A 13-week repeated dose study of three 3-monochloropropane-1,2-diol fatty acid esters in F344 rats

Abstract

3-monochloropropane-1,2-diol (3-MCPD), a rat renal and testicular carcinogen, has been reported to occur in various foods and food ingredients as free or esterified forms. Since reports about toxicity of 3-MCPD esters are limited, we conducted a 13-week rat subchronic toxicity study of 3-MCPD esters (palmitate diester: CDP, palmitate monoester: CMP, oleate diester: CDO). We administered a carcinogenic dose (3.6 × 10(-4) mol/kg B.W./day) of 3-MCPD or these esters at equimolar concentrations and two 1/4 lower doses by gavage with olive oil as a vehicle five times a week for 13 weeks to F344 male and female rats. As a result, five out of ten 3-MCPD-treated females died from acute renal tubular necrosis, but none of the ester-treated rats. Decreased HGB was observed in all high-dose 3-MCPD fatty acid ester-treated rats, except CDO-treated males. The absolute and relative kidney weights were significantly increased in the ester-treated rats at medium and high doses. Relative liver weights were significantly increased in the esters-treated rat at high dose, except for CMP females. Significant increase in apoptotic epithelial cells in the initial segment of the epididymis of high-dose ester-treated males was also observed. The results suggested that although acute renal toxicity was lower than 3-MCPD, these three 3-MCPD fatty acid esters have the potential to exert subchronic toxicity to the rat kidneys and epididymis, to a similar degree as 3-MCPD under the present conditions. NOAELs (no-observed-adverse-effect levels) of CDP, CMP and CDO were suggested to be 14, 8 and 15 mg/kg B.W./day, respectively.

Altered susceptibility of an obese rat model to 13-week subchronic toxicity induced by 3-monochloropropane-1,2-diol

“…Recently, we also reported that oral administration of 3-MCPD by gavage causes cell death in the ductal epithelium of the initial segment of the epididymis in F344 rats (Onami et al, 2014b). In the present study, the degrees of epididymal damage were higher in F344 and lean rats than in fatty rats.…”

“…Although we have examined in vivo genotoxicity and subchronic toxicity of 3-MCPD and their esters in an ordinary rat model (Onami et al, 2014a(Onami et al, , 2014b, there is a further concern that 3-MCPD might exert more potent toxicity in human population with specific risk factor including hyperlipidemia. In addition, it has been demonstrated that obesity is closely associated with risk for chronic disorders of kidney, one of the target organs of 3-MCPD toxicity (Chen et al, 2004;Ejerblad et al, 2006).…”

Proteomic analysis of 3-MCPD and 3-MCPD dipalmitate-induced toxicity in rat kidney

“…3-MCPD dipalmitate (equivalent to 10.34 mg/kg b.w. 3-MCPD) for 90 days did also not induce histopathological changes, but slightly elevated organ weight of the kidneys in a very recent study (Onami et al 2014b). By contrast, much higher doses also applied in the two aforementioned studies exerted histopathological effects (Li et al 2013;Onami et al 2014b), and administration of a high dose of 40 mg/kg b.w.…”

“…3-MCPD) for 90 days did also not induce histopathological changes, but slightly elevated organ weight of the kidneys in a very recent study (Onami et al 2014b). By contrast, much higher doses also applied in the two aforementioned studies exerted histopathological effects (Li et al 2013;Onami et al 2014b), and administration of a high dose of 40 mg/kg b.w. 3-MCPD or an equimolar 3-MCPD diester dose reduced eosinophilic bodies in the renal proximal tubular epithelium after 4 weeks of exposure (Onami et al 2014a).…”

“…Histopathological examination has confirmed that kidney is also the critical organ for 3-MCPD ester, but the observed changes after treatment with 3-MCPD dipalmitate in a 90-day oral rat study were slighter in comparison with equimolar 3-MCPD treatment (Barocelli et al 2011). A more recent oral 13-week study with rats revealed similar subchronic toxic effects of 3-MCPD fatty acid esters in comparison with free 3-MCPD (Onami et al 2014b). In an acute oral toxicity study, 3-MCPD esters induced acute kidney toxicity including renal tubular necrosis (Liu et al 2012).…”