E.V. Buehler

A comparison of eye irritation in monkeys and rabbits

Abstract The above study has shown that monkey and rabbit eyes respond differently to moderately irritating surfactant solutions. In addition when these materials are used as test solutions, the cup-aspirator when used on rabbit eyes has proved to be better than the Draize procedure in predicting the damage that would occur in the monkey. These results, in view of known human experience, strongly suggest that direct instillation of moderately irritating substances into the rabbit eye is not a satisfactory method for predicting possible hazard, and that new procedures such as the cup-aspirator must be developed and used to enable toxicologists to predict the safety of these materials. Differences in species response were attributed to anatomical and physiological differences and to the effect of conjunctival irritation on corneal response. Further study of the qualitative and quantitative properties of specific ocular lesions produced in rabbits and monkeys will be necessary for further elucidation of these differences.

SAFETY EVALUATION OF ZINC 2-PYRIDINETHIOL 1-OXIDE IN A SHAMPOO FORMULATION.

Abstract Safety evaluation data have been presented for a shampoo formulation containing zinc 2-pyridinethiol 1-oxide at 2% and 10% levels. In addition toxicity studies have been carried out in dogs with a w o emulsion of ZnPT. The dog seems to be the species most susceptible to the effects of the compound itself, but it shows no effects to the shampoo formulation. The Rodentia show paralytic symptoms when the material is ingested in the diet at rather low levels for a period of several weeks. No ocular toxicity is observed in rabbits, rats, or monkeys, but it is observed in the dog. The shampoo containing ZnPT did not produce sensitization or undue irritation of the skin. In addition the effect of the shampoo vehicle on rabbit eyes was not increased by the incorporation of ZnPT. Since the shampoo formulation investigated is emetic and does not penetrate the skin, there would appear to be no hazard associated with its use.

Two-year rat feeding study with trisodium nitrilotriacetate and its calcium chelate.

Abstract Trisodium nitrilotriacetate (Na 3 NTA) is currently being considered as a replacement for sodium tripolyphosphate (STP) as a builder in laundry detergent products. A chronic oral feeding study has been completed in which 0.03%, 0.15%, and 0.5% Na 3 NTA or 0.5% of the calcium chelate of NTA was fed to rats for up to 2 yr as part of the basic diet. The feeding of all test diets except 0.03% Na 3 NTA increased the incidence and severity of nephritis and nephrosis. An increased level of zinc was found in the bone of all test groups, but had no adverse effect on the general health of the rats. The feeding of 0.03% Na 3 NTA to rats as part of the basic diet for up to 2 yr elicited no apparent adverse effects on the physiologic or metabolic processes of these animals and is considered to be a no-effect level.

Effects of trisodium nitrilotriacetate on cadmium and methyl mercury toxicity and teratogenicity in rats

Abstract Groups of 20 mated female Charles River rats were given doses of either trisodium nitrilotriacetate (Na 3 NTA) alone or with CdCl 2 or CH 3 HgCl in their drinking water during organogenesis. Cadmium, as CdCl 2 , was fed at 0, 0.01, 1 and 4 mg/kg, and mercury, as CH 3 HgCl, was fed at 0, 0.02, 0.2 and 4 mg/kg. Na 3 NTA was given at 0, 0.1 or 20 mg/kg at each level of metal. The 0.01 mg/kg and 1 mg/kg levels of Cd had no effect on the dams. The 4 mg/kg level reduced their weight gains. Both 1 mg/kg and 4 mg/kg of Cd increased the number of defective fetuses, but did not produce any significant embryotoxicity. Na 3 NTA had no significant effect at any of the levels of Cd. Similarly, the 0.02 mg/kg and 0.2 mg/kg levels of methyl-Hg had no effect on dams, but the 4 mg/kg level reduced their weight gains. Unlike the Cd treated groups, the Hg treated groups did not recover quickly after the treatment with metal stopped. There were significant increases in the number of abnormal fetuses as the dose of Hg increased, but there was no significant change due to the presence of NTA. It was concluded that Na 3 NTA did not enhance the toxicity or teratogenicity of either CdCl 2 or CH 3 HgCl.

Two-year feeding and reproduction study in rats with linear alkylbenzene sulfonate (LAS).

Abstract Four groups of Charles River weanling rats, evenly divided by sex, were fed 0.5, 0.1, 0.02, and 0% LAS in their Purina laboratory chow diet for 2 yr. Individual body weights and feed consumption were recorded weekly for the first 12 wk, and thereafter at monthly intervals. Adverse effects on growth or feed efficiency were not observed during the 2 yr. At 8 and 15 mo, 5 males and 5 females from each of the groups were necropsied, hematologic values were determined, and tissues were taken for histologic studies. At the termination of the study (24 mo) all survivors were treated similarly. These examinations revealed no consistent dietary-induced changes which could be considered a toxic response. In addition, animals which showed significant loss of weight, development of tumors, or other evidence of severe abnormalities were sacrificed and tissues were preserved for study. The incidence of tumors and the common incidental diseases were similar in all dietary groups. Twenty males and 20 females (F0) from each of the groups were used for a reproduction study which extended into the second litter of the third generation (F3b). Effects noted in the reproduction studies could not be associated with the feeding of LAS as measured by the usual indices of reproduction or lactation efficiency.

Effects of trisodium nitrilotriacetate, trisodium citrate and a trisodium nitrilotriacetate-ferric chloride mixture on cadmium and methyl mercury toxicity and teratogenesis in rats

Abstract Groups of 20 pregnant rats were treated with 4 mg/kg of either Cd, as CdCl 2 , or Hg, as CH 3 HgCl, along with 20 mg/kg of either trisodium nitrilotriacetate (Na 3 NTA) or Na 3 citrate or Na 3 NTA plus 7 mg/kg of FeCl 3 per day from days 6 to 15 of gestation. The materials were administered in distilled and deionized drinking water. Both CdCl 2 and CH 3 HgCl were toxic to the dams. CH 3 HgCl was the more toxic of the two and produced an increase in the incidence of malformed fetuses, whereas CdCl 2 did not. Neither Na 3 NTA nor Na 3 citrate increased the incidence of malformed fetuses from dams fed Cd or Hg, but the addition of iron reduced the teratogenic effect of methyl-Hg. The concentration of Cd was increased in the liver and kidney by Na 3 NTA and citrate, while iron produced an even higher concentration of Cd in the liver, but not in the kidney. No significant amounts of Cd were found in any of the fetuses. Na 3 NTA, but not Na 3 NTA plus Fe or Na 3 citrate, reduced the amount of Hg in the liver and kidney, while only citrate reduced the Hg content in the fetus. None of the treatments produced differences in the concentration of Hg in the brain.

Intravenous toxicity of zinc pyridinethione and several zinc salts

Abstract The effects of the intravenous administration of zinc pyridinethione and sodium pyridinethione to dogs, rabbits, and monkeys are presented. Zinc pyridinethione produces “cholinergic-like” signs in dogs that can be reduced by the intravenous administration of atropine sulfate. These signs are apparently due to the zinc moiety since they are not produced by sodium pyridinethione, and can be caused in dogs by the intravenous administration of other soluble or insoluble zinc salts. Pyridoxine hydrochloride and nicotinic acid had a life-saving effect after the intravenous administration of a toxic dose of zinc pyridinethione emulsion in dogs, but not in monkeys.

The effects of disodium etidronate on the reproductive functions and embryogeny of albino rats and New Zealand rabbits

The disodium salt of ethane-1-hydroxy-1,1-diphosphonate (disodium etidronate, etidronic acid, EHDP™), a proposed anti-calculus agent, was tested in rats and rabbits for its effects on reproduction and embryogeny. It was found to be nontoxic to pregnant rats at dietary levels of 0.1 or 0.5% when ingested continuously from weaning, although the higher level appeared to be somewhat embryotoxic when administered only during organogenesis (days 6–15 of gestation). When intubed into pregnant rabbits, 500 mg/kg/day (comparable to 0.5% dietary level for rats) (on days 2 through 16 of gestation) was lethal to the dams. However, lower doses (25, 50, or 100 mg/kg/day) administered during a similar period were not toxic to either dam or embryo. There was no increase in the incidence of anomalous fetuses in either of the species receiving disodium etidronate orally when compared with the controls.

Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products

Abstract Disodium etidronate is an effective anticalculus agent and is being considered for inclusion in toothpaste and mouthwash formulations. Disodium etidronate and products containing disodium etidronate were investigated for acute and subchronic toxicity and primary irritation potential. At high levels, under both acute and subchronic conditions, po toxicity was reflected by effects on the kidney, characterized by convoluted tubule dilation and degeneration and/or elevated kidney to body weight ratios. From the standpoint of possible human ingestion, these tests indicate disodium etidronate would be safe for the consumer, on either an acute or subchronic basis, when incorporated at levels of 3% in toothpaste and 1% in mouthwash. When included in experimental dentifrice and mouthwash products, disodium etidronate does not increase the irritant potential of the po products when compared to control formulations, and is comparable in toxicity to other commercially available dentifrices and mouthrinses.

Use of the occlusive patch to evaluate the photosensitive properties of chemicals in guinea-pigs

Guinea-pig tests were conducted on a known photocontact allergen, tetrachlorosalicylanilide (TCSA), a known phototoxin, 8-methoxypsoralen, two reportedly weak photoallergens, musk ambrette and 6-methylcoumarin, and a negative control, octylphenoxy polyethoxyethanol (Triton X-15). The data show that under the test conditions used, photosensitivity responses can be produced, and combinations of these as well as the other biological responses can be readily defined. The results indicate that musk ambrette is photoallergenic, that 8-methoxypsoralen is phototoxic and that Triton X-15 is only a slight irritant. On the other hand, results with TCSA suggest that it is a strong contact allergen and photoallergen, while 6-methylcoumarin would be considered to be a weak contact allergen with weak phototoxic properties. Previous reports that barrier destruction or adjuvanticity is necessary to produce photoallergy to musk ambrette were not confirmed; by ensuring occlusion using standard methods, the photoallergic nature of the response to this material was clearly demonstrated. A device described elsewhere (Newmann & Parker, Fd Chem. Toxic. 1985, 23, 683) has made it possible to develop methods that can be used to differentiate clearly among the possible biological responses that can occur in guinea-pigs when photoreactive materials are applied to their skin and irradiated. The probable biological responses that need to be defined, under the above conditions, are primary irritation, delayed contact hypersensitivity, phototoxicity and/or photoallergenicity.