1,1,1-TRICHLOROETHANE
Explanation
This substance was evaluated for an acceptable daily intake for
man by the Joint FAO/WHO Expert Committee on Food Additives in 1980
(see Annex, Ref. 54). No toxicological monograph was issued.
Since the previous evaluation, additional data have become
available. This information is summarized and discussed in the
following monograph.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
1,1,1-trichloroethane was rapidly absorbed through the lungs and
the gastrointestinal tract. It was also absorbed through intact skin
(Stewart, 1968; Fukabori et al., 1977; Tsuruta, 1975). After
inhalation in mice it was found in blood, brain, kidney, and liver. A
first order pharmacokinetic model for both uptake and elimination was
found to fit the empirical data (Holmberg et al., 1977). After i.p.
injection (700 mg/kg) into the rat, 98.7% was expired unchanged, 0.5%
was expired as carbon dioxide, the remainder was excreted in the urine
as the glucuronide of 2,2,2-trichloroethanol and trace amounts of
uncharacterized metabolites were found in the carcass (Hake et al.,
1960). Trichloroacetic acid was identified as a metabolite in
the urine of rats (Eben & Kimmerle, 1974). Less than 0.5% of
1,1,1-trichloroethane was found to be dechlorinated in vitro by rat
liver microsomes (Van Dyke & Wineman, 1971). In an inhalation study
with human subjects the absorption rate of 1,1,1-trichloroethane was
not constant, but changed continuously throughout the study. For an
eight hour exposure period, retention ranged from 26 to 32%. Pulmonary
excretion of the solvent over a period of six days accounted for 90%
of the absorbed material. Urinary excretion of the metabolites was
slow, over a period of 12 days with most being eliminated during the
first eight days. The proportion of metabolized solvent was low, since
only an average of 1.8% of the retained solvent was excreted as
dechloracetic acid and 4.2% as trichloroethanol (Humbert & Fernandez,
1977).
Effects on enzyme and other biochemical parameters
Rats exposed to 20 µmol/l (489 ppm) (0.0489%) of
1,1,1-trichloroethane for six hours/day for four days were found to
have a marked sequestration of the solvent in the perirenal fat. The
solvent was detectable in the fat as well as brain and liver 17 hours
after the end of the four day exposure. Further exposure for two hours
on the fifth day was found to increase the brain and liver solvent
content 100-fold but in fat only 10-fold. No effect was found on brain
glutathione but decreased brain RNA content and increased acid
proteinase activity was observed. Liver microsomal cytochrome P-450
content decreased as exposure time was increased (Vainio et al., 1978;
Savolainen, 1977). 1,1,1-trichloroethane was reported to degrade the
haeme moiety of cytochrome P-450. Degradation appeared to require
metabolic activation since NADPH was a requirement for binding
(Ivanetich et al., 1978).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
The in vitro transforming potential of 1,1,1-trichloroethane
was shown in a Fischer rat embryo cell system (F1706). Rat embryo cell
subcultures containing genetic information of the murine type "C" RNA
oncovirus were treated with a minimally toxic concentration of the
compound (99 µl) in growth medium for 48 hours. After several
subcultures, the transformed cells were inoculated into newborn
Fischer rats. After 68 days there was a 100% (N=8) tumour incidence at
the site of injection. By 82 days postinoculation, acetone, the
negative control, did not induce tumours (N=13) (Price et al., 1978).
Groups of 50 male and 50 female B6C3F1 mice, five weeks of age
were administered technical grade 1,1,1-trichloroethane (containing 3%
para-dioxane and 2% impurities) in corn oil by gavage at two dosage
levels, five days per week for 78 weeks. The dosage, levels were
increased twice during the experiment. The time-weighted average doses
for the high- and low-dose mice were 5615 and 2807 mg/kg bw per day.
An untreated group of 20 mice of each sex were used as negative
controls; carbon tetrachloride was used in positive-control animals;
no vehicle-control animals were used.
About half of the treated and control males died within one year
of exposure. Five per cent. of the control, 18% of the low-dose, and
40% of the high-dose females died within one year. At 90 weeks, 15
low-dose males, 11 high-dose males, 2 negative-control males, 23
low-dose females, 13 high-dose females, and 11 negative-control
females remained alive and all survivors were killed in the 90th week.
There was a moderate depression of body weight throughout the study in
both sexes. Almost all organs, tissues, and gross lesions were
histologically examined. Hepatocellular adenoma, carcinoma, or
neoplastic nodules were found in four of 49 high-dose males. No other
liver tumours were found in treated or negative-control mice.
Virtually 100% of positive-control animals developed hepatocellular
carcinoma (National Cancer Institute, 1977). Because of the short
survival times, this study was not considered an adequate test of
carcinogenicity and is currently being re-run.
Groups of 50 male and 50 female Osborne-Mendel rats, seven weeks
of age, were administered technical-grade 1,1,1-trichloroethane
(containing 3% para-dioxane and 2% impurities) in corn oil by gavage
at two dosage levels (750 and 1500 mg/kg bw per day) five days per
week for 78 weeks. An untreated group of 20 rats of each sex were used
as negative controls; carbon tetrachloride treated animals served as
positive controls. All surviving animals were killed at 117 weeks of
age. Treated animals exhibited early mortality when compared to
controls. Only 3% of treated rats survived to termination of the
experiment. Only one proliferative hepatocellular lesion (adenoma)
occurred in rats treated with 1,1,1-trichloroethane. None occurred in
the negative-control group and several neoplastic nodules and
hepatocellular carcinomas occurred in the positive-control animals
(National Cancer Institute, 1977). Because of poor survival rates this
test of carcinogenicity is being re-run.
Groups of 96 male and 96 female Sprague-Dawley rats were
administered 1,1,1-trichloroethane via inhalation at a concentration
of 875 or 1750 ppm (0.0875 or 0.1750%) for six hours per day, five
days per week for 12 months. Groups of 192 untreated rats of each sex
served as controls. Rats were then held for observation until 30
months from the start of the experiment. No adverse effects were seen
in treated animals with respect to growth, demeanour, haematology,
urinalysis or mortality. Tissues from all animals were saved and
examined histologically. No discernible increase in tumours occurred
in treated animals over controls (Rampy et al., 1978).
Special studies on mutagenicity
1,1,1-trichloroethane was weakly mutagenic in Salmonella
typhimurium strain TA-100 with or without a microsomal activation
system (Simmon et al., 1977). Additional Salmonella studies have
shown negative results (Schumann et al., 1980). Results of a 29-test
battery of mutagenicity assays of the National Toxicology Programme on
1,1,1-trichloroethane were described as "overwhelmingly negative"
(Schumann et al., 1980).
Special studies on reproduction
Chicken embryo
Groups of fertilized chicken eggs were injected with 1,1,1-
trichloroethane and olive oil (total volume 25 µl) at 2, 3 and 6 days
of incubation. The approximate LD50 value varied between 50 and
100 µmol/egg. The eggs were examined after 14 days of incubation.
Gross external malformations were observed in 21% of the survivors and
3.6% of the vehicle controls. The malformations reported included
exteriorization of viscera, profound oedema, and eye and skeletal
abnormalities Elovaara et al., 1979).
Rat
Groups of Sprague-Dawley rats and Swiss-Webster mice were exposed
to 1,1,1-trichloroethane by inhalation for seven hours daily on days
6-15 of gestation at a concentration of 875 ppm (0.0875%) in air. A
commercial grade containing 5.5% inhibitors and impurities was used
giving a concentration of 50 ppm (0.005%) in the exposure chamber. A
significant increase was reported in absolute weight of the liver of
rats but not mice. The relative liver weights were unaffected in both
species. No other maternal toxicity was uncovered.
Certain soft tissue and skeletal abnormalities occurred in the
litters of exposed mice and rats that did not occur in litters of
control mothers. In mice, one of 13 litters had short tails, cleft
palates, and extra sternebra. Split and malaligned sternebra were
evident in two of 13 litters. In rats, 4% of the litters had
supernumerary vertebra. These effects were not statistically
significant, however. It was concluded that 1,1,1-trichloroethane
(875 ppm) (0.0875%) caused little or no maternal, embryonal or foetal
toxicity and that it was not teratogenic in either species under the
experimental conditions (Schwetz et al., 1975).
Acute toxicity
Animal Route LD50 Reference
Mouse Oral 11.2 g/kg Torkelson et al., 1958
i.p. 4.7 g/kg Gehring, 1968
i.p. 5 g/kg Klaassen & Plaa, 1966
inhl 13 500 ppm (1.35%)/10h Gehring, 1968
inhl 3 911 ppm (0.3911%)/2h Horiguchi & Horiuchi, 1971
Rat Oral 10.3-12.3 g/kg Torkelson et al., 1958
i.p. 3.8 ml/kg Klaassen & Plaa, 1969
inhl 18 000 ppm (1.8%)/3h Adams et al., 1950
Guinea-pig Oral 9.5 g/kg Torkelson et al., 1958
Rabbit Oral 5.7 g/kg Torkelson et al., 1958
Dog i.p. 3.1 g/kg Klaassen & Plaa, 1967
Short-term studies
Groups of male CF-1 strain mice were exposed to
1,1,1-trichloroethane at either 250 or 1000 ppm (0.025 or 0.1%) by
inhalation in air continuously for 14 weeks. Serial sacrifice of
control and high-exposure groups of mice from weeks 1 through 14
demonstrated significant alterations in the centrilobular hepatocytes
was shown by electron microscopy. These changes consisted of
vesiculation of the rough endoplasmic reticulum, loss of attached
polyribosomes, increased smooth endoplasmic reticulum, microbodies,
ballooned cisternae of the rough endoplasmic reticulum, and
triglyceride droplets. These effects were milder to minimal in the
low-exposure group. Necrosis of individual hepatocytes, inflammatory
infiltration, and hypertrophied Kupffer cells occurred in 40% of the
high-exposure group after 12 weeks (McNutt et al., 1975).
Groups of rats and cats were exposed to 1,1,1-trichloroethane
vapour at 73 ppm (0.0073%) four hours per day from 50 to 120 days.
Minor changes in the conditioned reflex activity of the cats were
found. Venous hyperaemia was observed in the liver, kidneys, heart,
and lungs of rats after 50 days and was more pronounced after 120
days. Protein dystrophy of the liver parenchymal cells was observed in
rats examined after 120 days of exposure. Emphysematous enlargement of
alveoli and bronchial epithelium swelling were noted in rats after 50
days and was more pronounced after 120 days. There were small amounts
of mucus and detached epithelial cells in the bronchial lumen. The
peribronchial nodules were hyperplastic (Tsapko & Rappoport, 1972).
OBSERVATIONS IN MAN
At least 30 fatalities associated with exposure to
1,1,1-trichloroethane have been reported in the literature. In all of
these cases death was due to severe depression of the CNS; autopsy
also revealed damage to the lungs, liver, and kidneys. One case of
possible hypersensitivity has been reported where neurological effects
were minimal while liver and renal damage was prominent though
reversible (Halevy et al., 1980; Bass, 1970; Caplan, 1976; Nathan &
Toseland, 1979). The pharmacodynamics of human intoxication has also
received attention (Stewart, 1961; Astrand, 1973; Seki, 1975).
Exposure of male employees in four printing plants at average
concentrations of 4, 25, 28, and 53 ppm (0.0004, 0.0025, 0.0028, and
0.0053%) has been investigated. Tests of vibrational sense, routine
laboratory examinations in haematology and urinalysis, and medical
interviews did not reveal any adverse effects. From the measured
decline in urinary concentrations of total trichloro- compounds, the
biological half-life of 1,1,1-trichloroethane was determined to be
8.7 ± 1.8 hours (N=7) (Seki et al., 1975).
An epidemiological study of 151 matched pairs of employees was
conducted in two adjacent textile plants, one of which used inhibited
1,1,1-trichloroethane as a cleaning solvent. The eight-hour TWA (time-
weighted-average) concentration ranged from 4 to 217 ppm (0.0004 to
0.0217%); exposure duration ranged from less than one to five years.
Cardiovascular and hepatic observations were of primary interest but
other health parameters were also studied. Statistical analysis of the
data did not reveal any exposure-related clinical findings (Kramer et
al., 1978).
Twenty-two female employees in a factory utilizing
1,1,1-trichloroethane as the only solvent were exposed to air
concentrations ranging from 110 to 990 ppm (0.011 to 0.099%) over a
six-year period. The women were divided into three risk groups and
compared with a reference group. No significant difference was
observed between exposed and unexposed females with respect to
clinical features, motor conduction, and psychometric data. "Neurotic"
type complaints (such as headache, anxiety, nervousness, insomnia,
etc.) were higher in the exposed group but this increase was not
significant (Maroni, 1977).
Comments
1,1,1-trichloroethane is rapidly absorbed through the lungs and
the gastrointestinal tract. The absorbed 1,1,1-trichloroethane is
primarily excreted through the lungs, with lesser amounts excreted in
the urine. Metabolites identified in the urine of man include
trichloracetic acid, and 1,1,1-trichloroethanol. Inhalation of
1,1,1-trichloroethane by rats and cats resulted in changes in the
liver, as well as venous hyperaemia in the liver, kidney, heart and
lungs. 1,1,1-trichloroethane caused little or no maternal or
foetal toxicity in mice and rats, nor was it teratogenic.
1,1,1-trichloroethane has not been demonstrated to be mutagenic in
bacterial systems.
Oral administration of 1,1,1-technical-trichloroethane to mice
resulted in liver tumours. However, this carcinogenicity study, as
well as a similar study in rats, is not considered adequate to
determine if 1,1,1-trichloroethane is carcinogenic because of the poor
survival of the test animals. The studies are being repeated.
EVALUATION
No ADI allocated.
FURTHER WORK OR INFORMATION
Results of ongoing life-time studies in rodents.
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Elovaara, E. Hemminki, K. & Vainio, H. (1979) Effects of Methylene
Chloride, Trichloroethane, and Trichloroethylene,
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Fukabori, S. et al. (1977) On the Cutaneous Absorption of
1,1,1 Trichloroethane, J. Sci. Labour, 53, 89-95
Gehring, P. J. (1968) Hepatotoxic Potency of Various Chlorinated
Hydrocarbon Vapours Relative to Their Narcotic and Lethal
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Hake, C. L. et al. (1960) The Metabolism of 1,1,1-Trichloroethane by
the Rat, Arch. Environ. Health, 1, 101-105
Halevy, J., Pitlik, S. & Rosenfeld, J. (1980) 1,1,1-Trichloroethane
Intoxication: A Case Report with Transient Liver and Renal
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Holmberg, B., Jakobson, I. & Sibvardsson, K. (1977) A Study on the
Distribution of Methylchloroform and n-Octane in the Mouse During
and After Inhalation, Scand. J. Work Environ. Health, 3,
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Horiguchi, S. & Horiuchi, K. (1971) An Experiment of 1,1,1-
Trichloroethane Vapor Exposure to mice (Supplementary Report on
the Toxicity of 1,1,1-Trichloroethane I.), Jap. J. Ind. Health,
13, 226-227
Humbert, B. E. & Fernandez, J. G. (1977) Exposition au 1,1,1-
Trichloroethane; Contribution à l'etude de l'absorption, de
l'excretion et du Metabolism sur des Sujets Humains, Arch. Mal.
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Chlorinated Hydrocarbons on Liver and Kidney Function in Mice,
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Maternally Inhaled Trichloroethylene, Perchloroethylene, Methyl
Chloroform, and Methylene Chloride on Embryonal and Fetal
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Occup. Hyg., 11, 71-79
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Vapor: Relationship of Expired Air and Blood Concentrations to
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Vapors on Animals, Farmakol. Toksikol. (Kiev), 7, 149-151
Vainio, H., Pfaffli, P. & Savolainen, H. (1978) Comparison Between
the Acute Toxicity of 1,1,1-Trichloroethane and 1,1,2-
Trichloroethylene (Abstract). In: Plaa, G. L. & Duncan, W. A. M.,
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WHO/FAO (1980) Evaluation of Certain Food Additives, 23rd report of
the Joint FAO/WHO Expert Committee on Food Additives, Technical
Report Series, 648, World Health Organization, Geneva, 1980
ANNEX
REPORT AND OTHER DOCUMENTS RESULTING FROM PREVIOUS MEETINGS ON THE
JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES
Documents marked with an asterisk may be obtained on request
from: Division of Environmental Health, World Health Organization,
1211 Geneva 27, Switzerland, or from Food Standards and Food Science
Service, Food and Agriculture Organization of the United Nations,
00100 Rome, Italy.
1. General principles governing the use of food additives (First
report of the Expert Committee). FAO Nutrition Meetings Report
Series, No. 15, 1957; WHO Technical Report Series, No. 129, 1957
(out of print).
2. Procedures for the testing of intentional food additives to
establish their safety for use (Second report of the Expert
Committee). FAO Nutrition Meetings Report Series, No. 17, 1958;
WHO Technical Report Series, No. 144, 1958 (out of print).
3. Specifications for identity and purity of food additives
(anti-microbial preservatives and antioxidants) (Third report
of the Expert Committee). These specifications were subsequently
revised and published as Specifications for identity and purity
of food additives, vol. I. Antimicrobial preservatives and
antioxidants, Rome, Food and Agriculture Organization of the
United Nations, 1962 (out of print).
4. Specifications for identity and purity of food additives (food
colours) (Fourth report of the Expert Committee). These
specifications were subsequently revised and published as
Specifications for identity and purity of food additives, vol.
II. Food colours, Rome, Food and Agriculture Organization of
the United Nations, 1963 (out of print).
5. Evaluation of the carcinogenic hazards of food additives (Fifth
report of the Expert Committee). FAO Nutrition Meetings Report
Series, No. 29, 1961; WHO Technical Report Series, No. 220, 1961
(out of print).
6. Evaluation of the toxicity of a number of antimicrobials and
antioxidants (Sixth report of the Expert Committee). FAO
Nutrition Meetings Report Series, No. 31, 1962; WHO Technical
Report Series, No. 228, 1962.
7. Specifications for the identity and purity of food additives
and their toxicological evaluation: emulsifiers, stabilizers,
bleaching and maturing agents (Seventh report of the Expert
Committee). FAO Nutrition Meetings Report Series, No. 25, 1964;
WHO Technical Report Series, No. 281, 1964 (out of print).
8. Specifications for the identity and purity of food additives
and their toxicological evaluation: food colours and some
anti-microbials and antioxidants (Eighth report of the Expert
Committee). FAO Nutrition Meetings Report Series, No. 38, 1965;
WHO Technical Report Series, No. 309, 1965 (out of print).
*9. Specifications for identity and purity and toxicological
evaluation of some antimicrobials and antioxidants. FAO
Nutrition Meetings Report Series, No 38A, 1965; WHO/Food
Add/24.65.
*10. Specifications for identity and purity and toxicological
evaluation of food colours. FAO Nutrition Meetings Report
Series, No. 38B, 1966; WHO/Food Add/66.25.
11. Specifications for the identity and purity of food additives
and their toxicological evaluation: some antimicrobials,
antioxidants, emulsifiers, stabilizers, flour-treatment agents,
acids, and bases (Ninth report of the Expert Committee). FAO
Nutrition Meetings Report Series, No. 40, 1966; WHO Technical
Report Series, No. 339, 1966.
12. Specifications for the identity and purity of food additives
and their toxicological evaluation: some emulsifiers and
stabilizers and certain other substances (Tenth report of the
Expert Committee). FAO Nutrition Meetings Report Series, No. 43,
1967; WHO Technical Report Series, No. 373, 1967.
*13. Toxicological evaluation of some antimicrobials, antioxidants,
emulsifiers, stabilizers, flour-treatment agents, acids, and
bases. FAO Nutrition Meetings Report Series, No. 40A,B,C;
WHO/Food Add/67.29.
14. Specifications for the identity and purity of food additives
and their toxicological evaluation: some flavouring substances
and non-nutritive sweetening agents (Eleventh report of the
Expert Committee). FAO Nutrition Meetings Report Series, No. 44,
1968; WHO Technical Report Series, No. 383, 1968.
15. Toxicological evaluation of some flavouring substances and
non-nutritive sweetening agents. FAO Nutrition Meetings Report
Series, No. 44A, 1968; WHO/Food Add/68.33.
*16. Specifications and criteria for identity and purity of some
flavouring substances and non-nutritive sweetening agents. FAO
Nutrition Meetings Report Series, No. 44B, 1969; WHO/Food
Add/69.31.
17. Specifications for the identity and purity of food additives
and their toxicological evaluation: some antibiotics (Twelfth
report of the Expert Committee). FAO Nutrition Meetings Report
Series, No. 45, 1969; WHO Technical Report Series, No. 430, 1969.
*18. Specifications for the identity and purity of some antibiotics.
FAO Nutrition Meetings Report Series, No. 43A, 1969; WHO/Food
Add/69.34.
19. Specifications for the identity and purity of food additives
and their toxicological evaluation: some food colours,
emulsifiers, stabilizers, anticaking agents and certain other
substances (Thirteenth report of the Expert Committee). FAO
Nutrition Meetings Report Series, No. 46, 1970; WHO Technical
Report Series, No. 445, 1970.
20. Toxicological evaluation of some food colours, emulsifiers,
stabilizers, anticaking agents, and certain other substances.
FAO Nutrition Meetings Report Series, No. 46A; WHO/Food Add/
70.36.
*21. Specifications for the identity and purity of some food
colours, emulsifiers, stabilizers, anticaking agents, and
certain other food additives. FAO Nutrition Meetings Report
Series, No. 46B; WHO/Food Add/70.37
22. Evaluation of food additives: specifications for the identity
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26. Evaluation of food additives: some enzymes, modified starches,
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FAO Nutrition Meetings Report Series, No. 50, 1972; WHO Technical
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27. Toxicological evaluation of some enzymes, modified starches,
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28. Specifications for the identity and purity of some enzymes and
certain other substances. FAO Nutrition Meetings Report Series,
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29. A review of the technological efficacy of some antioxidants and
synergists. FAO Nutrition Meetings Report Series, No. 50C,
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30. Evaluation of certain food additives and the contaminants
mercury, lead, and cadmium (Sixteenth report of the Expert
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WHO Technical Report Series, No. 505, 1972, and corrigendum.
31. Evaluation of mercury, lead, cadmium and the food additives
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32. Toxicological evaluation of certain food additives with a
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33. Toxicological evaluation of certain food additives including
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34. Evaluation of certain food additives (Eighteenth report of the
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35. Toxicological evaluation of some food colours, enzymes, flavour
enhancers, thickening agents, and certain other food additives.
FAO Nutrition Meetings Report Series, No. 54A, 1975; WHO Food
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36. Specifications for the identity and purity of some food colours,
flavour enhancers, thickening agents, and certain food additives.
FAO Nutrition Meetings Report Series, No. 54B, 1975; WHO Food
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37. Evaluation of certain food additives: some food colours,
thickening agents, smoke condensates, and certain other
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38. Toxicological evaluation of some food colours, thickening
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39. Specifications for the identity and purity of certain food
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40. Evaluation of certain food additives (Twentieth report of the
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WHO Technical Report Series, No. 599, 1976.
41. Toxicological evaluation of certain food additives. FAO Food
and Nutrition Series, No. 1A, 1978; WHO Food Additives Series,
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42. Specifications for the identity and purity of certain food
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43. Evaluation of certain food additives (Twenty-first report of
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Technical Report Series, No. 617, 1978.
44. Summary of Toxicological data of certain food additives. WHO
Food Additives Series No. 12, 1977.
45. Specifications for identity and purity of some food additives,
including antioxidants, food colours, thickeners, and others.
FAO Nutrition Meeting Report Series, No. 57, 1977.
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anticaking agents, antimicrobials, antioxidants and
emulsifiers. FAO Food and Nutrition Paper, No. 4, 1978.
47. Guide to specifications - General notices, general methods,
identification tests, text solutions, and other reference
materials. FAO Food and Nutrition Paper, No. 5, 1978.
48. Evaluation of certain food additives (Twenty-second report of
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Technical Report Series, No. 631, 1978.
49. Summary of toxicological data of certain food additives and
contaminants. WHO Food Additives Series, No. 13, 1978.
50. Specifications for the identity and purity of certain food
additives. FAO Food and Nutrition Paper, No. 7, 1978.
51. Evaluation of certain food additives (Twenty-third report of
the Joint FAO/WHO Expert Committee on Food Additives). WHO
Technical Report Series, No. 648, 1980.
52. Toxicological evaluation of certain food additives. WHO Food
Additives Series, No. 14, 1979.
53. Specifications for identity and purity of food colours,
flavouring agents, and other food additives. FAO Food and
Nutrition Paper, No. 12, 1979.
54. Evaluation of certain food additives (Twenty-fourth report of
the Joint FAO/WHO Expert Committee on Food Additives). WHO
Technical Report Series, No. 653, 1980.
55. Toxicological evaluation of certain food additives. WHO Food
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56. Specifications for identity and purity of food additives
(sweetening agents, emulsifying agents, and other food
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