The sugar substitute erythritol shortens the lifespan of Aedes aegypti potentially by N-linked protein glycosylation.

Adult male and female mosquitoes consume sugar as floral and extrafloral nectar. Earlier work demonstrated that mosquito populations and their vector potential are dependent upon the availability of sugar sources. Thus, a novel method of vector control may involve targeting sugar-feeding mosquitoes. Multiple human-safe sugar substitutes are already approved by the U.S. Food and Drug Administration and are readily available. However, plant-based sugar substitutes such as stevia (erythritol) have been shown to affect lifespan in other flies. Therefore, the current study was carried out to test the potential of commercially available sugar substitutes to adversely affect the survival, fecundity, and metabolism of adult Aedes aegypti mosquitoes. Of the four sugar substitutes tested, erythritol (Stevia), sucralose (Splenda), aspartame (Equal), and saccharin (Sweet'N Low), only erythritol negatively affected mosquito longevity and fecundity. The effect on fecundity was probably due in part to a corresponding decrease in glycogen and lipid levels over time in mosquitoes fed on erythritol. Comparative mosquito head transcriptomes indicated upregulation of a gene in the mannose biosynthesis pathway in females fed on erythritol, suggesting that N-linked glycosylation might be responsible for the negative impact of erythritol feeding in mosquitoes. Mosquitoes preferred sucrose when a choice was given but were not averse to erythritol. Our results suggest the possibility of using erythritol alone or in combination with sucrose as a component of attractive toxic sugar baits for a human-safe approach for mosquito control.

Erythritol, at insecticidal doses, has harmful effects on two common agricultural crop plants.

Erythritol, a non-nutritive polyol, is the main component of the artificial sweetener Truvia®. Recent research has indicated that erythritol may have potential as an organic insecticide, given its harmful effects on several insects but apparent safety for mammals. However, for erythritol to have practical use as an insecticide in agricultural settings, it must have neutral to positive effects on crop plants and other non-target organisms. We examined the dose-dependent effects of erythritol (0, 5, 50, 500, 1000, and 2000 mM) on corn (Zea mays) and tomato (Solanum lycopersicum) seedling growth and seed germination. Erythritol caused significant reductions in both belowground (root) and aboveground (shoot) dry weight at and above the typical minimum insecticidal dose (500 mM erythritol) in tomato plants, but not in corn plants. Both corn and tomato seed germination was inhibited by erythritol but the tomato seeds appeared to be more sensitive, responding at concentrations as low as 50 mM erythritol (in contrast to a minimum damaging dose of 1000 mM erythritol for corn seeds). Our results suggest erythritol may have damaging non-target effects on certain plant crops when used daily at the typical doses needed to kill insect pests. Furthermore, if erythritol's damaging effects extend to certain weed species, it also may have potential as an organic herbicide.

Acute and sub-chronic oral toxicity studies of erythritol in Beagle dogs.

Polyols, also known as sugar alcohols, are widely used in the formulation of tooth-friendly and reduced-calorie foods. Considering the significant health benefits of polyols in products formulated for human use, there is increased interest in evaluating potential uses in companion animal applications. Erythritol and xylitol are two polyols which are currently widely used in products ranging from reduced-sugar foods to personal care and cosmetics. Published studies have shown that both of these compounds are well-tolerated in rodents. Their toxicity profiles differ when comparing canine safety data. Doses of xylitol as low as 0.15 g/kg-BW in dogs can result in life-threatening hypoglycemia and acute liver failure, whereas erythritol is well-tolerated in dogs with reported No Adverse Effect Levels upwards of 5 g/kg-BW/day in repeat-dose studies. While pivotal studies substantiating the safe use of erythritol in humans have been published, there are limited published studies to support the safe use of erythritol in dogs. Here we present the results of an acute oral and a sub-chronic oral toxicity study in Beagle dogs. Given the potential health benefits of oral products formulated with erythritol and the data presented herein substantiating the safe use in dogs, erythritol can be safely used in products for canines.

Non-Nutritive Polyol Sweeteners Differ in Insecticidal Activity When Ingested by Adult Drosophila melanogaster (Diptera: Drosophilidae).

Previous work showed the non-nutritive polyol sweetener Erythritol was toxic when ingested by Drosophila melanogaster (Meigen, 1930). This study assessed whether insect toxicity is a general property of polyols. Among tested compounds, toxicity was highest for erythritol. Adult fruit flies (D. melanogaster) fed erythritol had reduced longevity relative to controls. Other polyols did not reduce longevity; the only exception was a weaker but significant reduction of female (but not male) longevity when flies were fed D-mannitol. We conclude at least some non-nutritive polyols are not toxic to adult D. melanogaster when ingested for 17 days. The longer time course (relative to erythritol) and female specificity of D-mannitol mortality suggests different mechanisms for D-mannitol and erythritol toxicity to D. melanogaster.

Erythritol: an interpretive summary of biochemical, metabolic, toxicological and clinical data.

A critical and comprehensive review of the safety information on erythritol was undertaken. Numerous toxicity and metabolic studies have been conducted on erythritol in rats, mice and dogs. The toxicity studies consist of long-term feeding studies conducted to determine carcinogenic potential, intravenous and oral teratogenicity studies to determine the potential for effects on the foetus, oral studies in which erythritol was administered over one or two generations to determine the potential for reproductive effects, and studies in bacterial and mammalian systems to determine mutagenic potential. The majority of the safety studies conducted were feeding studies in which erythritol was mixed into the diet at concentrations as high as 20%. The metabolic studies in animals have shown that erythritol is almost completely absorbed, not metabolized systemically and is excreted unchanged in the urine. The safety studies have demonstrated that erythritol is well tolerated and elicits no toxicological effects. The clinical program for erythritol involved a series of single-dose and repeat-dose, short-duration studies which have been used to investigate the human correlates to the physiological responses seen in the preclinical studies. The clinical studies showed erythritol to be well tolerated and not to cause any toxicologically relevant effects, even following high-dose exposure. Erythritol administered orally to humans was rapidly absorbed from the gastrointestinal tract and quantitatively excreted in the urine without undergoing metabolic change. At high oral doses, urinary excretion accounted for approximately 90% of the administered dose with minimal amounts appearing in the faeces. A comparison of the human and animal data indicated a high degree of similarity in the metabolism of erythritol and this finding supports the use of the animal species used to evaluate the safety of erythritol for human consumption. It can be concluded, based on the available studies that erythritol did not produce evidence of toxicity.

Four-week oral toxicity study with erythritol in rats.

Erythritol was orally administered to Wistar rats at dietary levels of 0, 5, and 10% for 4 weeks. Soft stools and diarrhea were observed in male and female animals of the 10% group and in female animals of the 5% group. These symptoms disappeared during the course of the study. Mean body weights of male rats in the high-dose group were significantly lower than those of controls during the course of the study. No such differences were observed in females. Small statistically significant changes in certain hematological, clinical chemistry, and urine parameters were noted in the high-dose group but were judged not to be biologically important. Weights of the cecum were increased relative to those of the controls. No treatment-related histological changes were observed. No ill effects, other than early diarrhea, were observed from erythritol levels at 5 or 10% in the diet. Based on these results, it was concluded that the feeding of erythritol at a dietary level of 10% did not result in toxicologically significant effects.

Subchronic oral toxicity studies with erythritol in mice and rats.

Erythritol is a sugar alcohol (polyol) with potential applications as a low-calorie, bulk sweetener. Ingested erythritol is efficiently absorbed and excreted unchanged via the urine since it is not metabolized systemically by the animal or human body. Erythritol was administered to four groups of 10 male and 10 female Swiss CD-1 mice and four groups of 15 male Wistar Crl:(WI) WU BR rats at dietary levels of 0, 5, 10, or 20% for 90 days. A fifth group of rats received a diet containing 20% erythritol on a time-restricted basis (6 hr/day), and a sixth group received a diet containing 20% mannitol for comparison. There were no treatment-related mortalities in either mice or rats. Soft stools and occasional diarrhea were observed in rats fed diets with 20% erythritol or mannitol but not in mice. Body weights were slightly yet significantly reduced in rats fed 20% erythritol or mannitol and in male mice of the 20% dose group. Erythritol intake in the high-dose group was approximately 12 g/kg body wt in rats and 44 and 45 g/kg body wt in male and female mice, respectively. Hematological and clinicochemical examinations of blood and plasma did not reveal any treatment-related effects. Urine output increased with increasing erythritol dose. In male and female mice of the 20% erythritol group, the creatinine-normalized urinary excretion of protein, K-glutamyltransferase (GGT), and electrolytes (Na+, K+, Ca2+, Pi, citrate) was significantly increased while urinary N-acetylglucosaminidase (NAG) remained unchanged. At the 10% level, significantly increased urinary protein (both sexes) and GGT (males only) excretion were seen. In rats, the creatinine-normalized urinary excretion of GGT, NAG, and some electrolytes (Na+, K+, and Ca2+) was increased in some erythritol groups but a clear dose-response relationship was evident only for calcium. On termination of the study, cecal enlargement was seen in rats of the 10 and 20% dose groups and in mice of the 20% dose group. Increased relative and absolute kidney weights were observed in both sexes of mice in the 20% erythritol group, in male mice of the 5 and 10% groups, and in rats of the 10 and 20% erythritol groups. Histopathological examination did not reveal any treatment-related abnormalities in either mice or rats. In conclusion, the ingestion of erythritol for 90 days at dietary levels of up to 20% did not produce signs of toxicity in mice or rats. In particular, the morphological integrity of the kidneys was not adversely affected by the treatment in either species. The increases in urinary excretion of protein, GGT, NAG, and electrolytes were considered to result from extensive osmotic diuresis and a potential overload of the renal excretory system at the high dose levels employed.

Embryotoxicity and teratogenicity study with erythritol in rats.

The embryotoxicity/teratogenicity of erythritol, a low-calorie polyol sugar substitute, was examined in Wistar Crl:(WI) WU BR rats. Erythritol was fed at dietary concentrations of 0, 2.5, 5, and 10% to groups of 32 female rats from Day 0 to 21 of gestation. The treatment was generally well tolerated and no mortality occurred in any group. Weight gain during gestation, food consumption, and food efficiency were similar in all groups except for a significantly reduced weight gain in the 10% erythritol group in Week 2 of gestation. Reproductive performance was not affected by the treatment but the fertility index was generally rather low (69% in both control and high-dose group). Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects. The slightly lower maternal body weight in the high-dose group was interpreted as a trivial result of the consumption of a low-calorie test substance in high amounts. In conclusion, no adverse effects were observed at erythritol doses of up to about 6.6 g/kg body wt/day, i.e., the highest dose tested.

Teratology study of erythritol in rabbits.

The effect of maternal ingestion of the reduced energy sweetener erythritol was investigated in KBL:JW strain pregnant rabbits. Animals received 1.0, 2.24, or 5.0 g/kg intravenously once daily from Days 6 to 18 of gestation. Maternal effects (auricular edema, and bradypragia) were observed in the high-dose group. No deaths or significant abnormalities occurred in animals given 1.0 or 2.24 g/kg. No effect was observed in the reproductive performance of the dams or in fetal development from ingestion at any of the treatment levels.

Chronic (1-year) oral toxicity study of erythritol in dogs.

The chronic oral toxicity of erythritol was examined by feeding erythritol at dietary levels of 0 (controls), 2, 5, or 10% to groups of four male and four female dogs for 53 weeks. Erythritol was well tolerated at all dose levels without evidence of diarrhea. Water consumption was slightly higher in the high-dose group than in controls. Body weights and weight gains were not affected by treatment. There were no clinically relevant changes in hematological or clinicochemical parameters attributable to treatment. In particular, plasma electrolyte concentrations remained unaffected. Evaluation of a number of urinary parameters (including electrolytes and renal enzymes) was hampered by widely varying urine volumes among individual dogs; however, the available data did not indicate treatment-related effects on the urinary excretion of electrolytes (K+, Na+, Mg2+, and Pi) or enzymes (gamma-glutamyltranspeptidase, N-acetyl glucosaminidase, and lactate dehydrogenase). Quantitation of erythritol in the urine demonstrated that 50 to 80% of the ingested dose was absorbed and excreted in the urine. Analysis of terminal organ weights did not reveal treatment-related differences. No histopathological changes attributable to treatment were observed in the kidneys or in any other organ or tissue examined. It was concluded that daily erythritol consumption of up to 3.5 g/kg body wt was well tolerated by dogs.

Mutagenicity studies on erythritol in bacterial reversion assay systems and in Chinese hamster fibroblast cells.

The sweetener erythritol tested negative in reverse mutation assays using Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and the WP2 uvrA strain of Escherichia coli. Erythritol tested negative in chromosome aberration tests using the Chinese hamster fibroblast cell line CHL/IU.

Chronic toxicity and carcinogenicity study of erythritol in rats.

The potential toxicity and carcinogenicity of erythritol, a low-calorie sugar substitute, were examined in Wistar Crl:(WI) WU BR rats. Groups of 50 rats of each sex consumed diets with 0, 2, 5, or 10% erythritol, or 10% mannitol, for a period of 104-107 weeks. To each of these main groups, two satellite groups of 20 males each were attached for interim kills after 52 and 78 weeks of treatment. At start of the study, the rats were 5-6 weeks old. The average intakes of erythritol in the 2, 5, and 10% groups were 0.9, 2.2, and 4.6 g/kg body wt/day for males and 1.0, 2.6, and 5.4 g/kg body wt/day for females, respectively. Mannitol intakes were 4.4 and 5.2 g/kg body wt/day in males and females, respectively. All treatments were well tolerated without diarrhea or other side effects. Body weights were significantly below control levels during most of the study in males of the 5% erythritol group and in males and females of the 10% erythritol and 10% mannitol groups. Survival of the animals was not adversely affected by the treatments. Hematological and clinicochemical examinations did not reveal noticeable changes which could be attributed to treatment. Analysis of urine samples collected during five 48-hr periods, from rats of the satellite groups in Weeks 26, 42, 50, and 78 and from rats of the main groups in Week 102, showed that about 60% of ingested erythritol was excreted unchanged. The urine volumes increased with increasing dietary erythritol levels. In line with previous observations on other polyols, erythritol and mannitol ingestion led to an increased excretion of urinary calcium and citrate. The urinary excretions of sodium, potassium, phosphate, N-acetylglucosaminidase (NAG), gamma-glutamyltransferase (GGT), low-molecular-weight protein (LMP), and total protein (TP) were slightly elevated in the 10% erythritol group. Increased GGT and NAG excretions also were seen occasionally at the 5% dose. Significantly increased relative cecum weights were seen in rats of either sex in the 10% mannitol and, somewhat less pronounced, 10% erythritol groups. Some cecal enlargement also was seen in the 5% erythritol group. The relative weight of the kidneys was highest in the 10% erythritol group, the difference from controls reaching statistical significance at interim kills (males) and termination (females). Except for more frequent pelvic nephrocalcinosis in female rats of all erythritol dose groups, the histopathological examinations did not reveal any nonneoplastic, preneoplastic, or neoplastic changes that could be attributed to the ingestion of erythritol. In male and female rats of the 10% mannitol group, pelvic nephrocalcinosis, which in females was associated occasionally with pelvic hyperplasia, was the only remarkable finding. The incidence and progression of nephrosis, which is commonly seen in aging rats of this strain, were not influenced by the treatments. In the absence of morphological alterations in the kidneys or other signs of nephrotoxicity, the increased excretions of NAG, GGT, LMP, and TP are regarded as innocuous, functional sequelae of the renal elimination of erythritol. In conclusion, the toxicological profile of erythritol in rats resembles that of other polyols in several respects. Except for nephrocalcinosis, which is commonly seen in polyol-fed rats, no other treatment-related, morphological changes were observed in the kidneys. Evidence for a tumor-inducing or tumor-promoting effect of erythritol was not seen.

Possibility of allergic reaction to dentin primer--application on the skin of guinea pigs.

We studied the allergic reaction of guinea pigs to glyceryl methacrylate (GM), hydroxyethyl methacrylate (HEMA) and meso-erythritol methacrylate (EM), which are used as dentin primers. On the 18th day of the application test, when macroscopic investigation revealed an inflammatory reaction, the methacrylic acid-treated group showed marked eschar formation in comparison with the control group. In each of the dentin primer groups, a slight degree of skin redness was noted, but there were no serious symptoms. On the 25th day, the applications were resumed macroscopic inspection on the 32nd day found eschar in the methacrylic acid group only. Therefore, this experiment with dentin primers suggests a delayed allergic reaction. Local irritability test showed a more severe reaction than the application test. In this test, all experimental dentin primers and methacrylic solution promptly showed inflammation, and the chemical compound, methacrylic acid was a factor in inflammation.