Male and female Fischer 344 rats were fed diets containing 0, 1.0, 2.0, or 5.0% titanium dioxide (TiO2) coated mica for up to 130 wk. This dosage regimen produced no consistent or biologically important changes in survival, body weight gains, hematologic or clinical chemistry parameters or histopathology. Under the conditions of this 130 wk feeding study there was no evidence that TiO2-coated mica produced either toxicologic or carcinogenic effects at dietary concentrations as high as 5.0%. The results suggest that dietary exposure to TiO2-coated mica does not pose a significant human health hazard.

No abstract

The objective of these studies was to assess the toxicological potential of orally administered tripeptides in rats. The studies employed powdered L-valyl-L-prolyl-L-proline (VPP)- and L-isoleucyl-L-prolyl-L-proline (IPP)-containing test articles, including (1) powdered Lactobacillus helveticus-fermented milk (FM), (2) pasteurized casein hydrolysate (CH) generated by Aspergillus oryzae protease, and (3) synthesized VPP. All test articles were administered by oral gavage to male and female Sprague-Dawley rats. Specific goals of the single-dose and repeated-dose studies were to (1) identify doses that produce evidence of systemic and/or local (i.e., gastrointestinal) toxicity (e.g., lowest-observable-effect level [LOEL]); (2) estimate the maximally tolerated oral dose (MTD); and (3) identify specific target organs for toxicity of these tripeptides. Single doses of CH (2000 mg/kg), powdered FM (2000 or 4000 mg/kg), or VPP (40, 200, or 400 mg/kg) were administered 14 days prior to study termination. No treatment regimen caused either antemortem (gross observations, body weight, and food consumption parameters) or postmortem (necropsy) evidence of either systemic or local toxicity. In the repeated-dose study, powdered FM (0, 500, 1000, or 2000 mg/kg body weight [BW]/day) was administered by gastric gavage to male and female rats for 28 consecutive days. Antemortem evaluative parameters included gross observations, ophthalmic examinations, and clinical pathology (clinical chemistry, hematology, and urinalysis). Post mortem parameters included necropsy, determination of organ weights, and microscopic examination of major organs. There was neither in-life nor postmortem evidence that powdered FM administration caused physiological or toxicological changes. Under the conditions of these experiments, the single-dose LOEL of powdered FM, CH, and VPP were found to be greater than 4000, 2000, and 400 mg/kg, respectively. The results of the repeated-dose study do not support identification of a target organ for powdered FM toxicity. Similarly, there was no evidence to support establishment of either the LOEL or MTD; both being greater than 2000 mg/kg/day for up to 28 consecutive days.

To evaluate the safety of dihydrocapsiate (4-hydroxy-3-methoxybenzyl 8-methylnonanoate; CAS No. 205687-03-2), a 13-week gavage toxicity study was conducted in Sprague-Dawley rats (10/sex/group). Test subjects received either dihydrocapsiate, 100, 300, or 1000 mg/kg/day, or vehicle by gavage and were observed for antemortem and postmortem signs of toxicity, which included changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. No changes attributable to the test article were observed in clinical signs, body weights, food consumption, water intake, ophthalmology, urinalysis, hematology, or histopathology. A number of sporadic blood chemistry differences were observed at the high dose between treated and controls, but were not of toxicological significance and were not attributable to the test article. These included increased alanine aminotransferase (ALT) activity in males; increased total protein in males and females; increased calcium, percentage of albumin fraction, and A/G (albumin/globulin) ratio and decreased percentage of gamma-globulin fraction in female rats. An effect, which was attributable to the test article, was increases in both absolute and relative liver weights in the high dose (both sexes). In the absence of histopathological changes attributable to the test article, the liver weight changes were considered adaptive (physiological) in nature and not of toxicological significance. It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 1000 mg/kg/day for both male and female rats in this 13-week gavage study.

A single-dose oral toxicity lethal-dose study was conducted to examine the toxicity of capsinoids contained in CH-19 Sweet extract. CH-19 Sweet extract was administered once by gavage to SPF (Crl:CD(SD)) Sprague-Dawley male and female rats at dose levels of 0 (vehicle), 5, 10, or 20 ml/kg of body weight (BW). The concentration of capsinoids in the CH-19 Sweet extract was 71.25 mg/ml; this resulted in administered dose levels of capsinoids of 356.25, 712.5, and 1425 mg/kg BW, respectively. The toxicity of CH-19 Sweet extract by single oral administration was low; only transient salivation or decreased spontaneous movement was observed on the day of administration at > or =10 ml/kg BW. It was concluded that the lethal dose of CH-19 Sweet extract was estimated to be higher than 20 ml/kg (1425 mg/kg as capsinoids) for both males and females since no deaths were observed at any dose in this study. A bacterial reverse mutation test of CH-19 Sweet extract was performed employing Salmonella typhimurium and Escherichia coli and using the preincubation method. Treatment with CH-19 Sweet extract did not increase the number of revertant colonies compared with negative controls either in the presence (+S9) or absence (-S9) of metabolic activation. An in vitro chromosome aberration test was conducted using Chinese hamster lung cultured cells (CHL/IU). Treatment with CH-19 Sweet extract failed to induce chromosome aberrations in either short-term or continuous treatment scenarios, with or without metabolic activation (-S9, +S9). In an in vivo micronucleus test using BDF(1) male mice, CH-19 Sweet extract failed to increase the incidence of micronucleated polychromatic erythrocytes (MNPCEs) or decrease the ratio of polychromatic erythrocytes (PCEs) in any of the treatment groups. These results suggest the absence of mutagenicity as well as in vitro and in vivo clastogenicity of capsinoids contained in CH-19 Sweet extract.

A 26-week oral toxicity study of capsinoids-containing CH-19 Sweet extract was conducted in Sprague-Dawley rats (20 males and 20 females per group) at 6 weeks of age. The test substance was administered by gavage for 26 weeks at dose levels of 0 (vehicle), 1.25, 2.5, and 5.0 ml/kg/day. The concentration of capsinoids in the CH-19 Sweet extract employed was 71.25 to 73.15 mg/ml, resulting in dose levels of capsinoids of 89.06 to 91.44, 178.13 to 182.88, and 356.25 to 365.75 mg/kg, respectively. Adverse test article-related changes were only observed in males, not in females, and within the males, only at the high dose (5.0 ml/kg). Within that group (high-dose males), increases were observed in the numbers of segmented neutrophils, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, liver weights, and in the incidence and severity of hepatocellular focal necrosis. No test substance-related changes were detected in clinical signs, body weight, food consumption, water intake, ophthalmology, or urinalysis. No adverse test article-related changes were observed in low- or mid-dose males or in females at any dose. Based on the results of this chronic gavage study, the target organ was the liver and the no observed adverse effect level (NOAEL) for CH-19 Sweet extract in the rat was 2.5 ml/kg/day in males and 5.0 ml/kg/day in females (178.13 to 182.88 mg/kg and 356.25 to 365.75 mg/kg as capsinoids, respectively).

Pharmacokinetics of the main capsinoid components of CH-19 Sweet extract (capsiate, dihydrocapsiate, and nordihydrocapsiate) were investigated in rats receiving a single gavage dose of extract containing 10 or 100 mg of capsinoids per kilogram in medium-chain triglyceride. Resultant blood levels of these capsinoids and a capsinoid metabolite, vanillyl alcohol, were measured in portal vein and systemic blood. Capsinoids were never detected. Portal compartment vanillyl alcohol concentrations and area under the plasma concentration versus time curve increased approximately with dose, whereas the time to maximum concentration of vanillyl alcohol was independent of dose (30 minutes post dosing), suggesting that precipitation in the stomach or intestines was unlikely. Vanillyl alcohol levels were just barely detectable in systemic plasma (5 minutes post dosing). Significant levels of vanillyl alcohol conjugates, sulfate, and glucuronide were detected in the systemic blood. Given that the orally administered capsinoids were never detected in the portal vein or systemic circulation, these compounds must be broken down (chemically or enzymatically) to vanillyl alcohol.

Dihydrocapsiate, (4-hydroxy-3-methoxybenzyl 8-methylnona- noate; CAS No. 205687-03-2) is a naturally occurring capsinoid compound found in nonpungent chili peppers. Although the safety of synthetically produced dihydrocapsiate has been previously evaluated, the purpose of this 13-week gavage toxicity study is to evaluate dihydrocapsiate produced with a slightly modified manufacturing process. Sprague-Dawley rats, 10 rats/sex/group, 6 weeks of age at study initiation, were administered the dihydrocapsiate daily by gavage at dose levels of 0 (vehicle), 100, 300, or 1000 mg/kg/day. The rats were observed for antimortem and postmortem signs of toxicity, including changes in clinical signs, body weights, food consumption, water intake, ophthalmology, clinical pathology (clinical chemistry, hematology, urinalysis), tissue findings (macroscopic and microscopic examination), as well as organ weights. There were no changes observed in clinical signs, body weight, food consumption, water intake, ophthalmology, urinalysis, hematology, or blood chemistry that were attributable to the administration of dihydrocapsiate. The only change observed attributable to the dihydrocapsiate administration involved the liver and that change occurred only at the high dose (1000 mg/kg). Both sexes had an increase in organ weights, but this increase correlated with a change in histopathology (i.e., hepatocyte hypertrophy) only in the males. No dihydrocapsiate-related histopathological changes were observed in males at doses < or = 300 mg/kg or in females at any of the doses tested (< or = 1000 mg/kg). It was concluded that the no observed adverse effect level (NOAEL) of dihydrocapsiate was 300 mg/kg/day for male rats and 1000 mg/kg/day for female rats in this 13 week gavage study.