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A dietary two-generation reproductive toxicity study of (2R,4R)-monatin salt in Crl:CD(SD) rats
Christine M Crincoli1, Witty A Brathwaite2, Phillip L Casterton3
1Cargill, Incorporated, 15407 McGinty Rd West, Wayzata, MN 55391, USA.
Abstract:
(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.
Insights
The artificial sweetener (2R,4R)-Monatin salt negatively impacted rat body weight and feed efficiency across all tested doses. The highest dose (35,000 ppm) also affected litter size and pup development, establishing a no-observed-adverse-effect level (NOAEL) at 15,000 ppm.
Area of Science:
- Toxicology
- Reproductive Toxicology
- Developmental Toxicology
Background:
- Monatin is a naturally occurring sweetener with potential applications.
- Assessing the safety of novel food ingredients is crucial for public health.
- Two-generation reproductive toxicity studies are standard for evaluating long-term safety.
Purpose of the Study:
- To evaluate the systemic, reproductive, and developmental toxicity of (2R,4R)-Monatin salt.
- To determine the no-observed-adverse-effect level (NOAEL) in a two-generation rat study.
Main Methods:
- Rats (Crl:CD(SD)) were fed diets containing (2R,4R)-Monatin salt at 5,000, 15,000, or 35,000 ppm for two generations.
- Evaluated endpoints included body weight, feed efficiency, reproductive parameters, and offspring development.
- Systemic, reproductive, and neonatal parameters were assessed.
Main Results:
- Reduced body weight and feed efficiency were observed at all dose levels.
- The highest dose (35,000 ppm) showed decreased implantation sites, litter size, and pre-weaning pup body weights.
- Reproductive performance, estrous cyclicity, and postnatal survival were unaffected.
- Pubertal development was slightly delayed in offspring secondary to reduced body weights.
Conclusions:
- The no-observed-adverse-effect level (NOAEL) for systemic, reproductive, and neonatal effects was determined to be 15,000 ppm.
- (2R,4R)-Monatin salt demonstrated dose-dependent adverse effects on growth and development in rats.
- Further research may be warranted to understand the mechanisms behind the observed effects.
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