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In Vitro genetic toxicology studies

Bacterial Mutagenesis (Ames) Assay

The test compound was examined for mutagenic activity in a series of in vitro microbial assays employing Salmonella and Saccharomyces indicator organisms. The compound was tested directly and in the presence of liver microsomal enzyme preparations from Aroclor induced rats. The compound was tested over a series of concentrations such that there was either quantitative or qualitative evidence of some chemically-induced physiological effect at the highest dose level. The low dose in all cases was below a concentration that demonstrated any toxic effect. The dose range employed for the evaluation of this compound was from 10 ug to 2000 ug per plate. The results of the test conducted on the compound were all negative in the absence or presence of a metabolic activation system. The test compound, 78-341, did not demonstrate genetic activity in any of the assays conducted in this evaluation and was considered not mutagenic under these test conditions.

Mammalian Cell Mutagenesis Assay

The test material, sucrose acetate isobutyrate, was evaluated for mutagenic activity at six concentrations which ranged between 25 ug/ml to 1000 ug/ml without and with rat liver S9 metabolic activation. No toxicity with either test condition was seen in either the soluble range (up to 25 ug/ml) or in the insoluble range, except for slight toxicity (60 to 70 percent relative survival) at the maximum concentrations tested of 1000 ug/ml. No significant or dose-related increases in mutant frequency were observed. Therefore, sucrose acetate isobutyrate was evaluated as being inactive in the CHO/HGPRT Forward Mutation Assay.

CHO Cell Chromosomal Aberration Assay

The objective of this in vitro assay was to evaluate the ability of Sucrose acetate isobutyrate (Special Lot #84 -8) to induce chromosome aberrations in Chinese hamster ovary (CHO) cells, with and without metabolic activation. The test article was soluble in DMSO or acetone, but was insoluble in water. The test article was dissolved in DMSO at a concentration of 605 mg/ml, and when diluted 1:100 in culture media to a final concentration of 6.05 mg/ml the test article came out of solution, reverting to its original clear viscous form. Additional stock dilutions were prepared and dosed in culture media until at a diluted concentration of 1.87 mg/ml the test article formed a fine precipitate which remained in an even suspension. DMSO was the solvent of choice with a top dose tested of 1.9 mg/ml. A one-half log series of dilutions was tested through 63.3 ng/ml in the range-finding assays. A dose range from 200 ug/ml to 2.0 mg/ml was tested. The test article caused no significant increases in chromosomal aberrations and is considered negative under the conditions of the assay.

Unscheduled DNA Synthesis (UDS) Assay

The test material, sucrose acetate isobutyrate, did not induce significant changes in the nuclear labeling of primary rat hepatocytes for an applied concentration range of 1000 ug/ml to .25 ug/ml. Eight treatments in this range were essentially nontoxic and the highest concentration (1000 ug/ml) was insoluble. None of the criteria used to indicate UDS were approached by the treatments, and no dose-related response was observed. Therefore, the test material was evaluated as inactive in the Primary Rat Hepatocyte Unscheduled DNA Synthesis (UDS) Assay.

In Vivo Genetic Toxicology Assays

Dominant Lethal Mutation Assay in Rats

One hundred male rats (Sprague-Dawley), 10-12 weeks old, were randomly assigned to five groups of 20 males each. Following a period of acclimation each group was randomly assigned one of the following treatments: 20, 200 or 2000 mg/kg sucrose acetate isobutyrate (experimental groups), 25 mg/kg Apholate (positive control) or corn oil only (negative control). All treatments were administered by gavage as a single dose in corn oil. Within two hours after treatment, the males were mated with two untreated, virgin females for the following week. Subsequent matings using naive females were conducted during the third, fifth and seventh weeks after treatment. Mating during these weeks represent samples of post meiotic, meiotic and pre-meiotic stages of spermatogenesis, respectively. Twelve to fourteen days from the mid-week of their caging and presumptive mating all females were sacrificed with an overdose of ether. The uteri were exposed and the total implantation sites were counted and categorized as comprising viable fetuses, early deaths or late deaths. The major statistics of interest in the dominant lethal assay are pregnancy rate, early deaths per pregnancy and mean total implantations, and an increase in early fetal deaths per pregnancy is a direct and unequivocal measure of dominant lethal mutations. In this study, the only increases in early fetal deaths per pregnancy were observed, as expected, in the positive control group. Therefore, it is concluded that quantities of sucrose acetate isobutyrate ranging from the proposed use level to 100 times this level; administered orally in single doses did not cause dominant lethal mutations in rats.


Endpoint Conclusion:

Justification for classification or non-classification