Evaluation of potential neurotoxic effects of occupational exposure to (L)-lactates.

Organo psycho syndrome (OPS) or chronic toxic encephalopathy (CTE) is a neurotoxic condition reported following long-term exposure to paints containing organic solvent and to other solvents. Lactate esters are finding wider use as solvents. Lactate esters have been well studied in standard toxicity tests, but specific neurotoxicity studies have not been conducted. No clinical signs of chronic neurotoxicity have been observed in standard toxicity tests. Lactate esters are rapidly hydrolyzed in the body to lactic acid and the corresponding alcohol. Alcohols have been reported to have acute neurotoxic effects, usually following high levels of ingestion. The literature on alcohols was reviewed to establish the no-observed-adverse-effect level (NOAEL) for acute neurotoxicity and to look for any evidence of chronic neurotoxicity from the alcohols produced by hydrolysis of the lactate esters. The NOAELs were compared with the potential amounts of alcohol produced by hydrolysis of different lactate esters at 200 mg//m(3) (the NOAEL for most of the lactate esters). In all cases neither acute nor chronic neurotoxicity would be expected based on the amounts of alcohol produced by hydrolysis of the lactate esters at their NOAELs. L-Lactic acid is a normal metabolite in the body and is not considered neurotoxic. Based on this information there is no evidence to suggest that L-lactate esters can cause any chronic neurotoxicity, OPS, or CTE.

Safety assessment of lactate esters.

Lactate esters have an oral LD50 greater than 2000 mg/kg and the inhalation LC50 is generally above 5000 mg/m3 and they may be potential eye and skin irritants, but not skin sensitizers. No evidence of teratogenicity or maternal toxicity was observed in an inhalation (2-ethylhexyl-l-lactate) or dermal study (ethyl-l-lactate). Subacute inhalation studies have been conducted at concentration up to 600 mg/m3 or higher on four lactate esters (ethyl, n-butyl, isobutyl, and 2-ethylhexyl-l-lactate). Degenerative and regenerative changes in the nasal cavity were noted in all studies. The NOAEL in ethyl, n-butyl, and isobutyl-l-lactate vapor studies was 200 mg/m3. For aerosol exposure, 2-ethylhexyl-l-lactate, the most toxic of the lactates, minimal damage to the nasal epithelium was noted at 75 mg/m3 with vapor being slightly less toxic than the aerosol. Lactates do not appear to cause systemic toxicity, except at very high concentrations (1800 mg/m3 or higher). These systemic effects may be secondary to severe irritation seen at high doses. Sensory irritation tests suggest that a vapor exposure limit of 75 mg/m3 ( approximately 15 ppm) should prevent irritation in humans and therefore an occupational exposure level for vapor of 75 mg/m3 is recommended. However, aerosol exposure should be kept as low as possible. The low vapor pressure of the higher molecular weight esters would tend to keep vapor exposure low and the odor of lactate esters serves as a warning of exposure. These lactate esters are readily biodegradable, suggesting little concern from an environmental point of view.

[1st use of lactitol in the treatment of porto-systemic encephalopathy]. / Erstmalige Anwendung von Lactitol in der Behandlung der porto-systemischen Enzephalopathie.

Lactitol (beta-galactosido-sorbitol) is not absorbed in the small bowel but metabolized by colonic bacteria, and should therefore be as effective in the treatment of portal-systemic encephalopathy as lactulose (beta-galactosido-fructose). This hypothesis was tested in a 61-year-old alcoholic with an end-to-side portacaval anastomosis and chronic portal-systemic encephalopathy. Under controlled conditions he was switched from optimized treatment with lactulose to several regimens with lactitol (40-68 g/day), after which he was maintained on the new treatment for 1 year. On lactitol his condition was at least as good as on lactulose, but lactitol produced no taste aversion because it is less sweet. In addition, the patient no longer had nausea after taking the drug because lactitol can be supplied in a nonhygroscopic, chemically pure, crystalline form and therefore is less hyperosmotic than lactulose, which is supplied with contaminations of galactose and lactose. Obviously the data in single case represent only a feasibility study. Nevertheless, the outcome in this patient, together with the advantages of the new sugar, justify the planning of controlled clinical trials.