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An oral lethal dose for humans was determined to be 0.014 mg/kg bw.

Additional information

In 1937 there was mass poisoning by the medication "Elixir Sulfanilamide" (manufactured by Massengill Co.), which contained 72% DEG as a solvent for sulphonamide (Geiling et al., 1937; Geiling and Cannon, 1938: Lynch, 1938; Calvery and Klumpp, 1939). Symptoms of poisoning after ingesting this preparation were described for 105 deaths and in a further 248 people, though it could not be excluded in every single case that the underlying disease being treated with the medication was jointly responsible for the symptoms. Repeated intake of the DEG-containing preparation led to dizziness and vomiting, and often headaches. Unless the medication was withdrawn, these symptoms were followed by polyuria, oliguria and finally anuria. Abdominal and back pains were often described. Prior to death there were disturbances of consciousness, coma and, in some children, tremors and convulsions, which are interpreted as a consequence of uraemia. If laboratory data were recorded (albuminuria, casts and erythrocytes in the urine, increased residual nitrogen in the blood), they confirmed progressive kidney failure. For 96 patients, death was attributed to ingestion of the medication. On average they died after 9.4 + 3.4 days. For the other 9 deaths the causal relationship was not certain. 200 adults and 48 children survived repeated ingestion of the preparation. The doses used were up to 340 ml (corresponding to 245 mL DEG). On average, doses of 44.2 mL (corresponding to 32 mL DEG) were survived by children up to 14 years and of 83.7 mL (corresponding 60 mL DEG) by persons of 15 years and older. The amounts of the substance actually absorbed cannot be assessed because ingestion of the medication was often soon followed by gastro-intestinal disorders, which led to discontinuation of the preparation (Calvery and Klumpp, 1939). A histological report is available for 12 intoxications resulting in death. Autopsy revealed generalized oedema (ascites, hydrothorax, hydropericardium, pulmonary oedema). In addition in some cases there was bleeding into the gastro-intestinal tract and lungs. The increased capillary permeability can be correlated with the clinical picture of acidosis and uraemia. The principal signs of intoxication were lesions in the kidneys and liver. There were cortical necroses and infarcts in the enlarged kidneys. The main microscopic finding was nephrosis with severe vacuolization of the tubular epithelium (hydropic degeneration). Both hyaline casts and accumulations of erythrocytes and leucocytes were described in the collecting tubules. As a rule the livers were enlarged, pale and of soft consistency. The picture corresponded to chronic congestion of the liver. Centrilobular hydropic degeneration was observed microscopically. Fatty degeneration was only observed at the margins of the liver. Signs of inflammation (infiltration of leucocytes) were only reported in 2 cases. The changes found in other organs could all be explained by the uraemia and terminal cardiac failure (Geiling and Cannon, 1938). In a report from South Africa concerning 7 children, a common cause of intoxication was shown retrospectively to be the use of sedatives in which DEG was used as solvent instead of propylene glycol. The picture of intoxication corresponded to that described for adults (see above). The following findings were recorded (frequency): feverish prodromal stage (7), vomiting (71, anuria (7), diarrhoea (3), dehydration (7), metabolic acidoses (7), hepatomegaly (7), disturbances of consciousness (5), enlargement of the kidneys (31, leucocytosis (7) (14,000-29,000/mm3), increased blood urea (7), increased SGPT with normal bilirubin (7), neurological symptoms (4). In all cases death occurred unexpectedly and suddenly through cardiac failure. The findings at autopsy were also similar to those reported for adults (see above), in particular, pathological lesions of the kidneys and liver. No pathological changes in the brain were diagnosed, even in the 4 cases which previously had neurological symptoms. No statements were made concerning the absorbed doses of DEG (Bowie and McKenzie, 1972). Another case has been reported concerning intoxication of a 65-year-old alcoholic after ingestion of about 150 mL of pure DEG. The man became comatose 16 hours after ingestion, necessitating artifical respiration. The patient also developed severe metabolic acidosis with high oxalate level in the urine. After plasma alkalization and peritonealdialysis the patient survived the poisoning without consequences, according to a follow-up investigation a year later (Auzepy et al., 1973). Telegina et al. (1971) reported a retrospective epidemiological study, without controls, on workers who had contact with DEG in the extraction of benzene and its homologues; no details of exposure levels were reported. After an exposure period of 1-9 years, no indication of an increased cancer risk was found in 90 workers (56 men, 34 women, age 20-49 years). Because of the inadequate methodology of the investigation, few conclusions can be drawn from this study, 15 mL DEG was tolerated by humans (Remmer, 1985). A figure of 30-60 mg is given as the safe daily dose for humans (Remmer, 1985; Altmann et al., 1986) No information is found in the literature concerning the occurrence of bladder stones in humans after ingestion of DEG. The above mentioned data were described in the BG data catalogue of 1999.

In a review article from Schep et al. (2009) all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, toxicity of DEG, diagnosis, and management were summarized. Most of the documented cases of DEG poisoning have been where DEG was substituted in pharmaceutical preparations. More often, these epidemics have occurred in developing and impoverished nations where there is limited access to intensive medical care and quality control procedures are substandard. The clinical effects of DEG poisoning can be divided into three stages: The first phase consists of gastrointestinal symptoms with evidence of inebriation and developing metabolic acidosis. lf poisoning is pronounced, patients can progress to a second phase with more severe metabolic acidosis and evidence of emerging renal injury which, in the absence of appropriate supportive care, can lead to death. If patients are stabilized, they may then enter the final phase with various delayed neuropathies and other neurological effects, sometimes fatal. Initial treatment consists of appropriate airway management and attention to acid- base abnormalities. Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite 2- hydroxyethoxyacetic acid (HEAA) ; hemodialysis can also be critical, and assisted ventilation may be required.

To investigate an outbreak of deaths among children from acute renal failure in Haiti to determine the etiology and institute control measures a case-control study (cohort study) and laboratory toxicologic evaluations were conducted (O'Brien, 1998). It was shown, that an epidemic of severe systemic toxicity and deaths from DEG-contaminated acetaminophen syrup occurred in Haiti. In the study 109 cases of acute renal failure among children were identified. The clinical syndrome included renal failure, hepatitis, pancreatitis, central nervous system impairment, coma, and death. Of 87 patients with follow-up information who remained in Haiti for treatment, 85 (98%) died; 3 (27%) of 11 patients transported to the United States for intensive care unit management died before hospital discharge. A locally manufactured acetaminophen syrup was highly associated with the disease (odds ratio, 52.7; 95% confidence interval, 15.2-197.2). Diethylene glycol (DEG) was found in patients' bottles in a median concentration of 14.4%. The median estimated toxic dose of DEG was 1.34 mL/kg (range, 0.22-4.42 mL/kg). Glycerin, a raw material imported to Haiti and used in the acetaminophen formulation, was contaminated with 24% DEG.

In a publication of Ferrari and Giannuzzi (2005) a massive intoxication that occurred in 1992 in Argentina as a result of the use of propolis syrup as a popular upper respiratory infection medicinal agent was analysed. The 15 victims were classified into three groups according to survival time from hospital admission up to the moment of death. Three groups were defined as follows: Group 1—patients that survived up to 3 days (three cases); Group 2—patients that survived between 4 and 5 days (three cases); Group 3—patients that survived between 6 and 21 days (nine cases). The clinical history of each patient was studied. Patients from Group 1 showed the highest values of anion gap, the lowest measures of base excess (BE) and more severe clinical manifestations. Correlation between pH and BE was r2 = 0.68, 0.99 and 0.55 for Groups 1, 2 and 3, respectively. A methanolic extraction was performed on the fatal victims’ viscera and blood, with subsequent concentration and purification. In 3 out of the 15 fatal cases (from Group 1), DEG was isolated from viscera and blood (femoral venous), between 48 and 72 h post ingestion. In the other victims, DEG could not be detected. The reason for this could be the long survival period of the victims after their ingestion of the syrup. Additionally, putrefying mechanisms could have been operating. Samples of the propolis syrup of each victim were studied by means of nuclear magnetic resonance (NMR) and quantified by gas chromatography/flame ionisation detection (GC/ FID). Results showed that syrup samples contained 65.0% (w/v) of diethylene glycol (DEG) and 32.0% (w/v) of propylene glycol (PG). A good correlation between the amount of DEG ingested and the anion gap (r2 = 0.63) for the 15 victims studied could be observed. The lethal dose for human beings estimated in this work ranged from 0.014 to 0.170 mg DEG/kg body weight. The lethal dose reported though is not reliable due to a wrong reporting in the publication.

To determine whether an atmosphere containing aerosolized ethylene glycol in a concentration that could be tolerated by human volunteers for most of each 24-h period would have any deleterious action on man, in a prison hospital twenty volunteers were exposed during 20 to 22 h per day to aerosolized ethylene glycol in mean daily concentrations between 3 and 67 mg/m3 (Wills, 1974). Nineteen men finished the planned one-month exposure. When the concentration of ethylene glycol within the chamber was raised to 200 or more mg/m3, the atmosphere could not be tolerated for more than a minute or two, the period of tolerance decreasing progressively as the concentration was increased further. Blood and urine specimens obtained from the volunteers at intervals during their prolonged exposure gave little evidence of the absorption of important quantities of ethylene glycol. No subject experienced any serious signs of toxicity assignable to the exposure, but there were complaints of irritation of the throat and fauces. Slight headache and low backache also were reported occasionally. The irritative phenomena became common when the concentration of ethylene glycol in the ambient air was raised to about 140 mg/m3. The irritative effects appear to rule out the possibility that a harmful amount of ethylene glycol could be absorbed from the respiratory tract of a healthy Individual who was unaware that he had been exposed to this substance.