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The FAO/WHO Expert Committee on Pesticide Residues since 1963 has been entrusted by the World Health Organization and the Food and Agriculture Organization with the responsibility of assessing possible hazards to man from the occurrence of residues of pesticides in foods. The toxicological and administrative decisions of this expert group are reviewed in this paper with particular regard to the scientific background which served as a basis to the allocation of acceptable daily intakes (ADIs). Exhaustive references to documents issued after each meeting have been assembled in a way intended to facilitate the search for important sources of information to the worker in toxicology who might not be completely familiar with the dynamics of this activity at the international level.

Groups of ten male and ten female rats were fed for 90 days on diets containing methylcellulose (10 or 4000 cP) or hydroxypropylmethylcellulose (10 or 4000 cP) at concentrations of 0, 3 and 10% (and in some cases 1 %). Groups of two male and two female beagle dogs received hydroxypropylmethylcellulose (10 cP) in their diets at concentrations of 0, 2 or 6 % for 90 days. No evidence of toxicity was observed in either rats or dogs as judged by mortality, body weights, food-consumption values, urine analyses, haematological evaluations, levels of serum components, organ weights and gross and histopathological examination of tissues. Two long-term (2-yr) studies in rats were conducted on methylcellulose (15, 400 and 4000 cP) at dietary levels of 0, 1 and 5 %, each dose level being fed to a total of 50 rats of each sex in the two studies. There was no evidence of treatment-related effects on mortality, body weights, food intake, haematology, levels of serum components, organ weights, gross and microscopic pathology or incidence of tumours. These studies contribute additional evidence for the inert nature of the methylcellulose materials. Furthermore, the long-term studies indicate that methylcellulose does not possess tumorigenic properties.

The acute and long-term toxicity of orally administered chlorpyrifos (O,O-diethyl-O-(3,5,6-trichloro-2-pyridyl) phosphorothioate), a broad-spectrum insecticide, has been determined. No sex or strain differences in acute oral toxicity were detected using two strains of rat, and LD50 values determined in several tests ranged from 118 to 245 mg/kg. LD50 values (in mg/kg) for other species were approximately 2000 for rabbits, 504 for guinea-pigs and 32 for leghorn chicks. Rats and dogs were maintained on diets providing doses of 0·0, 0·01, 0·03, 0·1, 1·0 or 3·0 mg chlorpyrifos/kg/day. In dogs, ChE activity in plasma was depressed by the 3·0, 1·0 and 0·1 mg/kg/day doses, and receiving 3·0 or 1·0 mg/kg/day. ChE activity of the brain of rats was depressed by a dose of 3·0 mg/kg/day. In dogs, ChE activity in plasma was depressed by the 3·0, 1·0 and 0·1 mg/kg/day doses, and that in red cells by the 3·0 and 1·0 mg/kg/day doses. Brain ChE was slightly depressed in dogs receiving the highest dose. In the long-term study, no clinical evidence of induction of cholinergic activity was observed in either species at any time. Depression of ChE activity was readily reversible when the control diets were substituted for diets containing chlorpyrifos. No significant effects related to treatment were observed in rats or dogs receiving any dose of chlorpyrifos, using the following criteria:mortality, body weights, food intake, haematological studies, urine analyses, clinical chemistry studies, organ weights and organ to body weight ratios, tumour incidence and gross and histopathological examination of tissues. It was concluded that 0·1 and 0·03 mg chlorpyrifos/kg/day fed in the diet for 2 yr produced no significant toxicological effect in rats and dogs, respectively. Even in animals receiving 3·0 mg/kg/day, no effects were observed other than a reversible depression of cholinesterase activity.

Groups of ten male and ten female rats were fed for 90 days in diets containing methylcellulose (10 or 4000 cP) or hydroxypropylmethylcellulose (10 or 4000 cP) at concentrations of 0, 3 and 10% (and in some cases 1%). Groups of two male and two female beagle dogs received hydroxypropylmethylcellulose (10 cP) in their concentrations of 0, 2 or 6% for 90 days. no evidence of toxicity was observed in either rats or dogs as judged by mortality, body weights, food-consumption values, urine analyses, haematological evaluations, levels of serum components, organ weights and gross and histopathological examination of tissue. Two long-term (2-yr) studies in rats were conducted on methylcellulose (15, 400 and 4000 cP) at dietary levels of 0, 1 and 5% each dose level being fed to a total of 50 rats of each sex in the two studies. There was no evidence of treatment-related effects on mortality, body weights food intake, haemotology, levels of serum components, organ weights, gross and microscopic pathology or incidence of tumours. These studies contribute additional evidence for the inert nature of the methylcellulose materials. Furthermore, the long-term studies indicate that methylcellulose does not possess tumorigenic properties.

Patents, published literature, and commercial usage have established the utility of the propylene glycol ether of methylcellulose (hydroxypropyl methylcellulose) as a food additive and as a formulation aid in drug products. Aqueous solutions of this cellulose gum, like methylcellulose, will gel upon heating. Feeding studies on Methocel, Methocel 60HG, and Methocel 65HG have previously been published. The results of feeding Methocel 70HG and Methocel 90HG in the diet of rats at levels of 0.3, 1.0, 3.0, 10.0, and 20.0 per cent for periods of ninety and eighty-four days, respectively, confirm previous chronic oral toxicity studies that the propylene glycol ether of methylcellulose is extremely low in repeated oral toxicity and that it can be used safely in the drug, food, and pharmaceutical fields where Methocel and Methocel 65 HG have been found suitable.

The toxicological properties of 4-tert-butyl-2-chlorophenyl methyl methylphosphoramidate (Ruelene®) have been studied extensively in laboratory animals. For a single oral administration, the LD50 values ranged from 490 to more than 1000 mg/kg in rabbits, rats, guinea-pigs and dogs. Single oral doses of Ruelene were administered to rats together with each of 14 commercial cholinesterase-inhibiting insecticides. Except for Ruelene with malathion, where the ratio of expected to observed values was 5·3, the effect on LD50 values was additive (with ratios ranging from 0·7 to 2·2). Feeding studies in dogs, carried out over a 12-wk period with 100 ppm malathion plus 20 ppm Ruelene or 10 ppm malathion plus 20 ppm Ruelene, showed no significant evidence of potentiation. In 90-day feeding studies in rats, no ill effects occurred at levels ranging from 30 to 1000 ppm Ruelene, except a peculiarly uniform decrease in blood- and/or brain-cholinesterase activity amounting to 40–60%. A 75-day feeding study in dogs showed no evidence of significant toxicological effect with diets containing 40 or 125 ppm Ruelene. At a level of 250 ppm, blood-cholinesterase activity decreased slightly and minor changes were observed microscopically in the liver. In a 2-yr dietary study in rats, 1000 ppm Ruelene caused slight growth retardation, degeneration of testes, atrophy of hind quarters and slight sciatic nerve degeneration. The only effect at the 100 ppm level was depression of cholinesterase activity in the blood. A multi-generation study in rats showed no effect on reproduction and fertility at dietary levels up to 500 ppm. Beagle dogs were maintained for 2 yr on dietary levels ranging from 10 to 2000 ppm Ruelene. The animals on the highest level of Ruelene manifested gross signs of intoxication and values of serum alkaline phosphatase and transaminase were elevated. These animals, as well as those fed 200 ppm Ruelene, showed depressed plasma- and erythrocyte-cholinesterase activities. Other biochemical and haematological findings and the results of gross and microscopic examination of the tissues were comparable with the controls. On the basis of these findings, an acceptable daily intake for man of 0·05−0·2 mg/kg/day can be calculated for Ruelene.

This laboratory became interested in acrylamide early in 1954, when it became apparent that the material had great potential as a monomer and comonomer to make resins with unique flocculating action, and later as a dry strength improver in the manufacture of paper and paperboard. At that time, there were no published data on the toxicity of acrylamide. Later, it was learned that American Cyanamid Com- pany was sponsoring work on the material, portions of which have been reported by Hamblin (1956) and Kuperman (1958) . It soon became quite apparent that the rather high and unusual toxicity of the monomer would require extensive toxicologic study in order that recommendations for safe industrial handling could be ascertained, and to evaluate the safety in commercial use of polymers or copolymers which might contain small amounts of residual acrylamide.

Methocel® 2602, a new methylcellulose preparation, is intermediate in gel point properties to Methocel® and Methocel® HG, and is superior to both in compatibility with organic solvents. The results of the feeding of Methocel® 2602 in the diet of rats for a period of one hundred and twenty-one days at levels of 1, 3, 10, and 30 per cent indicate that this new methylcellulose reparation is extremely low in chronic oral toxicity. Thus, it is believed that Methocel® 2602 is safe for uses in the drug, food, and pharmaceutical fields similar to those in which Methocel®, and Methocel® HG have been found suitable.

Polyacrylamide resins (Separan NP10 and AP30 flocculants) are high molecular weight polymers with low single oral toxicity to rats. Long-term feeding studies of these resins have involved three two-year studies in rats, one one-year study in dogs, and one two-year study in dogs. These poly-acrylamides are quite low in repeated oral toxicity. The laboratory animals tolerated 5–10% in their total diet without effects other than those believed to be attributable indirectly to the large, hydrophilic, nonnutritive bulkiness of the materials. The unequivocal “no ill-effect” levels were 1% in the diet of rats and 5–6% in the diet of dogs. Studies with carbon-14 tagged resin indicate that negligible amounts of polymer, if any, pass through the walls of the gastrointestinal tract of the rat. Fish were maintained in water containing 1000 ppm of these resins for 5 days and 100 ppm for 90 days without apparent adverse effect. Environmental health and medical surveys of industrial personnel confirm the low degree of hazard associated with these materials. Adequate bases exist for establishing the safety of these products from the public health aspect for many applications wherein small amounts may possibly occur in the food or drink of animals or human subjects.

A high gel point methylcellulose (Methocel HG) was given in single doses to normal healthy young adults. Only minor symptoms were reported, e. g., mild laxative effect, mild constipating effect, and a few instances of commonplace symptoms such as cramping, flatus, headache, and tenesmus which apparently were not related to the ingestion of Methocel HG. Essentially all of the ingested Methocel HG was eliminated in the feces within ninety‐six hours following administration.

Short- and long-term feeding studies of the pesticide, p -chlorophenyl- p -chlorobenzenesulphonate (ovex), have been carried out in rats and a 6-month feeding study in dogs. The acute oral LD 50 of ovex in rats was 2·05 g/kg and ranged from 0·64 to 5·66 g/kg in guinea-pigs, rabbits, mice and chicks. In the short-term study on rats fed on a diet containing 0, 0·03, 0·1, 0·3 or 1% ovex for 130 days toxic effects became apparent at the 0·1% level as evidenced by increased liver weight and slight cloudy swelling in the central areas of the liver. At the two highest dietary levels these effects were more pronounced and in addition growth retardation and slight to moderate degeneration of the tubular epithelium of the kidney were also observed. When animals were placed on a similar regime for 164 days and then allowed to partake of the control diet for the next 152 days the histopathological changes previously seen were now absent and liver weight was restored to normal even at the 0·3% level. In a 2-generation reproduction study involving rats given dietary levels of 0, 0·01, 0·03 or 0·3% ovex for 164 days no adverse effect on the number of litters, litter size or survival of young to weaning was seen at the lowest level although there were slight reductions in litter size at the 0·03 and 0·3% levels. At the highest level the mother's poor condition was conducive to the failure of the young to survive weaning. In a 2-yr study on rats maintained on a diet containing 0·63, 1·25, 2·5, 5, 15 and 50 mg ovex/kg growth retardation was only seen in females at the two highest levels. Very slight liver and kidney changes were first observed at the 2·5 mg/kg/day level but the slight fatty metamorphosis of the liver and slight chronic glomerulonephritis of the kidney became more pronounced with increasing dosage levels. Dogs receiving in their diet 0, 5, 15 or 50 mg ovex/kg/day for 6 months exhibited no toxic effects apart from a doubtful significant increase in liver weight found in the groups on the two highest dietary levels. Analysis of various tissues showed that repeated ingestion of ovex does not result in its accumulation in the tissues of rats and dogs. At high dosage levels ovex is preferentially retained in the fat, partly in muscle with traces in the liver. The no-effect level of ovex in the rat was estimated to be 1·25 mg/kg/day, a figure which provides a very wide margin of safety for the human consumption of foodstuffs likely to contain ovex residues.