Subchronic toxicity studies of sucrose acetate isobutyrate (SAIB) in the rat and dog.

Preliminary short-term toxicity studies of sucrose acetate isobutyrate (SAIB) in the dog demonstrated that addition of this additive to the diet was associated with an increase in liver size and elevated serum alkaline phosphatase activity with no evidence of pathological change by light microscopy. To determine the basis for these changes, a 12-week oral toxicity study of SAIB was conducted in the dog and a similar study was performed in the rat. SAIB was fed in the diet to groups of six beagle dogs of each sex at 0, 0.5, 1.0, 2.0 and 4.0%. SAIB was also fed to groups of 40 Sprague-Dawley rats of each sex at levels of 0, 2.5, 5.0 and 10.0%. In the rat study, in addition to routine toxicology parameters, hepatic microsomal enzyme induction was determined using a zoxazolamine hypnotic test, urinary ascorbic acid excretion and determination of hepatic carboxylesterase activity. Sodium phenobarbital was fed to groups of 20 rats of each sex at a dose of 100 mg/kg body weight/day by gavage as a positive control for hepatic microsomal enzyme induction. In the dog study, routine toxicological tests were supplemented by tests for bromsulfophthalein (BSP) retention, histochemical staining of liver sections for glycogen, phosphorylase, succinate dehydrogenase, and acid and alkaline phosphatases. Levels of liver lipid, protein, glycogen and carboxylesterase activity were also determined. Electron microscopic examinations were made on liver sections from the dog study at the end of the 12-week SAIB feeding period and after a 2-week withdrawal period. Administration of SAIB to rats did not reveal evidence of any effect on hepatobiliary function, and there was no indication of microsomal enzyme induction. Body weight gain of male rats fed SAIB was decreased, probably as the result of decreased palatability of the diet; SAIB did not affect body weight gain in females. The changes observed in the dogs fed SAIB included increased serum alkaline phosphatase activity with no change in serum alanine aminotransferase, aspartate aminotransferase or lactic dehydrogenase activity and no change in serum electrolyte, serum protein, glucose or bilirubin levels. No haematological changes were observed. BSP retention was observed at all SAIB dose levels. There were no SAIB-related pathological changes in any organ when examined by light microscopy. Examination by electron microscope revealed dilatation of bile canaliculi and an increase in smooth endoplasmic reticulum compared with controls. Histochemical studies also indicated increased enzyme activity of the bile canaliculi. The electron-microscope-revealed changes were completely reversed during a 2-week treatment withdrawal period. The dog study did not establish a no-effect level for changes in hepatobiliary function induced by feeding SAIB.

Subchronic oral toxicity of di-n-octyl phthalate and di(2-Ethylhexyl) phthalate in the rat.

The subchronic oral toxicity of di(2-ethylhexyl) phthalate (DEHP) and di-n-octyl phthalate (DNOP) was studied. Groups of 10 male and 10 female Sprague-Dawley rats were administered DEHP in the diet at 0, 5, 50, 500 or 5000 ppm for 13 wk. In a separate study, groups of 10 male and 10 female Sprague-Dawley rats were given DNOP (5, 50, 500 and 5000 ppm) in the diet while control groups received basal diet containing 4% corn oil and positive control groups were fed a diet containing 5000 ppm DEHP. Growth rate and food consumption were not affected by treatment with either compound. Hepatomegaly was observed in the highest dose groups of both sexes administered DEHP but not in the DNOP-treated animals. At the highest dose, DNOP caused threefold (females) and 12-fold (males) increases in liver ethoxyresorufin-O-deethylase activity while DEHP did not. Mild changes in serum biochemistries were mostly confined to rats in the highest dose group of DEHP, and included increased serum albumin and albumin/globulin ratio in both sexes and decreased cholesterol in female rats. Mild vacuolations in the Sertoli cells were observed in male rats exposed to 500 ppm DEHP. At 5000 ppm DEHP, there was mild to moderate seminiferous tubule atrophy and Sertoli cell vacuolation in males, and rats of both sexes showed hepatic peroxisome proliferation. Both DEHP and DNOP at 5000 ppm caused mild histological changes in the thyroid consisting of reduced follicle size and colloid density, and the liver consisting of endothelial nuclear prominence, nuclear hyperchromicity and anisokaryosis. There was accentuation of zonation of the hepatic lobules and increased perivenous cytoplasmic vacuolation in DNOP-treated rats. Trace quantities (3-5 ppm) of DEHP and DNOP were detected in the liver, and 15-31 ppm were found in adipose tissue of the highest dose groups. The no observed-effect-level was judged to be 50 ppm in the diet or 3.7 mg/kg body weight/day for DEHP, and 500 ppm or 36.8 mg/kg body weight/day for DNOP.

Experimental studies on acute and chronic action of azelastine on nasal mucosa in guinea pigs, rats and dogs.

Azelastine (CAS 37932-96-0) nasal spray (Allergodil, Rhinolast, Astelin) was investigated in acute experiments in guinea pigs and after a 26-week local application period with daily repeated administration for effects on ciliary beat activity (acute experiments) and morphology of nasal mucosa. The commercially available spray did not inhibit ciliary beat activity in guinea pigs nor did it cause any inflammatory or atrophic changes after 26-week daily local application on nasal mucosa in rats and dogs.

A three month inhalation toxicity study in the squirrel monkey (Saimiri sciureus) with terbutaline sulfate (Bricanyl).

A study of the subacute toxicity of inhaled terbutaline sulfate was performed in the Squirrel monkey (Saimiri sciureus). 3 groups of monkeys were exposed 1 h daily 7 days/week for 3 months to terbutaline sulfate aerosols at concentrations of 0.039, 0.185 and 0.799 mg terbutaline/litre of air respectively. A fourth group was a chamber control receiving air only. The following clinical parameters were evaluated: physical appearance and behavior, weight gain, ophthalmoscopic appearance, electrocardiograms, hemograms, blood biochemical profiles and urinalyses. At termination necropsies were conducted and organ weights determined. A variety of staining techniques was employed in the histopathological examination of tissues. Special attention was given to heart and lung. The distribution of goblet cells in sections from the main bronchi and trachea was also investigated. Occasionally a few animals in both the intermediate and high dose groups showed small amounts of exudate and frothing around the mouth during exposure to their respective terbutaline aerosols. No other changes that could be attributed to the exposure to terbutaline aerosols were seen in any parameter.

Studies on the spring rise phenomenon in ovine helminthiasis. I. Spring rise in stabled sheep.

Serial ova count studies were conducted to determine some of the characteristics of the spring rise in faecal shedding of nematode ova by parasitized sheep in flocks in the Montreal area. It was discovered that substantial spring rises occurred in most ewes following their lambing but that great variation existed in the magnitude, duration, and pattern of the rises. Although rams did not display increased ova counts, a slight but well-defined rise developed in one unbred ewe. Larval studies in ewes parasitized by a variety of nematode species, revealed that Haemonchus contortus was the major contributor to the spring rise in faecal ova output. Preparturient treatment of ewes with thiabendazole(1), at the rate of 100 mg./kg. of body weight, suppressed spring rise but failed to arrest completely the faecal shedding of nematode ova.