference was not statistically significant. In males a
    statistically non-significant decrease (-19%) in serum cholinesterase
    values was noted at 25 ppm. There were no statistically-significant
    differences between treated and control groups in erythrocyte or brain
    cholinesterease values for males or females of the F2 generation.
    Gross pathological examination of sacrificed F0, F1, and F2
    parental animals and F1b, F2b, and F3b progeny showed no
    alterations attributable to the administration of ethion at any dose
    level. There were no statistically-significant effects attributable to
    treatment in organ weight, organ-to-body-weight or organ-to-brain-
    weight ratios in parental or progeny animals of any dose group, in
    all 3 generations.

         Based on the results of serum cholinesterase determinations, the
    no-observed-effect level of ethion technical in CD albino rats
    appeared in this study to be 25 ppm, equal to 1.2 mg/kg b.w./day for
    males, and 4 ppm, equal to 0.2 mg/kg b.w./day for females
    (Salamon et al., 1985).

    Long-term studies

         See under "Special studies on carcinogenicity".

    COMMENTS

         Most of the required data for ethion have now been made available
    to the Joint Meeting, as well as some desirable and additional data.
    The required short-term toxicity study in dogs and desired further
    observations in man, however, have not been made available.

         The metabolism studies showed that ethion was slowly but almost
    completely absorbed after oral administration to rats, with peak blood
    levels reached 6 hours after dosing. After complete (> 99%)
    metabolism, ethion was rapidly eliminated, mainly by renal excretion.
    Urinary excretion of 14C-ethion was faster in animals pre-treated
    with repreated doses of unlabelled ethion. In both male and female
    rats, hens, and goats, ethion was extensively metabolized to a number
    of polar products, which were not ethion monooxon or ethion dioxon.

         In 2 long-term combined oral toxicity and carcinogenicity
    studies, 1 in rats and 1 in mice, no adverse effects were seen.
    Although toxic doses of ethion were not tested in these studies, the
    Meeting concluded that additional carcinogenicity studies in rats or
    mice were unnecessary.

         In a rat embryotoxicity/teratogenicity study, ethion induced
    skeletal variations consisting of delays in ossification and
    incomplete or absent ossification of several bones in fetuses at 0.6
    and 2.5 mg/kg b.w./day. These changes, which were considered to be
    related to fetal toxicity, are normally reversible. The only sign of
    toxicity in dams was hyperkinesia at the highest dose level.

         In a 3-generation reproduction study ethion had no effect on the
    reproductive performance, survival, growth, or development of rats. In
    this study a treatment-related decrease in serum cholinesterase
    activity was observed in F1 and F2 female rats at 4 and 25 ppm and
    in F1 and F2 male rats at 25 ppm, when compared to controls.

         A delayed neurotoxicity study in hens was carried out using a
    single oral dose equivalent to the LD75. No clinical signs of
    neurotoxicity were observed in this study. Some histological
    abnormalities were seen which had an unusual distribution and were
    difficult to evaluate. Furthermore, the dose used in this study was
    inappropriate. For these reasons the Joint Meeting requested an
    additional delayed neurotoxicity study.

         In 4 separate mutagenicity studies (3 in vitro and 1 in vivo)
    ethion was consistently non-mutagenic.

         The Meeting noted that most but not all of the required or
    replacement studies have been submitted. Owing to the controversial
    results of the neurotoxicity study in hens and the absence of the
    required short-term study in dogs, the Joint Meeting maintained a
    temporary ADI, although at a higher level.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Mouse:    81 ppm in the diet, equal to 1.3 mg/kg b.w./day in
                   males and 1.5 mg/kg b.w./day in females.

         Rat:      25 ppm in the diet, equal to 1.2 mg/kg b.w./day.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.006 mg/kg b.w.

    FURTHER WORK OR INFORMATION

    STUDIES WITHOUT WHICH THE DETERMINATION OF A FULL ADI IS
    IMPRACTICABLE, TO BE SUBMITTED TO WHO BY 1988:

         1.   A short-term toxicity study in dogs.
         2.   An additional delayed neurotoxicity study in hens.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND:

         Observations in man.

    REFERENCES

    Bodden, R.M. & Zietlow, D.C. Poultry metabolism study on ethion.
    1985      Unpublished report No. 6124-103 from Hazleton Laboratories
              America Inc., Madison, WI, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.

    Bosh, A. Metabolism study of 14C-labelled ethion in lactating goats.
    1985      Amendment No. 1. Unpublished report No. 6124-104 from
              Hazleton Laboratories America Inc., Madison, WI, USA.
              Submitted to WHO by FMC Corporation, Princeton, NJ, USA.

    Davidson, T.J., Thompson, S.W., & Becci, P.J. Delayed neurotoxic
    1982      evaluation of ethion technical in adult leghorn hens.
              Unpublished report No. 7141 from FDRL Laboratories, Inc.
              Submitted to WHO by FMC Corporation, Princeton, NJ, USA.

    Haworth, S.R., Wagner, V.O., & Coyle, L.M. Salmonella/mammalian -
    1984      microsome plate incorporation mutagenicity assay (Ames
              test). Unpublished report No. T2266.501 from Microbiological
              Associates, Bethesda, MD, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.

    Hoberman, A.M., Christian, M.S., & Christian, G.D. Teratogenic
    1983      potential of ethion technical in pregnant Crl:COBS CD(SD)BR
              Charles River rats. Unpublished report No. 106-001 from
              Argus Research Laboratories Inc., Horsham, PA, USA.
              Submitted to WHO by FMC Corporation, Princeton, NJ, USA.

    Jobsis, C.T. & Zietlow, D.C. Metabolism study of 14C-labelled ethion
    1985      in lactating goats. Unpublished report No. 6124-104 from
              Hazleton Laboratories America Inc., Madison, WI, USA.
              Submitted to WHO by FMC Corporation, Princeton, NJ, USA.

    Morrow, L.D. Lifespan oncogenicity study in mice utilizing ethion
    1985      technical. Unpublished report No. 410-0867 from American
              Biogenics Corporation, Decatur, IL, USA. Submitted to WHO by
              FMC Corporation, Princeton, NJ, USA.

    Morrow, L.D. & Mayhew, D.A. Twenty-four month combined chronic oral
    1985      toxicity and oncogenicity study in rats utilising ethion
              technical. Unpublished report No. 410-0866 from American
              Biogenics Corporation, Decatur, IL, USA. Submitted to WHO by
              FMC Corporation, Princeton, NJ, USA.

    Putman, D.L. & Melhorn, J.M. Subchronic in vivo cytogenetics assay
    1984      in male rats. Unpublished report No. T2266.102 from
              Microbiological Associates, Bethesda, MD, USA. Submitted to
              WHO by FMC Corporation, Princeton, NJ, USA.

    Salamon, C.M., Enloe, P.V., & Mayhew, D.A. Three-generation
    1985      reproduction study in albino rats with ethion technical.
              Unpublished report No. 450-0868 from American Biogenics
              Corporation, Decatur, IL, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.

    Selim, S. Absorption, distribution and excretion studies of ethion in
    1985a     the rat. Unpublished report No. PC-0031 from Biological Test
              Center, Irvine, CA, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.

    Selim, S. Rat blood kinetics of ethion following a single oral dose.
    1985b     Unpublished report No. PC-0036 from Biological Test Center,
              Irvine, CA, USA. Submitted to WHO by FMC Corporation,
              Princeton, NJ, USA.

    Selim, S. Interim report: analysis of metabolites in urine of rats
    1985c     dosed with ethion. Unpublished report No. PC-0035 from
              Biological Test Center, Irvine, CA, USA. Submitted to WHO by
              FMC Corporation, Princeton, NJ, USA.

    Thilagar, A., Pant, K.J., & Brauniger, R.M. Unscheduled DNA synthesis
    1984a     in rat hepatocytes. Unpublished report No. T2266.380 from
              Microbiological Associates, Bethesda, MD, USA. Submitted to
              WHO by FMC Corporation, Princeton, NJ, USA.

    Thilagar, A., Brauniger, R., & Kott, S. CHO/HGPRT mutation assay in
    1984b     the presence and absence of exogenous metabolic activation.
              Unpublished report No. T2266.332 from Microbiological
              Associates Inc., Bethesda, MD, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.

    Zietlow, D.C. Poultry metabolism study on ethion - Amendment No. 1.
    1985      Unpublished report No. 6124-103 from Hazleton Laboratories
              America Inc., Madison, WI, USA. Submitted to WHO by FMC
              Corporation, Princeton, NJ, USA.
    


    See Also:
       Toxicological Abbreviations
       Ethion (ICSC)
       Ethion (FAO/PL:1968/M/9/1)
       Ethion (FAO/PL:1969/M/17/1)
       Ethion (AGP:1970/M/12/1)
       Ethion (WHO Pesticide Residues Series 2)
       Ethion (WHO Pesticide Residues Series 5)
       Ethion (Pesticide residues in food: 1982 evaluations)
       Ethion (Pesticide residues in food: 1983 evaluations)
       Ethion (Pesticide residues in food: 1990 evaluations Toxicology)