Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

Regul Toxicol Pharmacol. 2012 Jul;63(2):196-208. doi: 10.1016/j.yrtph.2012.04.001. Epub 2012 Apr 11.


(R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester) has been developed as an oral source of ketones, which may be utilized for energy. In a 28-day toxicity study, Crl:WI (Wistar) rats received diets containing, as 30% of the calories, ketone monoester (12 and 15 g/kg body weight/day for male and female rats, respectively). Control groups received either carbohydrate- or fat-based diets. Rats in the test group consumed less feed and gained less weight than control animals; similar findings have been documented in studies of ketogenic diets. Between-group differences were noted in selected hematology, coagulation, and serum chemistry parameters; however, values were within normal physiological ranges and/or were not accompanied by other changes indicative of toxicity. Upon gross and microscopic evaluation, there were no findings associated with the ketone monoester. In a developmental toxicity study, pregnant Crl:WI (Han) rats were administered 2g/kg body weight/day ketone monoester or water (control) via gavage on days 6 through 20 of gestation. No Caesarean-sectioning or litter parameters were affected by the test article. The overall incidence of fetal alterations was higher in the test group; however, there were no specific alterations attributable to the test substance. The results of these studies support the safety of ketone monoester.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Diet*
  • Dietary Carbohydrates / administration & dosage
  • Dietary Fats / administration & dosage
  • Energy Intake
  • Energy Metabolism / drug effects
  • Esters
  • Female
  • Hydroxybutyrates / metabolism
  • Hydroxybutyrates / toxicity*
  • Ketones / metabolism
  • Ketones / toxicity*
  • Male
  • Maternal Exposure / adverse effects
  • Rats
  • Rats, Wistar
  • Reproduction / drug effects*
  • Toxicity Tests, Subacute*


  • (R)-3-hydroxybutyl (R)-3-hydroxybutyrate
  • Dietary Carbohydrates
  • Dietary Fats
  • Esters
  • Hydroxybutyrates
  • Ketones