CHINOMETHIONAT JMPR 1974
Explanation
Chinomethionat was reviewed by The 1968 Meeting (FAO/ WHO,1969)
under the name of oxythioquinox. An ADI was not allocated because of
the occurrence of liver hypertrophy at 10 mg/kg, the lowest dose
studied, in a long-term rat study. Further information was required on
metabolism and excretion, anti-spermatogenic effects, use patterns and
resultant residues, the nature of terminal residues, the levels of
residues in raw agricultural products moving in commerce and residue
levels in the total diet. Two year studies on rats at lower dosage and
a comparative evaluation of methods of analysis for regulatory
purposes were also required. Further studies on cutaneous toxicity,
including studies on photo sensitization, were regarded as desirable.
Further information has become available and is summarized and
discussed in the following monograph addendum.
IDENTITY
The common name originally recommended by B.S.I., oxythioquinox,
was withdrawn because it was not acceptable internationally. The
B.S.I. common name is now quinomethionate, the English equivalent of
the German chinomethionat.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Effects on enzymes and other biochemical parameters
Various enzymes found in intermediary metabolism of carbohydrates
were studied with regard to the inhibitory properties of
chinomethionat and its dithiol metabolite. Inhibition of sulfhydryl
enzymes including pyruvic dehydrogenase, succinic dehydrogenase,
malate dehydrogenase and alphaketoglutarate oxidase was observed.
Reduction of nitroreductase and reduced glutathione in the liver was
also observed. In vivo, its dithiol metabolite inhibited the same
systems. These observations indicated that inhibition of sulfhydryl
enzymes might be responsible for the toxicity in mammals (Carlson and
DuBois, 1970).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Rat
Groups of rats (25 males and 25 females per group) were fed
chinomethionat in the diet at a level equivalent to 100 mg/kg. The
animals were dosed 5 days per week for the first year, and 7 days per
week for the next 250 days. After 660 test days, it was calculated
that the animals had consumed a total of 16.7 mg/kg body weight. A
control group was administered saline solution subcutaneously at
weekly intervals. There was no effect on behaviour. The average
survival time was somewhat longer in the treated rats. In the treated
group, 11 animals died of malignant tumours with 13 deaths recorded
for controls. There was no apparent difference in the control and
treated group with regard to tumours in the survivors. There was a
high percentage of malignant and benign tumours in all groups
attributable to the long survival time observed in this study. There
was a suggestion of possible cirrhosis of the liver induced by
chinomethionat, possibly as a result of the high dose exhibiting a
certain degree of liver toxicity. Three adenomas of the thyroid were
observed (Steinhoff, 1970).
Special studies on mutagenicity
Mouse
Groups of male mice (12 mice per group) were administered
chinomethionat by single intraperitoneal injection at doses of 0, 50
and 100 mg/kg and mated with 3 virgin females at weekly intervals in a
standard dominant lethal test (Arnold, 1970). A reference material,
methyl methanesulfonate, was included in the study as a positive
control. The mating indices were slightly lower in the high dosed
group. In this study, chinomethionat was not mutagenic.
Special studies on spermatogenesis
Dog
Groups of dogs (2 males per group) were fed chinomethionat in the
diet for 90 days at levels of 0, 60, 150 and 500 mg/kg. There were no
effects at any dose on sperm count, sperm viability or number and
survival of progeny. At 500 mg/kg histological examination revealed a
mild reduction of germinal epithelium (Mastalski, 1971).
Special studies on teratogenicity
Rat
Groups of female rats were fed chinomethionat in the diet during
gestation from insemination to day 20 at dosage levels of 0 (11 rats),
100 (9 rats), 250 (11 rats) and 750 mg/kg (9 rats). At 750 mg/kg
embryo toxicity was observed with 8 of 9 litters. Although the dose
reduced growth of dams, no effect was noted on fetuses. No
malformations were noted in this experiment (Lorke, 1970).
Acute Toxicity
TABLE 1. Acute toxicity of chinomethionat
LD50
Species Sex Route (mg/kg) References
Rat M (adult) ip 95 Carlson and DuBois, 1970
M (weanling) ip 320 Carlson and DuBois, 1970
F (adult) ip 192 Carlson and DuBois, 1970
F (weanling) ip 325 Carlson and DuBois, 1970
F (oil) oral 1800 Steinhoff, 1970
F (saline) oral 4800 Steinhoff, 1970
F (oil) sc 3200 Steinhoff, 1970
F (saline) sc >6000 Steinhoff, 1970
Mouse Male ip 473 Carlson and DuBois, 1970
Female ip 458 Carlson and DuBois, 1970
TABLE 2. Acute toxicity of metabolite (6 methyl-2,3
quino-oxalinedithiol
LD50
Species Sex Route (mg/kg) References
Rat M (adult ip 38 Carlson and DuBois, 1970
M (weanling) ip 115 Carlson and DuBois, 1970
F (adult) ip 86 Carlson and DuBois, 1970
F (weanling) ip 124 Carlson and DuBois, 1970
Mouse M (adult) ip 249 Carlson and DuBois, 1970
F (adult) ip 263 Carlson and DuBois, 1970
In rats, marked diarrhoea and decreased activity were prominent
following acute poisoning. In addition, decreased blood pressure and
urine output were noted, perhaps as a result of water loss from
diarrhoea.
A slight protection against acute effects of chinomethionat was
noted with glutathione and cysteine but not with BAL (Carlson and
DuBois, 1970). The interaction with these agents provides some support
for the hypothesis that chinomethionat and its metabolite react with
sulfhydryl groups of cell constituents.
Short-term studies
Rat
Groups of 5 female rats were administered chinomethionat by
intraperitoneal injection of various daily dose levels. A daily dose
of 25 mg/kg was tolerated over the 60 day period suggesting a high
cumulative toxicity (Carlson and DuBois, 1970).
Groups of male rats (5 rats/group) were fed chinomethionat in the
diet at levels of 0, 10, 25, 60, 150, and 500 mg/kg for 90 days. At
500 mg/kg, a decreased growth rate was observed accompanied by an
enlarged liver, decreased microsomal enzyme activity and decreased
acetoacetate synthesis. This latter biochemical alteration was also
noted at 150 mg/kg. The enlarged liver was normal in histological
examination. Lipid content, DNA, protein and water content were not
affected. Analysis of the liver for chinomethionat indicated no
significant build-up or storage (Carlson and DuBois, 1970).
Long-term studies
Rat
Groups of rats (30 male and 30 female rats/group, the control
group contained 60 males and 60 females) were fed chinomethionat in
the diet at concentrations of 0, 3, 6 and 12 mg/kg for two years
(Loser, 1971). No effects were noted on growth, behaviour, food
consumption, clinical chemistry values, haematology, serum enzymes,
parameters related to liver functions, urine analyses, blood sugar and
cholesterol or on gross and microscopic analysis of tissues and organs
(Cherry et al., 1972). The incidence and distribution of tumours did
not indicate a potential carcinogenic action. A no-effect level in
this study was 12 mg/kg.
COMMENTS
Biochemical studies in 90-day feeding experiments with
chinomethionat in rats indicated relatively specific inhibition of
sulfhydryl enzymes, probably after its metabolic conversion to
6-methyl-2,3-quino-oxalinedithiol. At high dosages microsomal enzyme
activities were reduced and the livers were enlarged but no
histopathological changes were observed. No effects were noted on
parameters related to spermatogenesis in 90-day feeding studies in
dogs at 150 ppm or less, and only at the dietary level of 500 ppm was
there a small reduction of germinal epithelium. The results of
dominant lethal test for mutagenesis in mice and tests for teratogenic
action in rats were negative. The results of a long-term study
conducted over the life-time of rats indicated a similar incidence of
tumours in chinomethionat-fed rats and concurrent controls, however, a
severe hepatic cirrhosis was observed in an unspecified number of
treated animals. This study was conducted on SPF Wistar rats that have
a relatively high incidence of tumours which appeared late in the
life-span (1 000 days) of both treated and controls. The Meeting felt
that the report of these experiments was deficient, thus making
difficult a proper evaluation. However, a two-year feeding study in
rats showed that 12 ppm was a no-effect level as indicated by
extensive haematological, clinical chemistry and histopathology
examinations. No evidence of tumourigenesis was observed in this
study.
On the basis of the additional information available, the Meeting
allocated a temporary ADI.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Rat: 12 ppm in the diet, equivalent to 0.6 mg/kg bw.
ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.003 mg/kg bw.
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
Chinomethionat is generally used as a wettable powder at a
concentration of 0.03 - 0.1%.
The uses for additional crops proposed since the previous
evaluation (FAO/WHO, 1969) are summarized in Table 3. All applications
are foliar sprays before or during bloom for almonds and post-bloom
for avocados, macadamia nuts, citrus and papayas in sufficient
quantity to give full coverage.
TABLE 3. Summary of uses of chinomethionat proposed for
additional crops since 1968
Spray Volume
concentration, of spray, Number of
Crop % a.i. l/ha applications
Almonds 0.06 935-3740 1
Avocados 0.03 8100-8530 1
Macadamia 0.03-0.06 935-3740 3
nuts
Papayas 0.03-0.06 935 1
Citrus 0.045 935-9350 2
Data were provided on registered uses from Hungary, the
Netherlands and New Zealand. They are summarized in Table 4.
RESIDUES RESULTING FROM SUPERVISED TRIALS
Supervised trials were carried out on almonds (California, USA),
apples (Federal Republic of Germany, the Netherlands), avocados
(Florida, USA), barley (F.R.G.), cucumbers (the Netherlands, New
Zealand), currants, gooseberries (F.R.G.), grapes (New Zealand,
Missouri USA), grapefruit, oranges (Florida USA), limes (California,
USA), macadamia nuts, papayas (Hawaii, USA), rye (F.R.G.), tangerines
(Arizona, USA), tea (India), wheat (F.R.G.). The results of these
trials are summarized in Table 5. The data are from reports by Buyer
(1968-1972), Bevenue (1968a), Chemagro (1964-1968; 1969a, b; 1970) and
Post (1969).
The residues were generally low in flesh, kernels and pulps
(<0.1 mg/kg) and concentrated mainly in the hulls, peels and skins of
the various commodities. In apples, residues up to 0.5 mg/kg were
found in occasional individual samples 11 days after treatment. The
highest residue found in citrus fruit after 7-10 weeks was 0.9 mg/kg,
but this would presumably be largely in the peel (see "Fate of
residues in processing"). Residues in whole Papayas up to 3 mg/kg were
found after 7 days, but again most of the residue was in the peel.
Residues in the pulp one day after treatment were below 0.1 mg/kg.
TABLE 4a. Residues of chinomethionat resulting from supervised trials (at intervals up to 7 days)
Application
Rate Number Residues, mg/kg range, of chinomethionat at interval,
a.i., % of days, after last treatment*
Crop or g/ha l/ha No. Samples 0-1 2-4 5-6 7
Apples1 0.01% 1300 13 2-4 0.004-0.02 0.07-0.08 0.04-0.06 0.02-0.05
(0.01) (0.08) (0.05) (0.04)
Apples2 0.075% 200 1 - 0.07-0.3 0.09-0.2 0.05-0.2 -
Apples2 0.075% 200 4 - 0.1-0.3 0.02-0.13 - 0.05-0.13
Apples2 0.075% 200 4 - 0.05-0.08 0.02-0.04 0.07-0.23 -
Apples2 0.013% 1200 3 - n.d.-0.06 n.d.-0.05 - n.d.-0.05
Apples2 0.125% 200 1 - 0.3-0.9 0.06-0.3 0.04-0.06 -
Citrus3 0.045% - - 20 - - - 0.1-2
fruits
Cucumbers2 0.0075% - Each - 0.01-0.03 - - -
Week
Cucumbers2 0.0075% - Each 2 - 0.02-0.03 - - -
Weeks
Cucumbers2 0.0075% - 5 - n.d. - - -
Cucumbers4 8g/1000
skin plants - - - (0.12) (0.08)-(0.12) - (0.10)
pulp - - - (0.05) (0.05) - (0.05)
Currants (black, 0.0075% 1000 3 - 0.1-0.25 - - 0.02 (0.02)
red or white) (0.13)
Gherkins 0.0075% - 3 - 0.02 - 0.02 -
TABLE 4a. (Cont'd.)
Application
Rate Number Residues, mg/kg range, of chinomethionat at interval,
a.i., % of days, after last treatment*
Crop or g/ha l/ha No. Samples 0-1 2-4 5-6 7
Gooseberries 0.0075% 1000 3 2 (0.05) - - (0.02)
Grapes4 0.012% 900 2 1 0.4 - - 0.07
Macadamia 0.22% 935-3740 3
nuts5
kernels 20 0.02 (0.02) - - -
shell 20 0.02 (0.02) - - -
husk 20 7-12 (9.5) - - -
Papayas6 0.06% 935 3
peel 21 6-23 (15) - - 4-14 (8)
pulp 21 0.05-0.08 - - -
whole fruit 21 0.8-3.2 0.8-3.1 0.7-2.8 0.5-2.3
(2.1) (1.6) (1.3) (1.2)
Papayas6 0.09% 935 3
peel 21 5-29 (17) - - 2.5-22 (9.2)
pulp 21 0.05-0.08 - - -
whole fruit 21 0-7-4.3 0.9-3.0 0.6-2.9 0-4-3.1
(2.6) (2.0) (1.7) (1.5)
Tea7 185-370 224-675 1-2 12 20-90 - 0.1-0.4 0.1-0.4
g/ha
* Mean value in brackets
1 Bayer, 1969
2 Netherlands, 1974
3 Chemagro, 1964-1968
4 New Zealand, 1974
5 Chemagro, 1970
6 Bevenue, 1968a
7 Bayer, 1970
TABLE 4b. Residues of chinomethionat resulting from supervised trials (at intervals up to 75 days)
Application
Rate Number Residues, mg/kg range, of chinomethionat at interval,
a.i., % of days, after last treatment*
Crop or g/ha l/ha No. Samples 9-11 14 20-21 29-35 49-75
Almonds1 0.06% 3700-4600 2
kernels 8 - - - 0.02-0.07 -
(0.04)
hulls 8 - - - 3.5-14 -
(7.7)
Almonds1 0.12% 3700-4600 1
kernels 8 - - 0.02-0.07 - -
(0.04)
hulls 8 - - 9-19 (13) - -
Apples2 0.01% 1300 13 2-4 0.008-0.02 0.003-0.007 - - -
(0.01) (0.004)
Apples3 0.075% 200 1 - 0.04-0.06 - 0.02-0.07 - -
Apples3 0.075% 200 4 - 0.01-0.1 - 0.01-0.06 0.02-0.03 -
Apples3 0.075% 200 4 - n.d.-0.13 - - - -
Apples3 0.013% 1200 3 - 0.01-0.07 - n.d.-0.02 - -
Apples3 0.125% 200 1 - 0.2-0.5 - 0.03-0.1 0.01-0.03 -
Avocados4 0.045% 8100 3 3 - - - 0.03-0.09 0.01
whole fruit (0.06) (0.01)
Avocados4 0.09% 8530 3 3 - - - 0.06 0.05
whole fruit (0.06) (0.05)
Barley 100-125 - - 6 - - - - (0.1)
g/ha
TABLE 4b. (Cont'd.)
Application
Rate Number Residues, mg/kg range, of chinomethionat at interval,
a.i., % of days, after last treatment*
Crop or g/ha l/ha No. Samples 9-11 14 20-21 29-35 49-75
Citrus 0.045% - - 20 - 0.1-2 0.1-2 0.1-0.7 0.1-0.9
fruit6
Currants (black, 0.0075% 1000 3 - - n.d.-0.03 (0.02) - -
red or white) (0.02)
Gooseberries 0.0075% 1000 3 2 - (0.02) (0.02) - -
Grapes7 0.012% 900 2 1 - 0.02 0.004 - -
Rye8 100 g/ha - 1 1 - - - - n.d.10
Tea9 185-370 224-675 1-2 12 0.1-0.2 0.1 - - -
g/ha
Wheat8 100 g/ha - 1 1 - - - - 0.1
* Mean value in brackets
1 Chemagro, 1969a
2 Bayer, 1969
3 Netherlands, 1974
4 Chemagro, 1969b
5 Bayer, 1968
6 Chemagro, 1964-1968
7 New Zealand, 1974
8 Bayer, 1969
9 Bayer, 1970
10 101 days after treatment
TABLE 5. Effect of processing on chinomethionat resiclues in fruits
Application Days after Chinomethionat,
Fruit rate, % a.i. Process application mg/kg
Grapes 0.045 Fresh fruit (89% water) 0 7.1
Sun-dried 27 days (17%
water) 27 40
Grapes 0.045 Fresh fruit 0 2.0
Dried 150°F, 22 hours
(32% water). surface 1 1.3
Dried 150°F, 22 hours
(32% water). Internal 1 0.52
Grapes 0.045 Fresh fruit 0 0.55
80°C water dip, 5-20 sec.
Surface 1 0.31
80°C water dip, 5-20 sec.
Internal 1 0.16
Papayas1 0.06 Fresh whole fruit 0 3.6
1 7.7
3 4.0
5 3.5
7 3.7
Whole fruit puree 0 1.5
1 1.5
3 1.5
5 1.5
7 1.9
TABLE 5. (cont'd)
Application Days after Chinomethionat,
Fruit rate, % a.i. Process application mg/kg
Peeled fruit puree 0 0.2
1 0.24
3 0.25
Plums 0.03 Fresh fruit 40 0.14
Sun-dried 10 days, then
frozen (i.e. dried plums
or "prunes") 50 0.23
1 All residue values for papayas are means from two experiments.
FATE OF RESIDUES
In animals
To determine the total residue to be expected in animal tissues
and milk, dairy cattle were fed a diet containing 0.21 ppm
chinomethionat-2,3-14C for 25 days. Total carbon-14 residues were
<0.0006 mg/kg in milk and <0.01 mg/kg in meat, fat, liver, kidney,
heart and brain (Flint and Gronberg, 1970).
It was reported in the previous evaluation FAO/WHO, 1969 that
unidentified insoluble residues were found in apples and oranges.
Excretion studies have now been conducted to determine the biological
availability of the insoluble and soluble residues to animals. Apples
and oranges were treated on the tree with 14C-chinomethionat. The
fruit was picked and unchanged chinomethionat was extracted from the
surface. Peel from the fruit was fed to rabbits and dogs, either
directly or after extraction of the soluble residues. Measurement of
the radioactivity in the faeces showed that about 90% or more of the
insoluble residue had not been absorbed,(Everett and Shaw, 1968; Flint
and Gronberg, 1970). The biological availability of the soluble
activity was higher: soluble residues obtained from apple and orange
samples harvested 36 days after treatment contained available
radioactivity to the extent of about 40% and 25% respectively.
Goats were maintained for 30 days on a diet containing 50% of
dried orange pulp (Gronberg et al., 1973). The pulp was prepared
(Flint and Gronberg, 1973) by commercial procedures from oranges
treated on the tree with 14C-chinomethionat: it contained 3.8 mg/kg
total 14C residues of which 7% was unchanged chinomethionat. Total
14C residues in the tissues of the goats were 0.05 mg/kg in liver,
0.04 mg/kg in kidney, 0.004 mg/kg in milk, and less than 0.02 mg/kg in
meat, fat, skin, blood and brain.
In plants
The fate of chinomethionat-2,3-14C was investigated in
cucumbers, cucumber leaves and strawberries by Khasawinah (1970) and
in oranges by Flint and Gronberg (1973). A negligible amount of
radioactivity penetrated the fruit pulp of the cucumbers and oranges.
Most of the radioactivity in the treated leaves and peel was not
organo-extractable. The metabolic pattern was similar to that in
oranges and apples previously reported (FAO/WHO, 1969). The metabolite
2,3-dithiol-6-methyl-quinoxaline was identified. It was bound to
solids in cucumbers and was combined as three different water-soluble
conjugates with molecular weights of about 350 in cucumbers, cucumber
leaves and strawberries. The conjugates were not identified but were
probably sugars. Organo-soluble radioactivity accounted for only 9-10%
of the total recovered residue. The organo-soluble part of the
residues decreased while the insoluble part increased with time.
In soils
Laboratory studies using soil columns showed that chinomethionat
was strongly adsorbed by soils, particularly those with a high organic
matter content, and virtually none was leached with ten column void
volumes of water.
Residues in run-off water after application to soil plots or to
apple trees were not more than 1% of the applied material when
rainfall and irrigation amounted to a total of 2-6 inches during a
period of 2-4 weeks after the first treatment (Flint and Shaw, 1970).
Sandy and silt loam soils were treated with chinomethionat-14C
under laboratory conditions. The half-life of chinomethionat was 1-3
days. Loss of residue by volatilization was negligible (1.6% in silt
loam soil) during a 3-week period (Robinson and Flint, 1970).
Degradation was faster in non-sterile than in sterile soil, showing
the importance of microbial activity.
About half of the radioactivity was acetone-extractable after one
week and the organo-soluble metabolites appeared to be a mixture of
6-methyl-2,3-dithiolquinoxaline monomeric units, probably bound
together through disulphide linkages. The remaining radioactivity was
bound to the soil and could only be completely extracted by blending
with 0.1 N sodium hydroxide. Reduction of this alkali-extractable
residue followed by reaction with phosgene produced chinomethionat in
35-75% yield, indicating that at least part of the residue contained
the intact quinoxaline nucleus (Khasawinah, 1971).
Chinomethionat at a concentration of 24.3 kg/ha was incubated in
sandy and silt loam soils for 1 and 21 days prior to adding
glucose-14C. Microbial activity as measured by CO2 evolution was
unaffected in sandy or silt loam containing 1.4-1.8% organic matter,
but in a silt loam containing 4.6% organic matter, the rate of CO2
evolution was decreased to 42% and 65% of that in untreated soil for
1- and 21-day incubation periods respectively (Robinson and Flint
1970).
In water and under UV radiation
Breakdown in buffer solutions increased at higher pH values. At
30°C, the half-life decreased from 4 days at pH 5 to 1 day at pH7,
while the increase of the temperature to 50°C decreased the stability
at pH 5 by four- and at pH 7 by six-fold. In pond water outdoors at pH
7 and 32°C, the half-life was less than 4 hours (Flint and Shaw,
1970). Sunlight probably had an important effect since degradation of
chinomethionat in the presence of UV irradiation has been reported
(Gray et al., 1972). After 7.5 hours of radiation of oxythioquinox by
UV light at wavelengths above 280 nm at 25°C in benzene,
dimethylthieno [2,3-b : 4,5-b] diquinoxaline, dimethyl-p-dithiino
[2,3-b : 5,6-b] diquinoxaline, elemental sulphur and some minor
unidentified products were found in the reaction mixture.
In processing
Residues in dried fruit were determined after drying fresh grapes
and plums (Post, 1969; Olsen, 1970. See Table 6). When grapes were
washed in hot water for 5-10 seconds the residues decreased by 15%.
Residues in fresh grapes decreased by 10% after drying at 150°F for 22
hours: when allowance was made for the decreased water content, there
was a net loss of residue of 77% (Olson, 1970). Raisins prepared by
sun drying for 27 days contained residues at a level of about six
times that in the fresh grapes. There was a net loss of 25% of the
residue during the drying process however.
Sun drying for 10 days produced a residue level in dried plums
1.6 times that in the fresh fruit (Post, 1969).
Fresh papayas were processed to whole fruit puree which contained
about 40% of the residue found in unprocessed whole papayas (Bevenue,
1968). Peeled fruit puree contained less than 10% of the level in
whole unprocessed fruit.
Oranges treated on the tree with chinomethionat 2,3-14C (0.043%
a.i.) were harvested after 60 days and processed using procedures
similar to commercial operations. Residues of the parent compound were
found on the fruit surface and, to a slight extent, in the peel. The
total radioactivity in the peel was equivalent to about 6 mg/kg of
chinomethionat, and practically no residue was detected in the juice
from the peeled oranges. 67% of the total radioactive residue in the
peel was carried over into citrus pulp cattle feed. Only about 7% of
this was chinomethionat (Flint and Gronberg, 1973; see also previous
section).
RESIDUES IN FOOD MOVING IN COMMERCE
Chinomethionat was found in 10 apple samples during food
inspection in the Netherlands in 1973. Six of these contained less
than 0.1 mg/kg, two contained 0.1-0.2, and two 0.2-0.3 mg/kg.
In New Zealand 6 apple samples known to have been treated with
chinomethionat were analysed in 1971 and 4 in 1972. Of these, two in
1971 contained 0.02 mg/kg and one in 1972 contained 0.01 mg/kg.
Chinomethionat was not detectable in the other samples.
METHODS OF RESIDUE ANALYSIS
An additional gas-chromatographic method for plants has been
reported (Tjan and Konter, 1971), which required minimal clean-up of
the acetonitrile or benzene extracts. The recovery from apples, pears,
cucumbers and gherkins was 92-99%, the limit of determination being
0.1 mg/kg for these products.
A gas-chromatographic method has recently been developed for
chinomethionat in animal tissues and milk (Thornton, 1974). Samples
are extracted with acetone and chloroform and the extract is
evaporated to remove solvent. The solid residue is partitioned with
acetonitrile/hexane to remove the oil and purified by Florisil column
chromatography prior to gas chromatography. A second
gas-chromatographic column is used for confirmation of identity.
Detection is by electron capture with sensitivities of 0.1 and 0.01
mg/kg for tissues and milk respectively, and recoveries are generally
greater than 75%.
Residues of chinomethionat in oranges were determined by five
different analytical methods: GLC with both electron capture and
microcoulometric detection, colorimetry, polarography and
fluorescence. All five methods gave similar results. Since they
determine overlapping parts of the chinomethionat molecule each was
evidently measuring unchanged chinomethionat (Gaston et al., 1974).
The gas-chromatographic methods of Vogeler and Niessen (1967; see
1968 evaluation, FAO/WHO, 1969) and Thornton (1974) are suitable for
regulatory purposes.
NATIONAL TOLERANCES REPORTED TO THE MEETING
Tolerances have been established in several countries. Those
reported to the Meeting are listed in Table 6.
TABLE 6. National tolerances reported to the Meeting
Pre-harvest
interval Tolerance
Country Crop days mg/kg
Australia fruit and
vegetables 0.5
Canada cucumbers, water
melons, winter
squash 0.75
TABLE 6. (Cont'd.)
Pre-harvest
interval Tolerance
Country Crop days mg/kg
plums 1
cherries 3
apricots 4
strawberries 6
Denmark cucumbers 4
Finland cucumbers 4
Federal cucumbers, melons
Republic of (field grown and
Germany under glass), squash 4
fruit, vegetables 14 0.3
Hungary fruit 14 0.1
vegetables 7 0.1
Italy 21
Israel tomatoes, green
peppers, aubergines,
cucurbitaceae 2
leafy vegetables 7
fruits 10
grapes 14
strawberries 14
Japan cucumbers, strawberries,
aubergines 1
citrus 7
TABLE 6. (Cont'd.)
Pre-harvest
interval Tolerance
Country Crop days mg/kg
watermelons, melons,
sweet melons, pumpkins,
green peppers 3
Netherlands fruit 14 0.3
vegetables 3 0.3
New Zealand fruit 21
cucumbers, cucurbits 7
Norway general 7
cucumber (under glass) 4
Poland fruit 21
vegetables 21 0.3a
cucumbers 4
South Africa apples 14 0.5
pears, cucurbitaceae,
peaches, citrus fruit,
tomatoes 3 0.5
cotton 14 0.5
Spain general 15
cucumbers 10
melons 10
Sweden general 7
cucumbers 4
Switzerland cucumbers 3 0.1
fruit 21 0.1
TABLE 6. (Cont'd.)
Pre-harvest
interval Tolerance
Country Crop days mg/kg
Thailand general 7
United Kingdom apples 21
black currants 14
cucumber (under glass) 2
gooseberries 14
strawberries 14
vegetable marrow 7
Yugoslavia general 0.4
cucumber 7b
other crops 14b
a Proposed tolerances
b Proposed pre-harvest interval
APPRAISAL
Data available on residues in almonds, avocados, currants,
cucumbers, gherkins, gooseberries, grapes and macadamia nuts from
supervised trials at recommended rates indicate that the residues are
unlikely to exceed 0.1 mg/kg after pre-harvest intervals consistent
with good agricultural practice. The results of supervised trials on
citrus showed that residues up to 0.5 mg/kg could still occur after 60
days. However, other experiments showed that the residues accumulated
virtually only in the peel, and when such peels were processed into
cattle feed the unchanged chinomethionat was only 7% of the total
residue remaining in the feed. The secondary residues in meat and milk
were negligible. Residues on papayas were rather high, especially in
the peel, and residues up to 3 mg/kg were found in the whole fruit a
week after treatment.
Drying of fresh grapes and plums resulted in a residue level in
the dried fruit of about 2-6 times that in the fresh fruit. When
allowance was made for the decreased water content, however, there was
a net loss of residue. The residues were mainly on the surface of the
dried fruits. Processing fresh papayas to whole fruit puree and peeled
fruit puree removed about 60% and over 90% of the residue
respectively.
Laboratory studies using chinomethionat-2,3-14C indicated that
the organo-soluble metabolites in soil are probably disulphides of
6-methyl-2,3-dithiol quinoxaline monomeric units (about 50% of total
residues) and that the insoluble residues contained the intact
6-methylquinoxaline moiety.
It was reported that chinomethionat was adsorbed strongly by soil
and had little tendency to leach. Movement in soil was low under field
conditions. Less than 1% of the applied active ingredient was found in
run-off water after 2-6 inches of rainfall and/or irrigation.
Experiments on cucumbers and strawberries indicated that their
metabolism of chinomethionat is similar to that previously reported
for oranges and apples. The first step in chinomethionat metabolism is
its rapid hydrolysis to the less stable
2,3-dithiol-6-methylquinoxaline followed by further oxidation and
conjugation. Organo-soluble radioactivity accounted for only 9-20% of
the total recovered residue. The organo-soluble part of the residues
decreased while the insoluble part increased with time. Three
water-soluble conjugates were found in cucumbers and in their leaves.
These were probably sugar derivatives. No other metabolite has been
identified since the previous evaluation.
Feeding studies with lactating cows using radio-labelled
chinomethionat-2,3-14C showed that the total residues, expressed as
chinomethionat, were 0.0006 mg/kg in milk and 0.01 mg/kg in meat, fat,
liver, kidney, heart and brain. Results of experiments on rabbits,
dogs and goats confirmed that the biological availability of insoluble
and soluble residues in apples and oranges was low.
GLC and colorimetric analytical methods for residues are
available, which measure only the unchanged chinomethionat. The limit
of determination varies from 0.01-0.1 mg/kg depending on the method
and the kind of food sampled. The GLC methods are suitable for
regulatory purposes.
RECOMMENDATIONS
On the basis of the results of supervised trials, the following
temporary tolerances can be recommended.
TEMPORARY TOLERANCES
Pre-harvest
Temporary intervals on which
Tolerance recommendations
mg/kg are based (days)
Papayas (whole fruit) 5.0 0
(pulp) 0.1
Cucumbers, gherkins,
gooseberries 0.1 0
Macademia nut (kernels) 0.02* 0
Currants (black, red,
white) 0.1 7
Apples 0.5 14
Grapes 0.1 14
Almond kernels, avocado 0.1 28
Citrus fruits 0.5 60
Raw Cereals 0.1 60
Milk 0.01*
Meat 0.05*
*Limits of determination
FURTHER WORK OR INFORMATION
REQUIRED (by 1977)
1. Studies to identify, and evaluate the toxicity of, metabolites.
2. A method of analysis which determines the
2,3-dithio-6-methylquino-oxaline metabolite.
DESIRABLE
1. Studies on the relationships between observed liver enlargement
and reduced microsomal enzyme activity.
2. Studies of metabolism in non-rodent species.
3. Observations in man.
4. Information on the lower limit of determination of chinomethionat
in various crops using Vogeler's method.
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(Unpublished)
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See Also:
Toxicological Abbreviations
Chinomethionat (Pesticide residues in food: 1977 evaluations)
Chinomethionat (Pesticide residues in food: 1981 evaluations)
Chinomethionat (Pesticide residues in food: 1983 evaluations)
Chinomethionat (Pesticide residues in food: 1984 evaluations)
Chinomethionat (Pesticide residues in food: 1987 evaluations Part II Toxicology)