Safety evaluation of calcium L-methylfolate.

K.E Niederberger,R Boehni,T.H Broschard,R Moser,I Dahms

doi:10.1016/j.toxrep.2019.09.012

K.E Niederberger, R Boehni + Show 3 more

Open Access

https://doi.org/10.1016/j.toxrep.2019.09.012

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Abstract

Calcium L-methylfolate (L-5-MTHF-Ca; CAS Number 151533-22-1) is a source of folate and an alternative to folic acid for use in human food and food supplements. The safety of L-5-MTHF-Ca was evaluated by testing for genotoxicity, subchronic and prenatal developmental toxicity. In in vitro assays L-5-MTHF-Ca was not mutagenic and did not induce other chromosomal events. Additionally, L-5-MTHF-Ca was not genotoxic in the in vivo micronucleus test nor did it induce DNA damage in rat liver cells. In a subchronic toxicity study, rats administered up to 400 mg/kg bw/day of L-5-MTHF-Ca via oral gavage for 13 weeks had no treatment-related mortalities, and no treatment-related effects were identified on behaviour, body weight, food consumption, ophthalmology, haematology, or organ weights. No treatment-related macroscopic or histopathological findings were observed. Calcium and sodium levels increased with increasing dosage, however the slight increases were within historical control ranges and reversible after the recovery period. L-5-MTHF-Ca is neither teratogenic nor embryotoxic. Based on the results of the in vitro and in vivo studies, the safe use of L-5-MTHF-Ca as an ingredient in foods is supported. The no observed adverse effect level was the highest dose in the subchronic toxicity study, i.e. 400 mg/kg bw/day for male and female rats.

Highlights

Folate is a generic term referring to a family of water-soluble B vitamins that play an essential role in the synthesis of DNA and RNA, methionine regeneration, and in reactions required for normal cell metabolism and regulation [1]
L-5-MTHF-Ca did not induce gene mutations or other chromosomal events in the mammalian cell gene mutation assay in mouse lymphoma cells
In the original study report of the mammalian cell gene mutation assay, the different experimental series were mistakenly not assessed for compliance with the validity requirements defined in the protocol and the conclusion was reached that L-5-MTHF-Ca was weakly mutagenic in the test system in the absence of S9-mix and under conditions where strong cytotoxic effects occurred

Summary

Introduction

Folate is a generic term referring to a family of water-soluble B vitamins that play an essential role in the synthesis of DNA and RNA, methionine regeneration, and in reactions required for normal cell metabolism and regulation [1]. Maintaining an adequate folate status is important during periods of rapid cell proliferation and tissue growth such as gestation and infancy. Folate is naturally present in a wide range of foods with dark green leafy vegetables, legumes, peanuts, wheat bran and wheat germ serving as rich sources [5]. The predominant form of naturally present folate in food is L-5-methyltetrahydrofolate (L-5-MTHF). Following consumption of folate-containing food, several monoglutamate forms of folate cross the intestinal lining and are converted into L-5-MTHF which is normally the only form of folate to enter the human circulation [6]. The folate vitamer L5-MTHF is the main storage form in the human body and it is the predominant form of folate in breast milk [7,8]

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