Acephate was evaluated for acceptable daily intake by the Joint
    Meeting in 1976 (Annex, 1, FAO/WHO, 1977a) at which time an ADI of
    0-0.02 mg/kg b.w. was allocated. A toxicological monograph was
    published after that Meeting (Annex 1, FAO/WHO, 1977b). The ADI was
    based on no-effect levels taken from studies performed by Industrial
    Bio-Test Laboratories (IBT), most of which were later found to be
    invalid. Further data were evaluated in 1982, when a temporary ADI of
    0-0.003 mg/kg bw was allocated (Annex 1, FAO/WHO, 1983a). The
    temporary ADI was extended at a level of 0-0.0005 mg/kg bw in 1984
    (Annex 1, FAO/WHO, 1985b). Monograph addenda were published after the
    1982 and 1984 Meetings (Annex 1, FAO/WHO, 1983b and 1985c).

         Multigeneration reproduction and delayed neurotoxicity studies
    were required by 1987. These and a lifetime carcinogenicity study in
    mice were submitted for consideration by the present Meeting and are
    summarized in this monograph addendum.



    Toxicological Studies

    Special study on carcinogenicity

         Groups of Charles River CD-1 mice were fed acephate technical in
    the diet at levels of 0, 50, 250, or 1000 ppm for 104 weeks.
    Seventy-five males (22-26 gm) and 75 females (18-22 gm) comprised each
    group. Replacement groups were maintained for a period of 4 weeks,
    from which one male mouse was taken for use in the control group
    (previous animal missing) and one high-dose female mouse was used to
    replace an animal that was sacrificed  in extremis. A 1-year interim
    sacrifice of 10 mice/sex/group was made. The animals were maintained
    under standard laboratory conditions with regular water and dietary
    analyses. Test diets were prepared weekly.

         The mice were observed three times each weekday and twice daily
    on weekends and holidays. Individual weights and food consumption were
    measured weekly for the first 8 weeks of the study and monthly
    thereafter. Orbital venous blood was examined at termination for
    standard hematological variables in 19 mice/group/sex. At the end of
    the interim period and at termination of the study, animals were
    killed by carbon dioxide asphyxia. Post-mortem examinations were made
    and standard blocks examined.

         There was a treatment-related effect on body weight. Similar
    values for body weight were obtained for controls and the 50 ppm
    group, but animals in the mid- and high-dose groups showed decreased
    body-weight gain. In the mid-dose group this effect was apparent from
    13 weeks from the beginning of treatment in males and from 39 weeks in
    females. The effect was found in both sexes from 4 weeks after the
    beginning of treatment in the high-dose group, where the decrease in
    body weight compared to controls was most marked. Examination of food
    consumption data showed modest and marked reductions in intake in the
    250 and 1000 ppm groups, respectively.

         Mortality in treated and control groups was comparable. Although
    the hematological data are incomplete, no changes that might be
    attributable to treatment were found.

         At both the 12-month interim sacrifice and at terminal sacrifice
    significant effects were observed in the lungs. Lung changes consisted
    of clusters of pigmented macrophages, often associated with
    eosinophilic crystalloid bodies, alveolar hyalinosis, and acute
    rhinitis. This was clearly a compound-related effect, but it appears
    to have been due to resolution of lung infections; further examination
    showed the pigmented material in the macrophages to be hemosiderosis.

         A major significant finding in this study was an increase in
    treatment-related hyperplastic and neoplastic lesions in the liver in
    the high dose females. Twelve hepatocellular carcinomas, 3
    hepatocellular adenomas and 17 hyperplastic nodules were observed
    compared to 1, 0 and 2 in the control group, respectively.

         These figures represent cumulative values from all animals dying
    or sacrificed during the study, and killed at terminal sacrifice. From
    individual records it appears that some of these lesions are

         The liver changes observed in this study occurred in a
    dose-related manner and were maximal at doses that were clearly toxic.
    An increase in liver to body-weight ratio also occurred that was
    statistically significant in high-dose females. Hepatocyte hypertrophy
    in response to enzyme induction with subsequent hyperplasia, adenoma
    formation, and in some instances, to carcinoma, is not remarkable and
    is of doubtful prognostic significance for man.

         There was an increased incidence of splenic hemangiomas and
    hemangiosarcomas in this study (0-1 in controls, a maximum of 3
    hemangiomas in males at 1000 ppm).

         If the compound induced these tumors, induction was limited to
    the 1000 ppm dose-level, which is a toxic dose. Hence, this apparent
    increase may be the result of excessively high dosing, and, therefore,
    of minimal concern, a point reinforced by consideration of historical
    control data for the CDI mouse.

         The NOAEL in this study was determined to be 250 ppm (Spicer,

    Special study on Reproduction

         Acephate technical (98.7% purity) was administered in the feed to
    Crl:COBS 'CD' (SD) BR male and female rats at levels of 0, 25, 50 or
    500 ppm. Rats in each group of the first (F0), second (F1b), and third
    (F2b) generations initially consisted of 30 males and 30 females. Each
    rat was observed at least twice daily for evidence of clinical effects
    and was weighed at least once weekly.

         Animals in the first generation were given the test compound from
    the age of approximately 6 weeks for 10 weeks (75 days) prior to a
    three-week cohabitation period and throughout two subsequent gestation
    and lactation periods, until terminal sacrifice. Necropsies were
    performed on all control and high-dose animals in the F0, F1b, and F2b

         Food consumption data showed that females consumed more test
    material on a mg/kg bw basis than males in each generation. Both sexes
    ate more during the first week of the study than later, with a gradual
    decrease during the cohabitation period. In agreement with apparent
    nutritional needs, mg/kg bw/day intakes of acephate by the females
    were generally higher during pregnancy and lactation than during the
    last week of the cohabitation period.

         No deaths occurred in F0 animals. The only clinical effect noted
    was a localized alopecia in male rats. Average body weight and
    body-weight gain were comparable in the 10-week premating period,
    although some decrease in gain was seen in the highest-dose females at
    week 10. During the F1a gestation and lactation periods, these
    variables were not affected by the test diet. However, during the F1b
    gestation period the 500 ppm dosage appeared to reduce body weight and
    body-weight gain in pregnancy and, to a lesser extent, in early

         The administration of the test compound had no effect on mating
    index, fertility index (the percentage of mated rats which were
    pregnant), or gestation index (the percentage of pregnancies resulting
    in litters) in F0 or F1a litters, nor was the duration of gestation
    affected. At 500 ppm acephate, a decrease in the number of liveborn
    pups in the second litter was observed, which was possibly related to
    maternal effects (decreased ovulation and increased resorption)
    following the high food intake in the previous lactation period. The
    only change noted in the pups was a small reduction in body weight
    evident on days 14 and 21 post-partum due to supplementation of milk
    by the diet, which was accessible to the pups as they developed.

         Pregnancy rates (females pregnant/females mated) during the
    second F1b and F2b cohabitation periods were low for all groups,
    including the controls. The pregnancy rates during the first (F2a)
    cohabitation period was reduced in a non-significant manner in treated
    animals. Significantly fewer pups were delivered by the high-dose
    females and fewer pups were alive on day 4 post-parturition in litters
    from the high-dose F2a and F2b females.

         The histopathological data in this study produced no significant

         The NOAEL in this study was determined to be 50 ppm (Christian &
    Hoberman, 1986, 1987).

    Special study in Delayed Neurotoxicity

         Acephate technical (98.8% purity) was administered to a total of
    16 white Leghorn hens (48 weeks of age weighing 1162-1857 gms) by
    canula into the crop or proventriculus at 758 mg/kg bw which was the
    oral LD50 determined in aprevious study. Eight hens given distilled
    water only were used as controls; 600 mg/kg bw tri-o-tolyl phosphate
    was administered as a positive control to 6 hens. All birds were
    fasted for at least 15 hrs prior to dosing.

         After 21 days, birds in the treatment and negative control groups
    were redosed and observed for a further 21 days. Birds treated with
    tri-o-tolyl phosphate were killed at 21 days.

         Locomotor impairment was assessed twice weekly. Hens were dropped
    from a height of approximately 1 meter in order to evaluate landing
    ability. They were then made to walk about 8 mters and to hop onto a
    surface raised 10 cm above the floor, followed by a further hop of the
    same height. The brids were scored on an "ataxia" points system.

         There was no mortality, and no abnormalities of mobility were
    seen in the negative controls. The positive control birds had
    diarrhoea during the first day and ataxia appeared in three birds at
    day 14. Neurotoxicity was more evident from days 14 to 21, when 2 hens
    showed loss of coordination; 3 showed this change together with limb
    weakness and 1 was severly incapacitiated. In the treated group, 4
    hens died between 4 and 7 days after dosing and 5 died 3 or 4 days
    after the second dose. Symptoms of acute poisoning (diarrhoea and
    relative immobility) were noted but at no time was there evidence of
    neurotoxicity as assessed clinically.

         Histopathological assessment of the brain, sciatic nerve, and
    upper cervical, mid-thoracic, and lumbosacral sections of the spinal
    cord in acephate-treated animals showed no significant changes.
    Positive controls showed clinical and pathological changes typical of
    delayed neurotoxicity (Beavers & Jaber, 1985).


         A satisfactory multigeneration study in rats was reported in 1987
    with a no effect level of 50 ppm (2.5 mg/kg bw/day). A satisfactory
    delayed neurotoxicity study in Leghorn hens was negative at 785 mg/kg
    bw/day. A mouse life-time carcinogenicity study showed a significant
    increase in liver tumors at the highest dose in females with a
    no-effect level of 36 mg/kg bw/day. An apparent increase in splenic
    hemangioma/hemagiosarcoma was no considered significant when
    historical control data were considered.



          Mouse:   250 ppm in the diet, equal to 36 mg/kg bw/day
          Rat:     5 ppm in the diet, equivalent to 0.25 mg/kg bw/day
          Dog      30 ppm in the diet, equivalent to 0.75 mg/kg bw/day


         0-0.003 mg/kg bw.


         Observations in man.


    Beavers, J.B. & Jaber, M., 1985. Acute delayed neurtoxic study in
    chikens with Chevron acephate technical. Unpublished final report,
    from Wildlife International Ltd., St. Michaels, MD, USA. Submitted to
    WHO by the Chevron Chemical Company, Richmond, CA, USA.

    Christian, M.S. & Hoberman, A.M., 1986. Two generation (two litter)
    reproduction study in rats with Chevron acephate technical (Chevron
    Protocol S-2497). Unpublished interim report from Argus Research
    Laboratories Inc., Horsham, PA, USA. Submitted to WHO by the Chevron
    Chemical Company, Richmond, CA, USA.

    Christian, M.S. & Hoberman, A.M., 1987. Two generation (two litter)
    reproduction study in rats with Chevron acephate technical (Chevron
    Protocol S-2497). Unpublished final report from Argus Research
    Laboratories Inc., Horsham, PA, USA. Submitted to WHO by the Chevron
    Chemical Company, Richmond, CA, USA.

    Spicer, E.J.F., 1982. Lifetime oral carcinogenicity study in mice,
    ORTHENE Technical (RE-12420). Unpublished report No. 415-006 from
    International Research and Development Corporation, Mattawan, MI, USA.
    Submitted to WHO by the Chevron Chemical Company, Richmond, CA, USA.

    See Also:
       Toxicological Abbreviations
       Acephate (ICSC)
       Acephate (Pesticide residues in food: 1976 evaluations)
       Acephate (Pesticide residues in food: 1979 evaluations)
       Acephate (Pesticide residues in food: 1981 evaluations)
       Acephate (Pesticide residues in food: 1982 evaluations)
       Acephate (Pesticide residues in food: 1984 evaluations)
       Acephate (Pesticide residues in food: 1984 evaluations)
       Acephate (Pesticide residues in food: 1988 evaluations Part II Toxicology)
       Acephate (Pesticide residues in food: 1990 evaluations Toxicology)
       Acephate (JMPR Evaluations 2002 Part II Toxicological)
       Acephate (JMPR Evaluations 2005 Part II Toxicological)