PESTICIDE RESIDUES IN FOOD - 1980
Sponsored jointly by FAO and WHO
EVALUATIONS 1980
Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
and the
WHO Expert Group on Pesticide Residues
Rome, 6-15 October 1980
PROPARGITE
Explanation
Propargite was reviewed by the 1977 Joint Meeting (FAO, 1978), and
a temporary ADI for man was estimated to be 0-0.08 mg/kg bw.
Propargite is moderately toxic when administered orally to rats.
Propargite is readily absorbed, metabolized, and excreted rapidly
from the body. The metabolic products are predominantly oxidative
and/or hydrolytic reactions resulting in cleavage of the parent
ester and of the ether moiety. The metabolic products are polar
compounds, readily excreted or incorporated into natural
constituents in the body. Propargite is not teratogenic, nor did
it pose a problem with respect to reproduction in rats. In a
series of long-term and short-term studies in rats and dogs, there
were no unusual toxicological events that would raise questions
relative to the safety of the use of propargite. In a long-term
study in the rat, at 2,000 mg/kg, growth reduction and mortality
was seen. These effects were accompanied by variations in the
relative and absolute weight of several organs of the body noted in
survivors at the conclusion of the study. There is no indication
in the long-term rat study that propargite is a carcinogen. A
no-effect level of 900 mg/kg (the highest level tested) was seen in
the two-year dog study.
It was considered at the previous Meeting that, as propargite is
structurally related to `Aramite', a compound that is known to be
a carcinogen in animal studies, the need for a more definitive
carcinogenicity study was warranted. Further data relative to the
oncogenic potential of propargite in mice were made available to
the Meeting and were reviewed. These new data are considered in
this monograph addendum.
At the 1977 Meeting a number of temporary MRLs were recommended.
In 1978 (FAO/WHO, 1979) additional information was reviewed with
recommendations for new or revised temporary limits with some of
these revised in 1979 (FAO/WHO, 1980) on the basis of new data.
Propargite is scheduled for re-evaluation in 1981. However,
additional information has been received on the metabolic fate of
propargite in plants. This information, provided in response to
information considered desirable in the 1977 Evaluations (1978), is
reviewed in this addendum. Additional information on residues, use
patterns, and national tolerances are also evaluated.
DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special study on carcinogenicity
Mouse
In the preliminary dose range-finding study, groups of albino mice
(10 male and 10 female mice/group) were administered propargite in
the diet at dosage levels of 0, 600, 900, 1,350, 2,000 or 3,000
mg/kg for 30 days. Daily observations were made with respect to
general appearance and behaviour and for gross signs of toxicity
and mortality. Body weight and food consumption were recorded
weekly and gross examination of major tissues and organs was
performed on all animals.
Mortality was observed at 3,000 mg/kg (all deaths were in one group
of male mice housed together, but not in the other group of 5 males
nor in the females). Growth was depressed at 3,000 mg/kg in both
males and females and at 2,000 and above in females. Absolute and
relative organ weight changes were observed at all dose levels,
predominantly with respect to the liver. The principal
investigators considered that the increased liver weight was a
physiological response induced by the presence of propargite and
did not constitute a toxicological response. It was concluded that
a dosage not exceeding 1,000 mg/kg would be appropriate for a long-
term carcinogenicity bioassay in mice (Gallo and Bailey, 1976).
Groups of mice (60 male and 60 female, Charles River, CD-1
mice/group) were fed propargite in the diet at dosage levels of 0,
50, 160, 500 or 1,000 mg/kg for 18 months. Another group of
animals (15 male and 15 female mice/group) were fed 0, 500 or 1,000
mg/kg in the diet for one year. Animals were observed daily for
mortality and changes in appearance or behaviour. Growth and food
consumption data were measured weekly for 28 weeks, after which
data were recorded every other week. Data were recorded on
individuals for 36 weeks and then by groups of animals
corresponding to their caging. At 0, 52, and 78 weeks, haematology
examinations were performed. At the conclusion of the study
(either 52 or 78 weeks) all surviving animals were sacrificed and
subjected to gross and microscopic examinations of tissues and
organs. A statistical analysis was performed on all parameters to
distinguish differences between control and test groups.
There was no excessive mortality over the course of the study as a
consequence of the presence of propargite in the diet. There was
no effect of propargite on food consumption or growth. The
appearance and behaviour characteristics of all treated animals
were similar to those of controls. Haematological values were
unaffected by propargite at any dose level. At the conclusion of
the study, gross and microscopic examination revealed few
significant compound-related effects. There was no effect of
propargite on the distribution of either neoplastic or
non-neoplastic lesions. A slight reduction in kidney weight
was noted. An enlarged uterus was also reported in those animals
fed 1000 mg/kg. These gross changes were not accompanied by
pathological changes in the histological examination.
In summary, there is no indication of a tumorigenic or carcinogenic
effect of propargite in mice administered dietary levels up to
1,000 mg/kg for 18 months (Cox and Re, 1979).
Special studies on mutagenicity
Propargite was examined for its mutagenic potential in a series of
in vitro microbiological assays utilizing Salmonella spp. and
Saccharomyces spp. indicator organisms. Propargite was tested in
the presence and absence of a liver microsomal enzyme preparation
(S-9) obtained from Aroclor-induced rats. The concentration of
propargite ranged from 0.001 to 5 mg per plate.
The higher concentrations of propargite induced cellular toxicity,
but in all cases there were sufficient doses available to evaluate
propargite for its potential mutagenic effects. Propargite did not
induce mutagenic activity in either of the microbial test systems
and was considered to be nonmutagenic in these bioassays (Brusick
and Weir, 1977).
Special studies on teratogenicity
Groups of female rats (20 pregnant rats/group) were administered
propargite on days 6-15 of gestation at dosage levels of 0, 6, 25,
105, and 450 mg/kg/body weight/day. Propargite was administered as
a corn oil suspension. A positive control included in the study
was aspirin administered at a dose level of 250 mg/kg/body
weight/day. All animals were sacrificed on day 20 of gestation and
foetuses were removed and examined. The number of corpora lutea,
implantation sites, resorption sites, and live and dead foetuses
were observed. The foetuses were sexed and their body weight
determined. All foetuses were examined for gross abnormalities and
representatives were further examined for somatic and skeletal
malformations.
Maternal mortality in the high-dose group, administered 450 mg/kg,
was evident early in the study and this dose level was terminated.
Females at 105 mg/kg displayed signs of acute poisoning (blood
nasal discharge, alopecia, urinary incontinence, and bloody vaginal
discharge). While there were occasional toxic signs of poisoning
in the lower dose levels, there were no differences in any of the
treatment groups with respect to the maintenance of pregnancy,
implantation sites, numbers of live or dead foetuses or resorption
sites. Missing sternebrae and missing or reduced hyoid were
significantly increased in the two highest-dosed test groups (25
and 105 mg/kg), and an increased incidence of incomplete closure of
the skull was noted at the highest test group. There was an
increased number of smaller pups and haemorrhagic abdomen was
reported in more litters at the two higher dose groups than noted
either in the lowest dose group or in the controls. There were
no differences with respect to the average weight of live foetuses
in any of the groups. Aspirin, the positive control, induced a
significantly higher percentage of dams with resorption sites,
fewer live foetuses/dam and a reduced foetal weight. The
aspirin-treated parents gained less weight during the period of
gestation and the foetuses showed an increased incidence of
skeletal and soft tissue abnormalities compared to control
foetuses. Such effects include missing sternebrae; incomplete
ossification of vertebrae; incomplete closure of the skull;
incomplete ossification of extremities, and missing and reduced
hyoid.
Propargite is not teratogenic in the rat under conditions of this
assay. At a dose level of 25 mg/kg propargite-treated rats showed
an increase in missing sternebrae and retarded hyoid development.
These malformations are believed to be of questionable significance
in evaluating the teratogenic potential of propargite, as an
increased number of incomplete vertebrae, missing or reduced hyoid,
and an incomplete skull closure are indicative of retarded
development rather than a teratogenic effect, probably reflective
of the toxic maternal effect noted at the higher dose levels
(Knickerbocker and Re, 1979).
RESIDUES IN FOOD
USE PATTERN
The following represent current good agricultural practices in New
Zealand.
Crop Pest Application Rates Waiting Period
Apples Mites 60 g ai/100 litres 14 days
Berry fruit Mites 60 g ai/100 litres 3 days
Stone fruit Mites 60 g ai/100 litres 2 days
These good agricultural practices are generally comparable with
those reviewed by the 1977 Joint Meeting (FAO/WHO, 1978) except for
the New Zealand 2-day pre-harvest interval for stone fruit which is
significantly less than 14-day interval, on which basis limits were
recommended in 1977.
RESIDUES RESULTING FROM SUPERVISED TRIALS
Propargite residues resulting from supervised trials in New Zealand
are given in Table 1.
TABLE 1. Propargite Residues From Supervised Trials
Pre-Harvest Residues
Interval at Harvest
Crops Application Details (days) (mg/kg)
Apples 1 × 60 g ai/100 litres 5 2.5
Strawberries 2 × 30 g ai/100 litres 16 h 3.7
(3.6 kg ai/ha) 1 3.1
2 2.5
3 2.0
5 1.7
7 1.4
16 0.5
Peaches 1 × 33 g ai/100 litres 0 7.6
(2.0 kg ai/ha) 1 6.0
2 5.7
3 6.1
5 7.1
7 6.9
14 6.3
2 × 60 g ai/100 litres 1 2.0
(1.2 kg ai/ha) 3 1.26
7 0.88
14 1.0
Apples
The residue is within the 5 mg/kg limit recommended by the 1979
Joint Meeting.
Strawberries
The residues are within the 7 mg/kg limit recommended by the 1977
Joint Meeting, which used a 3-day pre-harvest interval.
Peaches
The residues are consistent with the 7 mg/kg limit recommended by
the 1977 Joint Meeting and the 14-day-pre-harvest interval on which
it was based. Even at the 2-day pre-harvest interval, considered
good agricultural practice in New Zealand, residues are consistent
with the limit previously recommended.
Propargite residues in raisins
Summary data from residue trials in California, USA (Canada, 1980)
are given in Table 2.
TABLE 2. Propargite Residues in Raisins
Application Rate Interval from
kg ai/ha or last Application Propargite
% ai Formulation (days) Residue (mg/kg)
0.054% Omite 30W 7, 8 1.3, 0.1
14 0.7, 0.3
0.11% Omite 30W 7, 8 0.9, 0.5
14 1.3, 0.6
1.8 Omite 30W 7,8 1.5, 0.1
14 1.1, 0.7
3.6 Omite 4D 7, 8 6.1, 0.5
14 0.4, 0.4
6 Omite 30W 7 0.9, 1.0
1.7, 2.2
1.4, 1.2
3.6 Omite 4D 7 2.9, 5.5
5.2, 5.9
0.3, 1.1
These data indicate that propargite residues on raisins will not
exceed the currently proposed 10 mg/kg limit on grapes if
applications are within the recommended 1.7-3 kg ai/ha or 0.054%
application rates and the 21-day recommended interval is observed.
FATE OF RESIDUES
In plants
Previous studies have shown that propargite is the principle
residue in plants and that residue loss is, at least in part, by
volatilisation. There are data supporting the view that propargite
is generally "non-systemic". It has been suggested that the
principal metabolic degradation products in plants are propargyl
alcohol and tert-butylphenoxy cyclohexanol with the possibility
of further degradation to butylphenol and cyclohexanediol.
However, this postulated metabolic pathway was not confirmed by
detection of residues of these products in plants.
Three additional studies on the metabolism of propargite in plants
have been submitted. In one study mature red kidney bean plants
were treated two times under greenhouse conditions with a
14C-phenyl labelled-propargite Comite(R) formulation (Curtiss and
Fuller, 1979) at rates equivalent to field usage rates of 1.4-2.1
kg active/ha. There was a 30-day interval between treatments and
from last treatment until harvest. Total residues in the dried pod
at harvest were 36.9 ± 6.85 mg/kg, of which approximately 60% was
extractable with acetone and methanol. Of these extractables 64.1%
was shown by TLC/LSC to be propargite, 19% was unidentified as
materials remaining at the origin, 6.7% was a compound with an Rf
similar to that of the glycol ether
[i.e.(2-[4-(1,1-dimethylethyl)phenoxy]cyclohexanol)] and the
remaining 10.5% was unidentified. Thus about 40% of the total
residue was unextractable, and about 30% of the extracted residue
was unidentified, that is 57% of the total residue was
unidentified. At a limit of detection of 0.05 mg/kg there were no
residues of significance in the dried beans, thus supporting the
view that residues are surface residues with little or no
translocation from foliar applications.
In another study (Henderson, 1979) Redhaven peaches were topically
treated with (phenyl-14C) formulated Omite(R) with a solution
concentration of 2600 mg/kg (0.26%) active or about 2 times the
maximum rate reported as good agricultural practice (FAO/WHO,
1978). Application was by micro-syringe in the field at a rate of
1.3 mg propargite to each of nine peaches. This would be 7 mg/kg
on a fruit basis if a 190 gm fruit were used. This approximates
zero day residues of 1.3-10.5 mg/kg reported for a 0.1% application
field trial application rate on nectarines (FAO/WHO, 1978).
Samples were analyzed by TLC/LSC at 0, 10, and 21 days after
treatment.
The peels and pulp were analyzed separately with results reported
on a whole fruit basis. Extraction was by multiple blendings with
acetone, which was subsequently filtered. Recoveries were said to
be 98.8%. Analysis was on silica gel TLC plates developed with
cyclohexane: ethylacetate (9:10) with unlabelled propargite
visualized under UV light. The 14C radioactivity of each segment
of the plate was determined by LSC and unextractable residues by
combustion.
The recovery of applied 14C with time was 97.2, 96.67 and 71.3
percent at 0, 10 and 21 days respectively with the extractable
portion only decreasing from 98 percent at zero day to 92.5 percent
at 21 days. Less that 3% of residual 14C material was in the pulp,
again supporting the view that propargite is generally
non-systemic. The distribution of residual 14C is shown in Table
3.
TABLE 3. Percentage Distribution of Residual 14C
Extractable Unextractable
Time Total
(days) Propargite Unidentified Unidentified
0 94.0 4.1 2 6
10 76.1 20.6 3.3 23.9
21 82.5 10 7.5 17.5
These data support other studies showing that propargite, per
se, is the principal residue on plants and that there are
substantial unidentified residues. The TLC/LSC profiles at 0 and
21 days indicate that any one component of the unidentified residue
on peaches would be less than about 10% of the total extractables,
although this can not be concluded from the 10-day profile. There
was no analysis for the glycol ether, which was tentatively
identified in the bean study using a similar TLC system.
In another study (Henderson, 1979) a 5000 mg/kg solution of
propargite was topically applied to apples at 55.5 mg/kg level on
a fruit basis to investigate whether residues of propargyl alcohol
would result. Residues were analyzed by flame ionization gas
chromatography at 0, 12 and 21 days after peeling and extraction
with DMSO. Detection limits were said to be 1.1 mg/kg propargyl
alcohol with 84% recoveries. No free propargyl alcohol residues
were detected at 0, 12 or 21 days.
RESIDUES IN COMMERCE OR AT CONSUMPTION
Residues reported in apples in New Zealand commerce and based on
biased sampling from crops known to be treated are as follows:
1977 Apples 12 samples N.D. - 1.5 mg/kg
mean = 0.77 mg/kg
These levels are well within the 5 mg/kg limit proposed by the 1975
Joint Meeting.
NATIONAL TOLERANCES REPORTED TO THE MEETING
Country Commodity Tolerance (mg/kg)
New Zealand pome fruit, berry fruit
and stone fruit 3
Federal Republic
of Germany hops (dried) 30
citrus fruit, tea (dry
manufactured) 5
fruit (except citrus) 3
cucumber, sugarbeet 0.5
beans (dried), cotton
seed, peanuts, maize
grain, potatoes, almonds,
walnut 0.1
EVALUATION
COMMENTS AND APPRAISAL
At the 1977 Meeting (FAO/WHO, 1978a, b) a temporary ADI for man was
estimated to be 0-0.08 mg/kg bw/day. Data have been provided in
response to a request to provide a satisfactory carcinogenicity
bioassay. A long-term mouse carcinogenicity study showed that
although there were increases in liver and other organ weights,
propargite was not carcinogenic.
Propargite is rapidly absorbed, degraded, and excreted from
mammalian systems and does not appear to bioaccumulate. It has a
low order of acute toxicity, is not a mutagen or a teratogen, nor
does it affect reproduction in the rat. Propargite has shown no
organ or tissue-specific effect when fed to rodents.
Administration of propargite to rats and dogs for two years failed
to induce any abnormal effects attributable to propargite.
However, in a short-term teratology study, delayed maturation of
foetuses at a dosage level of 25 mg/kg was observed.
Three new studies on the metabolism of propargite in plants have
been submitted. In two of these 14C-phenyl labelled propargite was
applied to bean plants and peaches respectively and in the other
apples were fortified with unlabelled propargite. The first two
studies support earlier studies, which have indicated that
propargite, per se, is the principal residue and that residues
are primarily surface residues with little evidence of
translocation.
The nature of unidentified residues, which may be from 6 to 50% of
the total residue depending on the commodity and time from
application, is still largely unknown. Although not entirely
conclusive, the study on peaches does suggest that no one component
of these unidentified residues is likely to be greater than about
10% of total extractable residues. However, this cannot be
concluded in the bean study where 19% of the extractables remained
at the origin of the TLC.
The bean plant study gives some indication of possible residues of
the glycol ether (2-[4-(1,1-dimethylethyl)phenoxy] cyclohexanol in
bean pods at about 7% of extractable residues. If confirmed, this
would disprove earlier suggestions that residues of this compound
are too volatile to result in residues.
On the other hand, at a detection limit of 1.1 mg/kg, there is no
evidence of terminal residues of free propargyl alcohol from the
use of propargite on apples. This does support, but does not
prove, suggestions that this compound may be too volatile for
residues.
New or revised information was provided on use patterns, residues
from supervised trials residues in commerce, and national
tolerances of New Zealand. Except in the case of raisins this
information is consistent with limits previously recommended and
does not require revisions in those recommendations. In the case
of raisins, the residue data show that residues on raisins from
good agricultural practices will not exceed the existing 20 mg/kg
limit on grapes. There is therefore no need for a separate limit
on raisins, which was based on a concentration factor of 2.5 times
the 10 mg/kg level for grapes.
Level causing no toxicological effect
Rat: 300 mg/kg in the diet equivalent to 15 mg/kg bw/day
Dog: 900 mg/kg in the diet equivalent to 47 mg/kg bw/day based on
actual dietary intake.
Estimate of temporary acceptable daily intake for man
0-0.08 mg/kg bw/day
The meeting concludes that the separate 25 mg/kg level for
propargite on raisins should be withdrawn since residues are
adequately covered by the 10 mg/kg limits on grapes.
FURTHER WORK OR INFORMATION
Required (by 1982)
Clarification of the delayed maturation effects observed in the
teratology study in the rat.
Desirable
1. Further confirmation of the postulated degradation pathway in
plants with particular attention to the characterization of
unidentified residues (free or conjugated) and the possibility of
residues of the glycol ether.
2. Additional data from supervised trials in countries other than
the U.S.A.
3. Information on the occurrence of residues in commodities in
commerce.
REFERENCES
Brusick, D.J. and Weir, R.J. Mutagenicity evaluation of D104 -
Final Report. (1977) Unpublished report (No. 2683) from Litton
Bionetics, submitted to the World Health Organization by Uniroyal
Chemical.
Canada. Propargite residues in raisins. Data provided to FAO by the
Canadian Inter-departmental Codex Committee on pesticide residues,
(1980).
Cox, G.E. and Re, T.A. Chronic oncogenic evaluation of Omite(R) in
CD-1 mice following 78 weeks of dietary treatment. (1979)
Unpublished report from Food and Drug Research Laboratories, Inc.,
submitted to the World Health Organization by Uniroyal Chemical.
Curtiss, K. and Fuller, G.B. The metabolic fate of propargite in
red kidney bean plants, Project No. 7918. (1979) Unpublished report
submitted by Uniroyal Chemical, Inc.
Gallo M.A. and Bailey, D.A. Range finding study with Omite(R) in
albino mice. (1976) Unpublished report from Food and Drug Research
Laboratories, Inc., submitted to the World Health Organization by
Uniroyal Chemical, Inc.
Henderson, S.K. Degradation of Omits (phenyl-14C) on Redhaven
Peaches, Project Number 7952. (1979) Unpublished report submitted
by Uniroyal Chemical, Inc.
Henderson, S.K. Analysis of Apples treated with Omite(R) for
propargyl alcohol, Report Number 7948. (1979) Unpublished report
submitted by Uniroyal Chemical, Inc.
Knickerbocker, M. and Re, T.A. Teratological evaluations of
Omite(R) technical in Sprague-Dawley rats. (1979) Unpublished
report from Food and Drug Research Laboratories, Inc., submitted to
the World Health Organization by Uniroyal Chemical.
See Also:
Toxicological Abbreviations
Propargite (Pesticide residues in food: 1977 evaluations)
Propargite (Pesticide residues in food: 1978 evaluations)
Propargite (Pesticide residues in food: 1979 evaluations)
Propargite (Pesticide residues in food: 1982 evaluations)
Propargite (JMPR Evaluations 1999 Part II Toxicological)