Ten-day and four-week toxicity and toxicokinetics studies of alpha-glycosyl isoquercitrin in juvenile Göttingen minipigs

Abstract

Background: Alpha-glycosyl isoquercitrin (AGIQ) is widely used as an anti-oxidative food additive in many products. Nevertheless, information on its safety and toxicity is still very limited. A 90-day toxicity study in rats and comprehensive genotoxic studies have proven AGIQ to be safe. Aim: The goal of this study was to assess the safety of use of AGIQ in infant formula. To test for potential adverse effects on growth or other safety issues specific for young animals, we performed a 10-day and a 4-week study in preweaning Gö ttingen minipigs. Method: Newborn minipigs were treated four times per day with oral AGIQ (0, 100, 300, or 1000 mg/kg/day) for 10 days or 4 weeks. Results: All animals remained in good health throughout both studies, and there were no treatment-related signs of toxicity or abnormal findings in blood parameters. In the 4-week study, yellow coloration of the bones was seen in all animals in the high-dose group with no related histological findings. Hepatocellular and sinusoidal/Kupffer cell iron deposition was seen in the liver of all animals in both studies, as expected after the routine administration of supplemental iron to newborn animals. There was sufficient evidence of systemic exposure based on plasma levels of AGIQ metabolites. Conclusion: Taken together, these findings show that oral administration of AGIQ in reconstituted milk supplement to preweaning Gö ttingen minipigs for 4 weeks at up to 1000 mg/ kg/day does not result in any adverse treatment-related effects and further support the safety of AGIQ as a food additive.

Identification of compound causing yellow bone discoloration following alpha-glycosyl isoquercitrin exposure in Sprague–Dawley rats

“…The primary purpose of this study was to determine the AGIQ metabolite responsible for the yellow bone discoloration previously noted in dietary exposure studies of AGIQ in rats (Nyska et al 2016;Tamano et al 2001), which has also been noted in minipig studies of AGIQ (Maronpot et al 2019). The absence of effects on survival, clinical condition, body weight, and food consumption and the presence of dose-dependent yellow femur discoloration at all dose levels in this study generally corroborated the results reported for those studies, with the exception of the decreased body weights observed in female rats at a dose level of 2.5% in one study (Tamano et al 2001).…”

Enzymatically Modified Isoquercitrin: Production, Metabolism, Bioavailability, Toxicity, Pharmacology, and Related Molecular Mechanisms

“…The primary metabolites of EMIQ thus far detected in plasma after oral administration to animals and humans are QU conjugates. Some methylated derivatives have also been detected, in particular the conjugates of isorhamnetin and tamarixetin ( Figure 3 , Table 1 ) [ 10 , 13 , 45 , 46 ]. The transformation of QU to glucuronides and sulfates mostly takes place in the enterocytes due to the action of UDP-glucuronosyltransferase and phenol sulfotransferase, respectively [ 42 , 44 ].…”

“…Compared to untreated control animals, there were no effects on weight gains and food consumption and no significant differences in hematological parameters and organ weights. The histological examination did not reveal any pathologies that could be related to the EMIQ-administration [ 46 ]. No severe adverse effects were found during a 4-week treatment with the same doses of EMIQ.…”

“…However, microscopic observations presented no change in bone growth or histological changes. The consumption of EMIQ also affected the color of urine, without affecting any of the parameters of the urinalysis [ 46 ].…”

Embryo-fetal developmental toxicity study of alpha-glycosyl isoquercitrin administered orally to New Zealand White rabbits

“…8,9 Previous toxicity assessments have shown that AGIQ is safe, non-carcinogenic, and non-genotoxic, 5,7,[10][11][12][13] but some of the earlier studies used incompletely characterized AGIQ and/or did not adhere to current Good Laboratory Practice (GLP). 6,10,12,13 Due to the current effort to expand the use of AGIQ in the consumer food and beverage industry, recent GLP-compliant studies of high-purity AGIQ (including comprehensive genotoxic assessment, 7 10-day and 4-week studies in preweaning Göttingen minipigs, 14 and a 90-day study in rats) 5 were conducted to augment the older toxicity database. These studies have generally confirmed the safety profile of AGIQ.…”