Alastair N. Worden

The toxicity of dimethyl sulphoxide (DMSO) for the dog, pig, rat and rabbit.

Dimethyl sulphoxide (DMSO) was tested for oral toxicity in rats and dogs, and dermal toxicity in rabbits and pigs. Oral administration was by gastric intubation as a 50% equeous solution, 5 days/week at levels equivalent to 9.0, 3.0 or 1.0 ml undiluted DMSO/hg/day. For dermal application 50% and 90% equeous solutions were used to give levels equivalent to 8.1, 4.5, 2.7 or 1.5 ml DMSO/hg/day, as one daily application for rabbits, and divided into two applications/day for pigs. Dogs were dosed for approximately 2 years and pigs for 1 year, although half the animals of both species were dosed for only 18 weeks. Rats were dosed for 18 months, but some were used for interim sacrifice after a year. Rabbits received applications to normal and abraded skin for 6 months. Minor changes in bodyweight and haematological values were observed, together with a physiological diuretic response to DMSO, but the target organ was the eye, principally the lenticular nucleus. Ocular effects in dogs started after 5-10 weeks dosing at 9 ml/kg and consisted of central (nuclear) lens changes with alteration of the refractive index (myopia); transitory equatorial opacities during the 5th month; central (nuclear) opalescence; and changes in the vitreous humour. Similar changes occurred more slowly at 3 ml/kg, the alterations to the vitreous being first observed after 9-10 months at this level. Progressive nuclear refractive changes occurred after dosing for considerably longer than 6 months at 1ml/kg, but none of the animals in this group manifested the opalescence. Biochemical investigation of the lenses revealed reduction of soluble protein (mainly alpha-crystallin), glutathione and water levels, and an increase of insoluble protein. Evidence of recovery was limited mainly to a reduction in the number of dioptres needed to correct nuclear refractive change. Cessation of dosing led to regression of refractive nuclear changes but did not prevent the appearance of opalescence at 3 ml/kg and above. Dogs were the most severely affected of the 4 species, with nuclear effects at 1ml/kg, extensive changes in the lens, and involvement of the vitreous. Pigs and rabbits were affected by dose levels of 2.7 ml/kg and 1.5 ml/kg respectively. Rats occasionally showed minimal changes at 9 ml/kg. The importance of the findings in dogs is discussed in relation to general toxicological protocols. It is emphasised that reversibility of signs, and adequate duration of administration, must both be considered when ascertaining whether changes occur at levels approximating to those of human intake.

Effects of lindane upon reproductive function in a 3-generation study in rats.

A 3-generation study, involving the feeding of lindane at dietary concentrations of 25, 50 or 100 ppm to CD strain rats, did not reveal any adverse effects upon reproductive function as compared with that of control animals. There were no major malformations, while the distribution of minor variants was not compound or dose-related. An examination at 21 days of age of 10 males and 10 females F3B animals in each group revealed a dosage related tendency for increased liver weight and enlarged hepatocytes were seen in some control and treated animals. The relevance of these latter findings was considered of doubtful importance compared with the lack of effects on the growth and reproductive performance of the preceding generations.

Clioquinol toxicity in the dog

A number of instances have been reported in the scientific literature in which acute intoxication with halogenated oxyquinolines has led in some species to convlusions, often followed by death. The toxicity of repeated doses of clioquinol has been investigated extensively in the dog. The clinical syndrome induced in this species is characterized by anorexia, weight loss, extremem muscle weakness and emaciation. In some animals surviving this impairment of condition for several weeks, neuropathy of the central nervous system, but not of the peripheral nerves ensued. It is suggested that these toxicological manifestations are less dependent on the dose-level than on the degree of absorption. Some suggestions regarding the aetiology of the lesions are made.

The feeding of diets containing up to 4% monosodium glutamate to rats for 2 years

Abstract Charles River CD rats were fed diets containing either 2.05% w/w sodium propionate or 1, 2 or 4% w/w monosodium glutamate (MSG) for 104 weeks. There were no adverse effects upon bodyweight gain, economy of food consumption, haematology, blood chemistry, organ weights or mortality by comparison with control rats receiving the basal diet. Water consumption, urinary volume and sodium excretion were increased at 2.05% sodium propionate or 4% MSG, and this appeared to be reflected in an increased incidence and earlier onset of spontaneous subepithelial basophilic deposits in the renal pelvis among treated rats. Focal mineralization at the renal corticomedullary junction occurred with equal frequency in all groups, including untreated controls. There were no other histological findings of significance.

Neuropathologic effects and comparative toxicity for dogs of isonicotinic acid hydrazide and its methanosulfonate derivative

Abstract Dogs were dosed orally once a day, 6 days per week, with isoniazid and its methanosulfonate derivative at various dosages over a period of 6 months. The principal objective was to study the chronic oral toxicity of the methanosulfonate, and the secondary objective was to make a comparison with isoniazid. For the latter purpose, the relationship accepted was the in vivo mouse tuberculosis assessment that 2.5 mg/kg/day of isoniazid was equivalent to 3.04 mg/kg/day of its methanosulfonate. Isoniazid methanosulfonate was tolerated by dogs at just above three times the level equivalent to the “maximum safe human dose level” for isoniazid. Deaths occurred at the equivalent isoniazid level. The difference was due in part to the different rate of absorption of the two compounds. Biochemical and hematologic findings were essentially negative, although a mild, nonprogressive anemia occurred with both drugs after 3 months of dosing. There were no constant histologic changes in the viscera, including the liver, or in the peripheral nervous system. At the higher dosages with both compounds, however, and to a lesser extent at the lower dosages, there was histologic evidence of brain damage. The changes affected principally the subcortical myelin of the cerebral hemisphe. Their nature was essentially the same with both drugs, probably being caused by edema. In some of the dogs dosed with isoniazid there was also microcavitation affecting the roof nuclei of the cerebellum, often with glial activation. These changes were present in only one animal dosed with the methanosulfonate derivative.

The oral toxicity of clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) in beagle dogs

When clioquinol was administered to Beagle dogs, disturbances in gait which were associated with abnormal reflexes and reactions, were seen in animals receiving 250 and 400 mg/kg body weight per day. Histopathological examination of the central nervous system (CNS) showed pathological change in the posterior columns of the spinal cord.

The feeding of diets containing up to 10% monosodium glutamate to beagle dogs for 2 years

Abstract Beagle dogs were fed diets containing either 5.13% w/w sodium proprionate or 2.5, 5.0 or 10.0% w/w monosodium glutamate (MSG) for 104 weeks. There were no adverse effects upon bodyweight gain, economy of food consumption, general behaviour, ECG, ophthalmological findings, haematology, blood chemistry, organ weights or mortality by comparison with control dogs receiving the basal diet. Urinary volume and sodium excretion were slightly raised in dogs receiving sodium propionate or MSG, but the ability to concentrate urine was unimpaired and there were no histological differences between treated and control animals.

The administration of maleic hydrazide and its diethanolamine salt to rats

Abstract Groups each of 25 male and 25 female rats from a closed outbred Wistar Colony were injected subcutaneously with 2 mg of either maleic hydrazide (MH) or of its diethanolamine derivative (MH30), in either arachis oil or water, twice weekly for 65 weeks, and the animals maintained under observation for a further 39 weeks. In the group receiving MH in arachis oil there were 4 subcutaneous tumours, compared with 1 in the control group receiving arachis oil alone. There was no significant elevation of tumour incidence in rats receiving MH in water, or MH30 in either arachis oil or water, and none of the treatments appeared to affect the incidence of hepatic or mammary gland tumours. The results do not support the findings on a very small number of rats of the same strain employed by Dickens and Jones, nor those obtained by the technique of Epstein and his co-workers, but are in keeping with the findings of Barnes and his collaborators and support the safety-in-use of MH or MH30.

Feeding studies on lenacil in the rat and dog.

Abstract Lenacil (Herbicide 634), 3-cyclohexyl-5,6-trimethyleneuracil, was incorporated at levels up to 10,000 ppm in the diets of rats and dogs in studies lasting 2 years. There was an almost complete absence of toxic responses in both species, with no evidence of carcinogenicity, and the only effects that could be attributed to lenacil were impaired food utilization and rate of body weight gain in rats receiving the high level; these effects were not manifested until the dosage had been raised to the equivalent of a daily intake of 400 and 800 mg/kg body weight, respectively, in females and males. A relative increase in liver weight was apparent in both sexes at termination, by which time the daily intake had approximated 1000 mg/kg for over a year, but this is not regarded as having a toxicologic significance. A dietary daily intake equivalent to 50 mg/kg throughout was without effect in animals of either sex. There were negative findings also in reproductive studies in rats in which dietary concentrations of up to 500 ppm were fed over 3 generations, with no evidence of a teratogenic effect. The dogs remained normal throughout, and 2 of the females that became accidentally pregnant after receiving the high level of lenacil for over a year, gave birth to litters of healthy pups.

Toxicity of gusathion for the rat and dog

Abstract Gusathion or O,O -dimethyl- S (4-oxobenzotriazin-3-methyl) phosphorodithioate (guthion) was subjected to toxicity studies lasting 2 years in rats and dogs. In the rat study, a dietary concentration of 50–100 ppm gusathion (approximately 5–10 mg/kg body weight/day) was tolerated without adverse effect upon growth, food consumption, renal function, hematopoiesis, or survival, although convulsive episodes were recorded for some females, and blood plasma, erythrocyte and brain cholinesterase values were depressed. In terms of cholinesterase inhibition, the 5 ppm and 2.5 ppm were virtually “no effect” levels. In the dog study, an “effect level” was eventually obtained when the dietary concentration of gusathion for the high-level group had been raised stepwise from an initial 50 ppm, abnormal signs following almost immediately when the level was changed from 150 ppm (approximately 5 mg/kg/day) to 300 ppm (approximately 10 mg/kg/day). There was only a slight depression of cholinesterase after feeding at 50 ppm for a year. No organ damage that could be attributed to gusathion was found at any dose level in either species.