Joseph F. Borzelleca

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.

Lifetime toxicity/carcinogenicity studies of FD & C Blue No. 1 (brilliant blue FCF) in rats and mice.

FD & C Blue No. 1 was fed to Charles River CD rats and CD-1 mice as a dietary admixture in lifetime toxicity/carcinogenicity studies. The rat study was conducted with an in utero phase in which the compound was administered to the F0 generation rats (60/sex/group) at dietary concentrations of 0.0%, 0.0%, 0.1%, 1.0% or 2.0%. After randomly selecting the F1 animals, the lifetime phase was initiated at the same levels with 70 rats/sex/group, including two control groups. The maximum exposure times were 116 and 111 wk for males and females, respectively. The no-observed-adverse-effect levels are dietary concentrations of 2.0% for males (1072 mg/kg body weight/day), and 1.0% for females (631 mg/kg/day) based on a 15.0% decrease in terminal body weight and decreased survival in the high-dose females compared with the combined control groups. Charles River CD-1 mice (60/sex/group) were fed FD & C Blue No. 1 as a dietary admixture at levels of 0.0%, 0.0%, 0.5%, 1.5% or 5.0% in a lifetime toxicity/carcinogenicity study. The maximum exposure time was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse-effect level established in this study is a dietary concentration of 5.0% (7354 mg/kg/day and 8966 mg/kg/day for male and female mice, respectively.

Humoral and cell-mediated immune status in mice exposed to trichloroethylene in the drinking water☆

Abstract A 14-day study using male CD-1 mice exposed to trichloroethylene (TCE) by daily po gavage suggested inhibition of cell-mediated immunity. Therefore, an evaluation of the immune status was undertaken after exposure of male and female mice to TCE in the drinking water for either 4 or 6 months. The immunological parameters assessed were humoral immunity, cell-mediated immunity, lymphocyte responsiveness, bone marrow function, and macrophage function. Females were more affected than males by TCE, particularly after a 4-month exposure. In the female, humoral immunity was inhibited only at the highest concentrations of TCE (2.5 and 5 mg/ml), whereas cell-mediated immunity and bone marrow stem cell colonization were inhibited at all four concentrations of TCE (0.1, 1.0, 2,5, and 5 mg/ml). The males were relatively unaffected after both 4 and 6 months compared to effects observed in the 14-day study.

Toxicology of trichloroethylene in the mouse

Abstract The purpose of this study was to evaluate the acute and subchronic toxicology of trichloroethylene (TCE) in the mouse. The oral LD50 in female mice was 2443 mg/kg (95% confidence limits of 1839–3779 mg/kg) and in male mice was 2402 mg/kg (95% confidence limits of 2065–2771 mg/kg). After determination of the LD50 by the oral route, a 14-day study was done in male CD-1 mice in which TCE was administered daily by gavage at 24 and 240 mg/kg. A subchronic drinking water study was designed based on these data, in which TCE at concentrations of 0.1, 1.0, 2.5, and 5.0 mg/ml was used, and mice of both sexes were exposed for 4 or 6 months. There was a decreased body weight gain at the highest dose, which could be attributed to a decrease in fluid consumption. The most significant effects attributable to TCE were an increase in liver weight in both sexes accompanied by increased nonprotein sulfhydryl levels in the males, and an increase in kidney weight in both sexes accompanied by increases in protein and ketones in the urine. TCE failed to elicit any other adverse effects.

The toxicity of some halomethanes in mice

Abstract The acute toxicity of trichloromethane, bromodichloromethane, dibromochloromethane, and tribromomethane was studied in mice following administration by gastric gavage. Gross pathological changes included fatty infiltration of the liver and signs of hemorrhage in the kidneys, adrenals, lungs, and brain. Median lethal doses (LD50) were also calculated. Generally, the males were more sensitive to each of the compounds than females.

Macronutrient substitutes: Safety evaluation

Macronutrient substitutes, reduced-calorie substances used to replace organoleptic and/or functional properties of fats and sugars in the diet, may become a significant part of the diet as the trend toward lower fat and lower calorie diets continues. Procedures currently used to evaluate the safety of traditional food additives (microadditives) may be inadequate to properly assess the safety of macronutrient substitutes (macroadditives) because of the unique nature of these substances and the potentially large intakes. An evaluation procedure is proposed that recognizes the benefits to be derived from the test material, uses a structured approach to obtain animal and human nutritional and toxicological (including kinetic and dispositional) data that are critically evaluated and that provide a basis for further testing, encourages consultation with the regulatory agency (FDA), and recommends postmarketing surveillance of the macronutrient substitute. The proposed scheme differs from the traditional approach in many respects, such as using dispositional and kinetic data, assessing nutritional status, using human data collected under carefully controlled conditions early in the process, and consulting with the FDA. A case-by-case approach is recommended for safety evaluation of these macroadditives.

Effects of 1,2-dichloroethane and 1,1,1-trichloroethane in drinking water on reproduction and development in mice

Abstract A multigeneration reproduction study was modified to include screening for dominant lethal and teratogenic effects of 1,2-dichloroethane (1,2-DCE) and 1,1,1-trichloroethane (1,1,1-TCE) in drinking solution (Emulphor:deionized water, 1:99, v v ). Male and female ICR Swiss mice received either 1,2-DCE at concentrations of 0, 0.03, 0.09, or 0.29 mg/ml or 1,1,1-TCE at concentrations of 0, 0.58, 1.75, or 5.83 mg/ml. These concentrations were designed to yield daily 1,2-DCE doses of 0, 5, 15, or 50 mg/kg and 1,1,1-TCE doses of 0, 100, 300, or 1,000 mg/kg. No taste aversion was evident for either of the chemicals at any concentration. There appeared to be no dose-dependent effects on fertility, gestation, viability, or lactation indices. Pup survival and weight gain were not adversely affected. 1,2-DCE and 1,1,1-TCE failed to produce significant dominant lethal mutations or terata in either of the two generations tested.

Safety Evaluation of Ferrous Bisglycinate Chelate

Ferrous bisglycinate chelate (Ferrochel) is a highly stable chelate that can be added to most foods. Data from human and animal studies indicate that the ferrous iron is readily bioavailable with fewer side-effects than the more commonly used iron salts. The acute oral LD50 for male and female Sprague-Dawley (S-D) rats is 2800 mg/kg body weight (560 mg/kg body weight iron [confidence limit (CL) 399-786] as the active ingredient). Male and female CD (Sprague Dawley-derived) rats were fed ferrous bisglycinate as a dietary admixture at doses of 0, 100, 250 and 500 mg/kg body weight/day. There were no biologically or statistically significant dose-related differences between the control and treated animals with respect to body weight gain, food consumption, food efficiency, behavioural effects, clinical chemistries, haematology, absolute and relative organ weights, or gross and microscopic findings. Hepatic non-heme iron concentrations were elevated, indicating that the ferrous iron had been absorbed. The no-observed-adverse-effect level (NOAEL) was 500 mg/kg body weight/day, the highest dose tested.

A chronic toxicity/carcinogenicity study of FD & C Yellow No. 5 (tartrazine) in mice.

Charles River CD-1 mice were fed FD & C Yellow No. 5 in the diet at levels of 0.0, 0.0, 0.5, 1.5 or 5.0% in a long-term toxicity/carcinogenicity study. Each group consisted of 60 males and 60 females. Maximum exposure was 104 wk for both males and females. No consistent, significant compound-related adverse effects were noted. The no-observed-adverse effect level established in this study was 5.0% (8103 mg/kg/day and 9735 mg/kg/day for male and female mice, respectively.)

Assessment of cassia gum

Cassia gum is approved for use in Europe by the Commission Directive (EEC No. E 499) and is listed in the Annex of the Council Directive (70/524/EEC) as a stabilizer (thickening and gelling agent) in the manufacture of canned pet foods (for cats and dogs). It is also approved for use in Japan and is listed as a food additive in The Ministry of Health and Welfare Announcement No. 160 (10 August 1995). A panel of experts in the areas of toxicology, pharmacology and food science was assembled to review the safety of cassia gum for use as a thickening agent in human and pet foods in the United States. The available data on cassia gum and structurally related gums demonstrate a lack of toxic effects in animals. This review is the basis for the consideration of cassia gum as generally recognized as safe (GRAS) under conditions of its intended use as a thickening agent in human and pet foods.