Studies of the Toxicological Potential of Capsinoids: VII. A 13-Week Toxicity Study of Dihydrocapsiate in Rats

Abstract

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 pharmacologic increase in activity of plasma transaminase derived from small intestine in animals receiving an acyl CoA: diacylglycerol transferase (DGAT) 1 inhibitor

“…Therefore, it is very important for the risk management of new drugs that DILI or suspected DILI is appropriately evaluated. However, it is sometimes difficult to estimate the potential risk of DILI in humans from the results of non-clinical standard toxicity studies required in the guidance as in the case of mild and transient increase in blood transaminase levels without any obvious finding indicative of DILI, including alteration of other hepatic function parameters and degenerative histopathological findings in the liver in non-clinical toxicity studies for pharmaceuticals (Balfour et al, 1990;Blane, 1987;Gould and Scott, 2005;Kodama et al, 2008).…”

Effects of spaced feeding on gene expression of hepatic transaminase and gluconeogenic enzymes in rats

“…In the case of drug-induced liver injury (DILI), blood transaminase levels increase up to 10-100 fold as consequences of the release of hepatocellular enzyme proteins from the damaged tissue into the circulation. On the other hand, we sometimes encounter mild and transient increases in blood transaminase levels without any obvious finding indicative of DILI, including alteration of other liver function parameters and degenerative histopathological findings in the liver both in clinical and non-clinical studies for pharmaceuticals (Balfour et al, 1990;Blane, 1987;Gould and Scott, 2005;Kodama et al, 2008).…”

A 90-day toxicity and genotoxicity study with high-purity phenylcapsaicin

“…63 The observed diffuse hepatocellular hypertrophy described corresponds to previously reported findings of hepatocellular hypertrophy/increased liver weights in capsaicin analogue studies. 57,62,64,65 It has been suggested that low incidences are within the normal range for rats 62 and that hepatocellular hypertrophy when observed alone can be an adaptive response. 66 Again, hepatocellular hypertrophy alone is not considered to be of adverse nature.…”