Charlottesville, VA, United States
Charlottesville, VA, United States

Time filter

Source Type

Hlywka J.J.,Kraft Foods Inc. | Brathwaite W.A.,Cargill Inc. | Rihner M.O.,Toxicology Regulatory Services | Nikiforov A.I.,Toxicology Regulatory Services | Eapen A.K.,WIL Research Laboratories
Food and Chemical Toxicology | Year: 2013

R,. R-Monatin [2. R,4. R- isomer of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid] is one of four natural constituent isomers in the root bark of Sclerochitin ilicifolius; and " arruva" is the common/usual name that is proposed to represent R,. R-monatin salt forms, which have potential use as high potency sweetener food ingredients. In the present study, groups of male and female Crl:CD-1(ICR) mice were exposed to 0 (control), 5000, 10,000, 20,000, or 35,000. ppm of arruva in the diet for 90. days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower mean body weights and cumulative body weight gains were noted in the 35,000. ppm group when compared to the control group. Mean body weights in the 35,000. ppm group males and females were 9% and 7% less than the control group, respectively, at week 13. In the absence of observations associated with systemic toxicity and in consideration of the magnitude of body weight difference, these effects were not considered toxicologically significant. Based on the results of this study, the dietary no-observed-adverse-effect level (NOAEL) of arruva for 90. days in male and female mice was 35,000. ppm (equivalent to an exposure level of 5764 and 8013. mg/kg bw/day, respectively). © 2012 Elsevier Ltd.


PubMed | Cargill Inc., Toxicology Regulatory Services and WIL Research
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

Groups of Crl:CD-1 (ICR) mice (60/group/sex) were fed 0 (2 control groups), 5000, 20,000, or 40,000 ppm of enzymatically sourced (2R,4R)-monatin salt (R,R-monatin) in the diet for up to two years. There were no adverse effects on survival, incidence of palpable masses and tumors, feed consumption, hematology or serum chemistry parameters, organ weights, or ophthalmic, macroscopic, and microscopic examinations. The only notable effect was statistically significantly lower mean body weights and body weight gains in all treated groups, which generally occurred throughout the study and were most likely a result of caloric dilution of the test diets and not considered adverse. There were no test article-related changes in the incidence or occurrence of neoplastic diseases in mice on this study. The no-observed-effect-level (NOEL) for carcinogenicity of R,R-monatin fed to mice for 24 months was 40,000 ppm, the highest dietary concentration tested, which was equivalent to approximately 6502 and 7996 mg/kg bw/day in males and females, respectively.


PubMed | Cargill Inc., Toxicology Regulatory Services and WIL Research
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

In a combined chronic toxicity/carcinogenicity study, groups of Crl:CD(SD) rats were fed 0 (2 control groups), 5000, 20,000, or 40,000 ppm (2R,4R)-monatin salt (hereafter R,R-monatin) in the diet for up to one year in the chronic toxicity phase and up to two years in the carcinogenicity phase. There were no adverse effects on survival, incidence of palpable masses, neoplasms, organ weights, or ophthalmic examinations. The only notable effect was statistically significantly lower mean body weights and body weight gains in all treated groups generally throughout the study, which were most likely a result of caloric dilution of the test diets. Effects of long-term R,R-monatin ingestion by rats were predominantly focused on the urinary system (i.e., clinical pathology alterations indicative of electrolyte and pH imbalances, increased incidence of renal calculi, mineralization and bone hyperostosis, and increased severity of chronic progressive nephropathy). The no-observed-adverse-effect level (NOAEL) for R,R-monatin from the chronic toxicity phase was 20,000 ppm (equivalent to an exposure level of 1080 mg/kg bw/day for males and 1425 mg/kg/day for females) and from the carcinogenicity phase was 5000 ppm (equivalent to an exposure level of 238 and 302 mg/kg bw/day for males and females, respectively).


Weeks J.A.,Science Johnson | Guiney P.D.,Science Johnson | Nikiforovz A.I.,Toxicology Regulatory Services
Integrated Environmental Assessment and Management | Year: 2012

N,N-diethyl-m-toluamide (DEET) is a key active ingredient in many insect repellents available commercially throughout the world. Owing to its popularity among consumers for nearly 30 years, considerable work conducted in the past has demonstrated-and continues to demonstrate-that human exposure to DEET poses no significant health risk to the general population. The results of several studies reported in this paper describe more recent work to understand the environmental fate of DEET, particularly in surface waters and soil, and the potential hazards to aquatic and terrestrial organisms. In summary, DEET enters the environment through several pathways: directly into air during spray application; to surface water from overspray and indirectly via wastewater treatment plant (WTTP) discharges (as a result of washing of skin and laundering of clothing); or to soil via overspray and application of treated sewage as an amendment. Multimedia environmental fate modeling predicts that DEET entering the environment is retained either in receiving waters (~79%) or in soil (~21%). Based on its physicochemical properties, DEET is expected to be moderately mobile in the soil column. In surface waters and soil, DEET degrades at a moderate to rapid rate (its half-life is measured in days to weeks). The small amounts of DEET retained in air are subject to rapid photooxidation via hydroxyl radical-mediated degradation or, if in droplet form, gravitational settling to soil or water. DEET does not interfere with ozone formation in the upper atmosphere. The bioaccumulation potential of DEET is low; it is neither a persistent, bioaccumulative toxicant nor a persistent organic pollutant.Amongaquatic species, acute effect concentrations range between 4 and 388 mg/L. The chronic no-observed effect concentrations (NOEC) for daphnids and green algae range from approximately 0.5 to 24 mg/L. Measured concentrations of DEET in surface waters are several hundreds to thousands of times lower than the lowest NOEC measured, and thus the probability for adverse effects to environmental species is low. A separate paper by Aronson et al. (this issue) supports this conclusion by quantitatively exploring the risks to the aquatic environment using a combination of monitoring data and exposure modeling. © 2011 SETAC.


Hlywka J.,Cargill Inc. | Brathwaite W.A.,Cargill Inc. | Rihner M.O.,Toxicology Regulatory Services | Nikiforov A.I.,Toxicology Regulatory Services | Eapen A.K.,WIL Research Laboratories
Food and Chemical Toxicology | Year: 2011

The root bark of Sclerochitin ilicifolius contains an intensely sweet substance analytically identified as isomers of 2-hydroxy-2-(indol-3-ylmethyl)-4-aminoglutaric acid and generically coined " monatin." Groups of male and female Crl:CD(SD) rats were fed 0 (control), 5000, 10,000, 20,000 or 35,000. ppm R,. R-monatin salt in the diet for 90. days. There were no toxicologically relevant clinical or histopathological findings in any of the test article-treated groups. Significantly lower cumulative body weight gains were noted in the 35,000. ppm group. Mean body weights in the 35,000. ppm group males and females were 7% and 12% lower, respectively, than the control group at study week 13. In the absence of other observations associated with systemic toxicity and lower food consumption, the magnitude of the body weight difference in the 35,000. ppm group females relative to the control group exceeded 10%, which indicated attainment of a maximum tolerated dose (MTD) level. Based on the results of this study, and conservatively assuming the body weight observations at the MTD to be indicative of an adverse effect, the dietary no-observed-adverse-effect level (NOAEL) of R,. R-monatin salt for 90. days was 20,000. ppm in female rats (approximately 1544. mg/kg. bw/day) and 35,000. ppm in male rats (approximately 2368. mg/kg. bw/day). © 2011 Elsevier Ltd.


Merel S.,University of Arizona | Nikiforov A.I.,Toxicology Regulatory Services | Snyder S.A.,University of Arizona
Chemosphere | Year: 2015

N,N-diethyl-m-toluamide (DEET), the active component of many insect repellents, is among the most frequently detected compounds in aqueous environments with concentrations reported in the ngL-1 to μgL-1 range. However, DEET is often detected in blanks and reported concentrations differ significantly depending on the analytical technique employed. In addition, relatively sparse data are available regarding the seasonal variability of DEET concentrations in water and there are apparent inconsistencies with expected use patterns. Therefore, the present study investigates potential interferences affecting the detection and quantification of DEET then the geographical and seasonal variations of DEET concentrations. To examine potential analytical interferences, DEET was analyzed in five geographically-diverse wastewater effluents using both gas chromatography and liquid chromatography coupled to mass spectrometric detectors. At times, the concentrations quantified by the employed analytical methods varied significantly. Five compounds with similar molecular weights and structures as DEET were investigated as potential mimics and some were shown to induce an overestimation of DEET. Further experimentation suggested that the solvents used in sample preparation and HPLC analysis are another possible source of interference. Besides potential interferences, the seven-month weekly monitoring of DEET in the primary effluent of a wastewater treatment plant demonstrated a clear seasonal trend with decreasing concentration from summer to winter. These data collectively demonstrate that there are many challenges in the quantification of DEET in complex environmental samples and that co-occurrence of similarly structured substances present in the water sample and/or the solvents used for the analysis could induce analytical bias. © 2015 Elsevier Ltd.


PubMed | iCardiac Technologies, Cargill Inc., GL Fisher Consulting LLC, Bjornsson Associates LLC and 2 more.
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

Enzymatically-synthesized (2R,4R)-monatin has, due to its pure sweet taste, been evaluated for potential use in foods. Non-clinical studies have shown that (2R,4R)-monatin is well tolerated at high dietary concentrations, is not genotoxic/mutagenic, carcinogenic, or overtly toxic. In a pharmacokinetic and metabolism study involving 12 healthy males, consumption of a single oral dose (2 mg/kg) of (2R,4R)-monatin resulted in a small reduction of heart rate and prolongation of the QTcF interval of 20-24 ms, corresponding to the time of peak plasma levels (t(max)). These findings were evaluated in a cross-over thorough QT/QTc study with single doses of 150 mg (2R,4R)-monatin, placebo and positive control (moxifloxacin) in 56 healthy males. Peak (2R,4R)-monatin plasma concentration (1720 538 ng/mL) was reached at 3.1 h (mean tmax). The placebo-corrected, change-from-baseline QTcF (QTcF) reached 25 ms three hours after dosing, with QTcF of 23 ms at two and four hours. Using exposure response (QTc) analysis, a significant slope of the relationship between (2R,4R)-monatin plasma levels and QTcF was demonstrated with a predicted mean QT effect of 0.016 ms per ng/mL. While similarly high plasma levels are unlikely to be achieved by consumption of (2R,4R)-monatin in foods, QTc prolongation at this level is a significant finding.


PubMed | Cargill Inc., WIL Research Laboratories, Toxicology Regulatory Services and Harris Group Inc.
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

(2R,4R)-Monatin salt (Na/K) [sodium/potassium (2R,4R)-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate, hereafter R,R-monatin] was administered in the diets of groups of Beagle dogs (4/sex/group) at concentrations of 0 (basal diet), 5000, 20,000, or 35,000 ppm for 13 weeks. There were no effects on survival, clinical observations, body weight and body weight gain, feed consumption and feed efficiency, functional observational battery, ophthalmic examination, and electrocardiographic evaluation. No adverse effects on hematology, serum chemistry, and urinalysis parameters were reported. A statistically significant decrease in testicular weights associated with germ cell hypocellularity and reduced luminal sperm in the epididymides was reported in all treated male groups. Based on these findings, the dietary no-observed-adverse-effect level (NOAEL) of R,R-monatin for 90 days was considered 35,000 ppm for female dogs (approximately 1101 mg/kg bw/day) and <5000 ppm for male dogs (approximately <151 mg/kg bw/day).


PubMed | Cargill Inc., WIL Research Laboratories, Caledonia, Toxicology Regulatory Services and Harris Group Inc.
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

(2R,4R)-Monatin salt [sodium/potassium 2R,4R-2-amino-4-carboxy-4-hydroxy-5-(3-indolyl) pentanoate] was fed at 5000, 15,000, or 35,000 ppm to Crl:CD(SD) rats over two generations. Reduced body weights were observed at all dose levels. Sustained effect on body weight gain at 35,000 ppm in the F0 and F1 parental animals was associated with lower feed efficiency, soft stool, and slightly lower numbers of implantation sites. Lower numbers of pups born and live litter size at 35,000 ppm were considered secondary to slightly lower numbers of former implantation sites in the dams. Spermatogenic endpoints, estrous cyclicity, reproductive performance, mean gestation length, and parturition were unaffected in the F0 and F1 generations. There were no effects on F1 and F2 generation postnatal survival. Reduced pre-weaning pup body weights at 35,000 ppm resulted in lower F1 and F2 body weights at study termination. Slight delays in pubertal landmarks in the F1 offspring were considered secondary to the reduced pup body weights. The no-observed-adverse-effect level (NOAEL) was 15,000 ppm for systemic, reproductive, and neonatal effects based on test article-related effects on body weight and food efficiency, slight decrease in maternal implantation sites and corresponding reduction in live litter size, and reductions in pre-weaning pup body weights at 35,000 ppm.


PubMed | Cargill Inc., University of Minnesota, Toxicology Regulatory Services and Charles River Laboratories Ashland LLC
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2016

The potential toxicity of corn starch fiber was assessed and compared to polydextrose, a commonly used bulking agent with a long history of safe use in the food supply. Groups of male and female Crl:CD(SD) rats were fed 0 (control), 1,000, 3,000, or 10,000 mg/kg-bw/day corn starch fiber in the diet for 90 days. The polydextrose reference article was offered on a comparable regimen at 10,000 mg/kg-bw/day. Following a single gavage dose of [

Loading Toxicology Regulatory Services collaborators
Loading Toxicology Regulatory Services collaborators