Toxicology studies with N-acetylglycine.

N-acetylglycine (NAGly) has been identified as a minor constituent of numerous foods. The current paper reports the outcome of in vitro and in vivo genotoxicity, acute oral and repeated dose dietary toxicology studies conducted with NAGly. No evidence of genotoxicity was observed with NAGly in vitro bacterial tester strains or in vivo bone marrow micronucleus studies conducted in mice. No mortalities or evidence of adverse effects were observed in Sprague-Dawley rats following acute oral gavage with NAGly at a dose of 2000 mg/kg of body weight or following repeated dose dietary exposure to NAGly at targeted doses of 100, 500, or 1000 mg/kg of body weight/day for 28 days. No biologically significant or test substance related differences were observed in body weights, feed consumption, or clinical pathology response variables in any of the treatment groups. Based on these results it was concluded that NAGly is not genotoxic or acutely toxic. Further, the no-observed adverse-effect-level (NOAEL) for systemic toxicity from repeated dose dietary exposure to NAGly was 898.9 mg/kg of body weight/day for male rats and 989.9 mg/kg of body weight/day for female rats.

Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat.

The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250 mg/kg per dose (total daily dosages of 0, 50, 250, or 500 mg/kg bwt/day [mg/kg bwt/day]) for 13 weeks and the functional observational battery (FOB), automated tests for motor activity and neuropathological examination were conducted. In the immunotoxicity study, animals were exposed by inhalation to 0, 25, 100, or 500 ppm ethylbenzene (approximately 26, 90, or 342 mg/kg bwt/day as calculated from physiologically based pharmacokinetic modeling). Immunotoxicity was evaluated in female rats using the splenic antibody-forming cell plaque-forming assay in sheep red blood cell sensitized animals. The no-observed-effect level for the oral gavage study was 50mg/kg bwt/day based on increased relative weights of the liver and kidneys in the male rats. The no-observed-adverse-effect level (NOAEL) for adult neurotoxicity was the highest dose tested 500 mg/kg bwt/day. The NOAEL for the immunotoxicity evaluation was the highest tested exposure concentration, 500 ppm (342 mg/kg bwt/day).

N-acetyl-glutamic acid: evaluation of acute and 28-day repeated dose oral toxicity and genotoxicity.

N-acetyl-glutamic acid (NAG) is an endogenously produced mammalian substance and minor constituent of commonly consumed foods. This paper reports the outcome of genotoxicity and acute and repeated dose (28-day) oral toxicology studies conducted with NAG. No evidence of genotoxicity was observed with NAG in in vitro or in vivo studies. No mortalities or evidence of adverse effects was observed in Sprague-Dawley rats following acute oral gavage with NAG at a dose of 2000 mg/kg of body weight. No adverse effects were observed in rats following repeated dose dietary exposure to NAG at target concentrations corresponding to doses of 100, 500, or 1000 mg/kg of body weight/day for 28 days. All rats survived until scheduled sacrifice and no biologically significant or test substance related differences were observed in body weights, feed consumption, clinical signs, functional observational battery (FOB), ophthalmology, hematology, coagulation, clinical chemistry, organ weights or histopathology of any of the treatment groups. Based on the observed results it is concluded that NAG is not genotoxic or acutely toxic. The no-observed-adverse-effect-level (NOAEL) for systemic toxicity from repeated dose (28-day) dietary exposure to NAG was 914 mg/kg of body weight/day for male rats and 1007 mg/kg of body weight/day for female rats.

Acute and repeated dose oral toxicity of N-acetyl-l-aspartic acid in Sprague-Dawley rats.

N-acetyl-l-aspartic acid (NAA) is a constituent of the mammalian central nervous system (CNS) that has been identified in a number of commonly consumed foods. The current study reports the outcome of acute and repeated dose oral toxicology studies conducted with NAA in Sprague-Dawley (SD) rats. No mortalities or evidence of adverse effects were observed in SD rats following acute oral administration of 2000mg/kg NAA. In a separate study, NAA was added to the diets of SD rats (n=10/sex group) at concentrations corresponding to daily doses of 10, 100, or 1000mg/kg/day for 14 consecutive days and 100, 500, and 1000mg/kg/day for another 14 days. All rats survived until scheduled sacrifice and no differences in body weights, feed consumption values, or clinical signs were observed in any of the treatment groups. No biologically significant differences were observed in functional observational battery (FOB), motor activity evaluations, ophthalmologic examinations, hematology, coagulation, clinical chemistry, or organ weights of any of the NAA treatment groups. Further, no test substance-related gross or microscopic changes were observed in NAA exposure groups. Based on these results, NAA was not considered acutely toxic following oral exposure to 2000mg/kg and the no-observed-adverse-effect-level (NOAEL) for systemic toxicity from repeated dose dietary exposure to NAA is 1000mg/kg/day.

Sexual maturation data for Crl Sprague-Dawley rats: criteria and confounding factors.

BACKGROUND: Considerable concern exists in the scientific community regarding potential effects of endocrine disruptive or modulating environmental agents on male and female reproductive development and capacity. Existing data show that in utero and postnatal exposure of rodents to endocrine modulating chemicals can influence the timing and progression of sexual differentiation and/or maturation (e.g., balanopreputial separation and vaginal opening). METHODS: Sexual maturation data from various types of littering studies using International Gold Standard (IGS) Crl Sprague-Dawley rats were evaluated for consistency with both historical observations and published values from other laboratories. In addition, litters from two developmental neurotoxicology studies were statistically analyzed to identify whether increasing the numbers of pups per litter evaluated affected the interpretation of sexual maturation data sets. RESULTS: Control values for preputial separation and vaginal opening ages ranged from PD 45.0 to 48.0 and from PD 32.0 to 34.0, respectively, regardless of the number of pups evaluated per litter. However, statistically significant delays in sexual maturation were present when three rats/sex/litter were evaluated that were not present when only one randomly selected rat/sex/litter was evaluated. CONCLUSIONS: Standardized procedures and criteria are required to provide consistent intra-laboratory values and reduce inter-laboratory differences in sexual maturation observations. When such criteria are used, these endpoints provide sensitive measures for detecting alterations in sexual maturation. However, our analyses demonstrate that the ability to detect statistically significant and biologically important differences in these endpoints is sometimes impaired by the currently common practice of evaluating only one randomly selected rat/sex/litter. Evaluation of three rats/sex/litter improved the sensitivity of the statistical analysis in detection of treatment-related effects and reduced the probability of identifying a false negative result.