ACEPHATE
EXPLANATION
Acephate was evaluated for acceptable daily intake by the Joint
Meeting in 1976 when an ADI of 0-0.2 mg/kg bw was allocated (Annex I,
FAO/WHO, 1977b). The ADI was derived from no-effect levels based on
studies performed by Industrial Bio-Test Laboratories (IBT). Further
data were evaluated in 1982, when a temporary ADI of 0-0.003 mg/kg bw
was allocated (Annex I, FAO/WHO, 1983a). The temporary ADI was reduced
to 0-0.0005 mg/kg bw in 1984 (Annex I, FAO/WHO, 1985c) in view of the
inadequacy of the multigeneration study and the lack of a delayed
neurotoxicity study. An ADI at the level of 0-0.003 mg/kg bw was
allocated in 1987 when multigeneration reproduction, delayed
neurotoxicity and lifetime carcinogenicity studies were submitted for
evaluation by the Joint Meeting (Annex I, FAO/WHO, 1988b). Since a
cholinesterase study in human volunteers by IBT has been validated
(Cavalli, 1978), it was reconsidered. Statistical analysis of
in vitro cholinesterase inhibition data, which were previously
reviewed by the Joint Meeting in 1984 (Annex I, FAO/WHO, 1985c), has
also been reconsidered.
EVALUATION FOR ACCEPTABLE INTAKE
BIOCHEMICAL ASPECTS
Effects on enzymes
Regression analysis of in vitro data on inhibitory activity of
acephate technical on brain and red blood cell (RBC) acetyl-
cholinesterase (ACHE) and plasma cholinesterase (ChE) from rat, monkey
and human tissues was performed. Calculated I50 are reported in
Table 1 (Griffis, 1988).
Table 1. I50 values (37°C, 60', pH 8.0) for acephate techmical
I50 (mM)
(95% confidence limits)
Brain RBC AChE Plasma
rat 1.25-1.72 1.04-1.47 2.84-5.22
monkey 2.78-3.38 1.90-3.17 1.43-2.49
human 3.88-5.22 2.41-2.87 1.56-1.76
BIOLOGICAL DATA
Special study on delayed neurotoxicity
In two experiments, groups of 6 adult hens were given by gavage
200 or 700 mg/kg bw acephate technical (98% purity). In each
experiment a group of 3 hens received DFP (0.200 mg/kg bw i.m.). The
control animals received only water. Twenty-four hours after dosing,
brain neuropathy target esterase (NTE) and AChE of survivors were
measured. Results are summarized in Table 2 (Wilson, 1988).
Table 2. Hen brain NTE and AChE activities 21 hours after treatment
Compound Dose % control
(no.) NTE AChE
acephate 200 mg/kg (5) 74 18
acephate 700 mg/kg (3) 55 12
DFP 0.2 mg/kg (3+3) 43-46 33-41
Toxicological studies
Observations in humans
Combinations of acephate and methamidophos were orally
administered to human volunteers. They received either a combination
(methamidophos/acephate) of 1:9 or 1:4 daily (divided in three equal
doses). Controls (two males and two females) received corn oil. The
1:9 group (three males and three females) was administered the
combination for consecutive periods of 21 days at grading doses of
0.1, 0.2 and 0.3 mg/kg bw/day followed by a 7-day recovery period
after which the dose was increased to 0.4 mg/kg bw/day (females only)
for 10 days. The 1:4 group (two males and two females) received the
combination at doses of 0.1 and 0.2 mg/kg bw/day for 21 consecutive
days. No effect was noted on RBC cholinesterase at any dose. In the
1:9 group, plasma cholinesterase activity was affected at the
0.3 mg/kg dose in males and only slightly at the 0.4 mg/kg dose in
females. In the 1:4 group, both males and females showed decreased
plasma cholinesterase at the 0.2 mg/kg dose level.
The NOAEL in this study was determined to be 0.3 mg/kg bw of
acephate in combination with 0.03 mg/kg bw of methamidophos or
0.2 mg/kg bw of acephate in combination with 0.04 mg/kg bw of
methamidophos (Garofalo, 1973).
The validated raw data support the above conclusions regarding
cholinesterase activities. The dosing is also supported by analysis of
samples of blood and urine of the study subjects. No information was
available to support the claim of no clinical effects at any of the
administered doses (Cavalli, 1978).
COMMENTS
Acephate was evaluated for acceptable daily intake by the Joint
Meeting in 1976 when an ADI of 0-0.02 mg/kg was allocated. The ADI was
obtained on no-effect levels based on studies performed by Industrial
Bio-Test Laboratories (IBT), most of which were later considered to be
invalid. An ADI at the level of 0-0.003 mg/kg bw was allocated in 1987
when multigeneration reproduction, delayed neurotoxicity and lifetime
carcinogenicity studies were submitted for evaluation by the Joint
Meeting.
In vitro data showed minimal differences in the sensitivity of
rat, monkey and human plasma cholinesterase and erythrocyte and brain
acetylcholinesterase to inhibition by acephate.
A study in humans demonstrated no effect on erythrocyte
acetylcholinesterase at any of the dose levels used (up to
0.3 mg/kg bw in combination with 0.03 mg/kg methamidophos or
0.2 mg/kg bw in combination with 0.04 mg/kg bw methamidophos).
Acephate caused inhibition of brain neuropathy target esterase in
hens at a dose lower than the LD50. The Meeting was therefore aware
of the possibility that in extreme conditions of exposure, which are
unlikely to occur in food, acephate may have the potential of causing
delayed polyneuropathy.
The Meeting was also aware that methamidophos is found as a
residue in crops treated with acephate.
On the basis of the rat NOAEL (brain acetylcholinesterase), the
rabbit NOAEL for teratogenicity, and the human volunteer study, the
Meeting agreed to establish an ADI at a higher level.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXOLOGICAL EFFECT
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
Rabbit: 3 mg/kg bw/day
Man: 0.3 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.03 mg/kg bw
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
Further observations in man.
REFERENCES
Cavalli, R.D. 1978. Data validation Industrial Bio-Test report
no. 636-02498. A study on the effects of orthene and monitor on plasma
and erythrocyte cholinesterase activity in human subjects during
subacute oral administration. Submitted to WHO by Chevron Chemical
Company, Richmond, CA, USA (Unpublished).
Garofalo, M. 1973. A study on the effects of orthene and monitor on
plasma and erythrocyte cholinesterase activity in human subjects
during subacute oral administration. Industrial Bio-Test Laboratories,
Inc. report no. 636-02498. Submitted to WHO by Chevron Chemical
Company, Richmond, Ca, USA (Unpublished) (Validated by EPA, USA).
Griffis, L.C. 1988. Statistical analysis of acephate in vitro
cholinesterase inhibition data. Chevron Environmental Health Center,
Inc. Submitted to WHO by Chevron Chemical Company, Richmond, CA, USA
(Unpublished).
Wilson, B.W. 1988. Cholinesterase and neurotoxic esterase studies in
chickens with Chevron Acephate technical. Preliminary Report submitted
to WHO by Chevron Chemical Company, Richmond, CA, USA (Unpublished).
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: 1987 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)