FAO/PL:1968/M/9/1
WHO/FOOD ADD./69.35
1968 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD
THE MONOGRAPHS
Issued jointly by FAO and WHO
The content of this document is the result of the deliberations of the
Joint Meeting of the FAO Working Party of Experts and the WHO Expert
Committee on Pesticide Residues, which met in Geneva, 9-16 December,
1968.
FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS
WORLD HEALTH ORGANIZATION
Geneva, 1969
BHC (TECHNICAL GRADES)
IDENTITY
Chemical name
(Mixed stereoisomers of) 1,2,3,4,5,6-hexachlorocyclohexane.
Note: Lindane, the gamma-stereoisomer of
1,2,3,4,5,6-hexachlorocyclohexane of purity 99 per cent (minimum),
has been evaluated earlier (FAO/WHO, 1967) when various temporary
tolerances were proposed.
Synonyms
BHC: benzene hexachloride; HCH, 666: hexachlor; HCCH.
Formula
C6 H6 Cl6
Technical BHC is a mixture of a number of sterioisomers, principally
alpha-BHC, beta-BHC, gamma-BHC and delta-BHC. The proportion of the
isomers in different technical mixtures can vary widely. Two grades
are covered by specification WHO/SIT/2.R3 (approved 25 October 1965),
the compositional requirements of which relate merely to the
gamma-isomer content.
Technical HCH: 12.0 to 16.0 per cent gamma isomer;
Refined HCH: 16.1 to 98.9 per cent gamma isomer.
Other isomers reported are eta-, zeta- and
theta-hexachlorocyclohexanes and a small proportion of hepta- and
octachlorocyclohexanes may also be present. The following analyses
have been reported for the grade containing approximately 13 per cent
of gamma-isomer.
Percentage composition according to:
Ramsey and Kauer
Slade Patterson, et al., Riemschneider, Lehman,
1945a 1946 1947 1955 1965
Alpha-BHC Up to 70 65-70 55 55-80 64
Beta-BHC 5 5-6 14 5-14 10
Gamma-BHC 10-12 13 12 8-15 13
Delta-BHC 7 6 8 2-16 9
(continued)
Percentage composition according to:
Ramsey and Kauer
Slade Patterson, et al., Riemschneider, Lehman,
1945a 1946 1947 1955 1965
Eta-BHC - - 3-4 3-5 1-3
Heptachloro- - 4 - - -
cyclohexane
Octachloro- - 0.6 - - -
cyclohexane
Other technical grades containing approximately 36-40 per cent or
approximately 75 per cent gamma-isomer also appear to be available.
Other information on identity and properties
The technical grades of BHC are amorphous off-white to brown powders
with a persistent, musty odour and with no characteristic melting
point. The products are stable towards light, heat, air, moisture and
acids but are dehydrochlorinated by alkalis at ordinary temperatures.
While the individual isomers have different chemical and physical
properties, the differences are small in each case. Thus, all the
isomers are only sparingly soluble in water; the literature has been
reviewed by Gunther et al. (1968), typical values for alpha-, gamma-
and delta-BHC being 10 ppm and beta-BHC 5 ppm at 20°C. The solubility
of technical BHC is also recorded as about 10 ppm; but rising with
prolonged equilibration to 20 ppm (24 h) and 32 ppm (36 h). Like other
organochlorine insecticides, the BHC isomers are generally soluble in
organic solvents. Davidek and Janicek (1967) have studied the effect
of technical BHC on the stability of beta-carotene but with somewhat
inconclusive results; a stabilizing influence is suggested for BHC
concentrations between 10 and 100 ppm.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biochemical aspects
Female rats were injected intraperitoneally with two per cent
chlorine36 labeled alpha- or gamma-hexachlorocyclohexane in oil (100
and 40 mg respectively) and the excretion pattern was determined over
40 days. Only 75-80 per cent of the total radioactivity was excreted;
80 per cent of this amount was eliminated in the urine and 20 per
cent in the faeces. Of the urinary activity 60 per cent was found as
chloride ion and 40 per cent as chlorinated organic compounds; the
latter being greater just after administration. The gamma isomer was
eliminated more rapidly than the alpha isomer (Koransky et al., 1964).
The ß isomer is eliminated the most slowly of all the isomers. A
possible metabolite of the mixed isomers is 1,2,4-trichlorobenzene
(Lehman, 1965).
The alpha, ß and delta-isomers appear to have an antagonistic effect
against the biological activity of the gamma-isomer, since they lower
the toxicity of the latter when injected into mice, rabbits and dogs
(McNamara and Krop, 1948; van Asperen, 1954). Differences in rates of
the metabolism of the isomers occur in mice. After subcutaneous,
intravenous and intraperitoneal injection, the alpha, gamma and
delta-isomers are rather rapidly broken down, none being excreted in
the urine. The gamma and delta-isomers are metabolized at a higher
rate than the alpha-isomer, but the ß-isomer is metabolized very
slowly indeed (van Asperen, 1954). The alpha, ß and gamma-isomers of
BHC produce, even after a single application, a considerable
acceleration of the detoxication processes in the liver microsomes of
rats in vitro. The toxicity of some convulsant drugs is also lowered
(Ghazal et al., 1964).
The alpha, beta, gamma and delta-isomers of BHC are stored unaltered
in the fat of rats and dogs (Davidow and Frawley, 1951). They are also
stored in the body fat of humans as shown in the following table:
BHC isomers Total
Country Date alpha beta gamma BHC References
United States 1964 0.03 0.60 0.63 Hayes et al., 1965
of America
0.28 1.39 1.67)
India 1964 > Dale et al., 1965
0.06 0.80 0.86)
New Zealand 1964-65 0.08 0.40 Tr. 0.48 Dacre, 1968
Great Britain 1965-67 0.28 0.31 Abbott et al., 1968
Australia 1966 0.12 0.39 0.25 0.76 Wasserman et al., 1968
BHC isomers have been detected in the urine of people who have not
been exposed directly to these insecticides: alpha, 0.0003-0.0004;
gamma, 0.0002-0.0004; delta, 0.0004-0.0009 ppm (Cueto and Biros,
1967).
Pharmacological activity
The alpha and gamma isomers are both convulsant poisons, the beta and
delta isomers are depressants, and the epsilon and eta isomers appear
inactive (Gero, 1959).
Acute toxicity
Animal Route Isomer LD50 (mg/kg) References
Mouse oral Mixture 700 Furman, 1955
Mouse oral alpha 1000 Burkatskaya, 1959
Mouse oral beta 1500 Burkatskaya, 1959
Mouse oral gamma 200 Burkatskaya, 1959
Rat oral alpha 500 Burkatskaya, 1959
Rat oral beta 2000 Burkatskaya, 1959
Rat oral gamma 300 Burkatskaya, 1959
Rat oral alpha 1500 Riemschneider, 1949
Rat oral beta 2000 Riemschneider, 1949
Rat oral gamma 225 Riemschneider, 1949
Rat oral delta 750 Riemschneider, 1949
Rat oral alpha 1700 Slade, 1945b
Rat oral beta No deaths Slade, 1945b
Rat oral gamma 190 Slade 1945b
Rat oral delta 1000 Slade, 1945b
Rat oral Mixture 1250 Slade, 1945b
Rat oral Mixture 600 Lehman, 1951
Short-term studies
Dog. Three dogs received daily oral doses of 50 mg/kg (2000 ppm) of
technical BHC containing 15.3 per cent gamma-isomer. They did not
survive beyond 35, 45 and 48 days and some liver damage was noted in
the animals (Woodard and Hagan, 1947).
Long-term studies
Rats. Groups of 10 male and 10 female rats were fed 0, 10, 50, 100
or 800 ppm technical BHC in corn oil solution for two years. Mortality
was increased, and body-weight gain was decreased at 800 ppm. Liver to
body-weight ratio was increased at 100 and 800 ppm. Histopathological
examination showed slight to moderate increase in the amount of focal
nephritis, and moderate testicular atrophy at 50 ppm and above.
Incidence of neoplasms was normal in all groups. Haematological data
were not reported (Fitzhugh et al., 1950).
Two year feeding studies on the various isomers to rats indicated
no-effect levels at <10 ppm (beta), 10 ppm (alpha), <800 ppm (delta),
and 50 ppm (gamma). Gross effects resulted from 10 ppm (beta), 100 ppm
(alpha) and 100 ppm (gamma). (Metcalf, 1955)
Comments
Due to the widely differing toxicological properties of the
constituents of BHC (technical grades), no estimate of acceptable
daily intake for man is possible until the material is standardized
and specific contents are laid down. The pure gamma-isomer of BHC
(Lindane, gamma-BHC) has already been evaluated for toxicity (see FAO,
PL:CP/15; WHO/Food Add./67.32, 1962, pp. 126-141) and an estimate of
the acceptable daily intake for man was made at 0-0.0125 mg/kg
body-weight. The data in that monograph should be used in conjunction
with any assessment of the toxicity of BHC (technical grades).
RESIDUES IN FOOD AND THEIR EVALUATION
Use pattern
Whereas hexachlorocyclohexane is widely used both in agricultural and
veterinary practice and also in public health, food storage and for
other purposes, there is no clear understanding as to what proportion
of the use is as lindane (99 per cent plus gamma-isomer) and what
proportion is as technical grades of BHC. The last Joint Meeting was
informed that total BHC production in the United States of America in
1963 was 3060 tons, including 720 tons of lindane, the annual
world-wide use of BHC being estimated at 60 000-70 000 tons, including
5000-6000 tons lindane (i.e. only 10 per cent of the total). The same
meeting also noted the occurrence of different isomers of BHC,
particularly beta-BHC, in human fat and human milk and concluded that
this indicated a widespread use of technical grades of BHC. So far as
is known, the general use pattern (though not necessarily the extent)
of BHC is similar to that for lindane.
Residues may arise from the use of technical grades of BHC; but since
the different isomers of BHC differ in their degree of persistence,
residues resulting from the use of "technical BHC" are of variable
composition. Daily intakes and tolerances can only be considered in
terms of individual isomers or (should this prove to be the case)
specific combinations of these. Residue analyses results should
separately record any residues of BHC isomers (particularly alpha-,
beta-, and gamma-isomers).
Residues resulting from supervised trials
Little, if any, specific information is available relating to residues
other than of gamma-BHC.
Residues in food moving in commerce or at consumption
The Netherlands Government has consolidated residue information for
the period 1964-66 for shipments of imported cereal produce (Anon.,
1968). The multi-detection system of analysis used was sensitive to
0.01 ppm gamma-BHC, small residues of which were detected in a
relatively high proportion of the samples (received from all over the
world); the proportion was less in 1966 than in previous years but in
no instance is reference made to other BHC isomers, and it is not
clear whether this is because these were not specifically sought in
the analysis or because residues were absent.
While there is, in general, relatively little residue information
relating to specific BHC isomers other than gamma-BHC, much of the
information of this kind that is available relates to total diet
studies. Cummings (1966) however, reports United States results as
"lindane and/or BHC". The proportion of samples found to contain
detectable residues and the levels in individual diet categories are:
Percentage of samples
containing detectable Level of residue
residues (ppm)
Dairy products 42 trace - 0.010
Meat, fish products 47 0.001 - 0.046
Grain, cereal products 68 trace - 0.11
Potatoes 20 trace - 0.001
Leafy vegetables 26 trace - 0.015
Legume vegetables 21 trace - 0.002
Root vegetables 16 trace - 0.015
Garden fruit 33 trace - 0.016
Fruit 32 trace - 0.009
Oil, fats, etc. 33 0.001 - 0.007
(Continued)
Percentage of samples
containing detectable Level of residue
residues (ppm)
Sugars, etc. 40 trace - 0.023
Beverages 67 less than 0.001
More recently, Duggan (1968) has summarized the whole of the United
States monitoring programme and results for the period mid-1963 to
mid-1967. Gamma-BHC and BHC are recorded separately, the intakes for
the high consumption (approximately twice normal) diet being shown in
Table I, and the results for individual market-basket groups in Table
II, Total diet study results for the period October 1966 to October
1967 are also available for England and Wales using multidetection
system of analysis capable of detecting alpha-, beta- and gamma-BHC
isomers individually (limit of detection 0.001 ppm) (Abbott et al.,
1969). Results are shown in Table III.
TABLE I. UNITED STATES TOTAL DIET RESULTS FOR GAMMA-BHC AND BHC
Gamma-BHC BHC
Dietary intake rate - mg/kg/day
1964-65 0.00007 0.00003
1965-66 0.00006 0.00004
1966-67 0.00007 0.00003
Three-year average 0.00007 0.00003
Average incidence (per cent)
1964-65 15.8 6.5
1965-66 12.3 6.0
1966-67 10.6 8.9
Daily intake (mg)
1964-65 0.004 0.002
1965-66 0.004 0.004
1966-67 0.005 0.002
TABLE II. UNITED STATES INDIVIDUAL MARKET BASKET RESULTS FOR GAMMA-BHC AND BHC, PPM*
gamma-BHC BHC
Domestic Imported Composite Domestic Imported Composite
Large fruit T T TT T T TT
Small fruit T T - T T -
Grains and T T 0.008 T T TT
cereals
Leaf, stem
vegetables 0.01 T TT T T TT
Vine, ear
vegetables T T 0.002 T T TT
Root T T TT T 0.02 TT
vegetables
Beans T T TT T T -
Eggs T T - T T -
Nuts T 0.01 - T 0.08 -
Processed 0.04 0.01 - T T -
foods
Animal T T - T - -
grains
Milk (fat T - - 0.01 - -
basis)
Dairy T 0.01 - 0.02 0.14 -
products
* Raw domestic and imported samples; ready-to-eat composite samples.
T - less than 0.005 ppm; TT - less than 0.001 ppm.
TABLE III. BHC ISOMERS IN TOTAL DIETS (ENGLAND AND WALES) PPM
Alpha-BHC Beta-BHC Gamma-BHC
Mean Range Mean Range Mean Range
Meats 0.0045 nil-0.060 0.0055 nil-0.050 0.0065 nil-0.060
Fats 0.0305 nil-0.160 0.0165 nil-0.080 0.0125 nil-0.080
Fruit, 0.001 nil-0.006 0.002 nil-0.012 0.002 nil-0.007
preserves
Root * nil-0.004 0.002 nil-0.008 0.0015 nil-0.012
vegetables
Green 0.001 nil-0.020 0.0015 nil-0.010 0.003 nil-0.035
vegetables
Milk 0.0015 nil-0.007 0.0005 nil-0.002 0.001 nil-0.004
Cereals 0.002 nil-0.011 0.003 nil-0.018 0.0085 0.001-0.050
Total 0.003 nil-0.012 0.003 nil-0.010 0.004 0.002-0.013
* Less than 0.0005.
Bro-Rasmussen et al. (1968) have examined 260 samples of Danish milk
and dairy produce during the period 1964-65 and found a mean alpha-BHC
residue level of 0.05 ppm on a fat basis (approximately 0.002 ppm on
the whole milk) with a maximum value of 0.28 ppm. Corresponding values
for gamma-BHC were: average 0.02 ppm; maximum 0.11 ppm. The average
alpha-BHC residue in butter was also 0.05 ppm on a butter fat basis
(gamma-BHC 0.01 ppm). From 0.005 to 0.04 ppm alpha-BHC was found in
animal feeds.
Fate of residues
General comments
All hexachlorocyclohexane isomers are fat soluble and are persistent
to different extents.
In plants
There is little or no information on the terminal residues arising
from the use of technical mixtures of BHC isomers on plants.
In animals
Egan (1965a) has reported the residue levels of alpha- and
gamma-isomers in sheep fat following dipping with BHC.
In storage and processing
Duggan (1968) has summarized recent United States market basket
residue survey work. A summary of the results for raw produce in the
United States of America, imported and otherwise, are given above.
In man
Egan et al. (1965b) and Abbott et al. (1968) have reported residues of
BHC isomers in human fat and human milk. Alpha-, beta- and
gamma-isomer residues were normally found in all fat samples with
beta-BHC predominating to the extent of 90 per cent of the total BHC
residue. The mean total BHC residues 1964-1965 was 0.42 ppm; standard
error, 0.03 ppm; median value, 0.39 ppm; geometric mean, 0.34 ppm; 95
per cent confidence limits of 0.29-0.41 ppm. Similar results were
found 1965-1967, with 90-95 per cent, beta-BHC, the remainder of the
residue containing roughly equal amounts of alpha- and gamma-BHC; mean
total level, 0.31 ppm; standard error, 0.01 ppm; median value, 0.29
ppm; geometric mean, 0.25 ppm; 95 per cent confidence limits,
0.22-0.27 ppm. The arithmetic mean beta-BHC level for the whole period
was 0.28 ppm. For 23 prematurely born infants the mean beta-BHC level
was 0.12 ppm (range 0.0-0.55 ppm). The average total BHC residue found
in 19 samples of human milk was 0.013 ppm, nearly all of it beta-BHC.
Methods of residue analysis
The general remarks on methods of residue analysis, on multidetection
systems and on methods for residues of organochlorine pesticides
(FAO/WHO, 1967) apply to the determination of BHC isomer residues. The
quantitative gas chromatography determination of alpha-, beta-,
gamma-, delta-, epsilon- and eta-BHC isomers, together with gamma- and
epsilon-heptachlorocyclohexanes, in admixture has been described by
Davis and Joseph, 1967. A number of published gas chromatographic
multidetection systems of organochlorine pesticide residue analysis
can be used for the separate detection and estimation of alpha-, beta-
and gamma-BHC isomers although for optimum separations, special column
fillings are desirable. Thus the separation of beta- and gamma-BHC
isomers can be controlled by the amount of Epikote resin included in
the column stationary phase; a cyanosilicone column is particularly
useful for BHC isomer analysis.
National tolerances
There are no established tolerances for technical mixtures of BHC
isomers as such; nor for individual isomers other than the
gamma-isomer. There are some tolerances for total BHC; in some there
is need for clarification of the position as between tolerances for
total BHC and for gamma-BHC.
RECOMMENDATIONS FOR TOLERANCES AND PRACTICAL RESIDUE LIMITS
Appraisal
While technical grades of BHC are widely used in agriculture, there is
a range of different commercial products but little information on the
composition and relative use of these. There is also little residue
data for isomers of hexachlorocyclohexane other than the gamma-isomer;
but some indication that the beta-isomer is the most persistent.
There are published residue methods capable of separating, and
measuring separately, the principal steroisomers. Analyses should
report separately any residues of these (and in particular of the
alpha, beta, and gamma-isomers) found.
Recommendations
For the above reasons no recommendations for residue tolerances can be
made at the present time.
Further work or information
Required (before acceptable daily intakes or tolerances can be
established):
1. Information on all of the principal technical grades of BHC,
expressed in terms of specific isomers, as follows:
(a) the chemical nature of terminal residues in plants, animals
and their products;
(b) the required rates and frequencies of application,
pre-harvest intervals and the resultant residues;
(c) residue levels in raw agricultural products moving in
commerce;
(d) the disappearance of residues during storage and processing;
(e) residue levels in total diet studies.
2. Short- and long-term feeding studies and a reproduction study in
animals on individual isomers and commonly marketed technical
products.
3. Metabolic studies of isomers in animals.
4. Determination of the effects on enzyme processes, especially those
involving liver microsomes (cf. lindane).
5. Study of the interaction of the isomers of BHC and residue levels
in tissues.
Desirable:
1. Information on the relative amounts of lindane and technical grades
of benzene hexachloride used in various countries.
2. Clarification by governments of whether established tolerances are
for technical grades of benzene hexachloride or for lindane (99 per
cent gamma-isomer only).
3. Further information on the composition of all commercially
available technical BHC products and on the amounts of these used
for agriculture and veterinary purposes in the different countries
of the world.
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