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Appendices 1-18 to: Report on the Health Effects of Selected Pesticide Coformulants

66     Human toxicity

66.1     Single and repeated dose toxicity

66.1.1     Inhalation

Twenty male volunteers (prisoners, age not reported) were exposed for 30 days, 20-22 hours a day, to ethylene glycol atmospheres (aerosol, diameters of droplets 1-5 µm) containing mean concentrations of 17 to 49 mg/m³ (lowest concentration: 0.8 mg/m³; highest concentration: 67 mg/m³). Fourteen other volunteers, as a control group, were treated as similarly as possible to the exposed group. Follow-up observations were made on both groups two weeks after the end of the exposure period. No subject experienced any serious signs of toxicity, but there were complaints of irritation of the throat and slight headache and low backache were also reported occasionally.

During the last two weeks of the experiment, the concentration of ethylene glycol was intentionally increased up to 308 mg/m³ during the absence of the volunteers and observation was made of their responses to these elevated concentrations of the aerosol when they re-entered the exposure chamber. When the volunteers returned to a concentration of ethylene glycol in the chamber air of 188 mg/m³, this concentration was irritating but could be tolerated for 15 minutes. A concentration of 244 mg/m³ could not be tolerated for more than a minute or two and a concentration of 308 mg/m³ could not be tolerated at all. Other similar trials revealed that concentrations of ethylene glycol in the air greater than about 200 mg/m³ were intolerable due to strong irritation of the upper respiratory tract, with a burning sensation along the trachea and a burning cough. The irritation became common when the concentration of ethylene glycol in the chamber air was raised to about 140 mg/m³.

Exposure to ethylene glycol under the conditions of this study produced no significant alterations of the haematological, clinically chemical, or clinically pathological parameters studied, including the concentrations of urea nitrogen and creatinine in the blood of the exposed volunteers.

(Wills et al 1974).

Troisi (1950 – quoted from LaKind et al. 1999 and from BUA 1991) examined 38 female workers at a condenser factory who were exposed for 1½ to 5 years to vapour from a mixture of ethylene glycol (40%), boric acid (55%), and ammonia (5%) kept at a temperature of 105 °C. Nine workers reportedly suffered from nystagmus and frequently lost consciousness; five other workers exhibited nystagmus only. Following changes to the production process which precluded further exposure, the reported symptoms ceased to occur.

66.1.2     Oral intake

There are numerous case reports in the literature of poisoning in humans due to accidental or intentional ingestion of ethylene glycol. In the United States, 6 to 60 deaths/year have been attributed to ethylene glycol ingestion. (LaKind et al. 1999, Jacobsen & McMartin 1997, ACGIH 2001, BUA 1991, ATSDR 1997).

The clinical symptoms of acute ethylene glycol poisoning can be divided into three (and occasionally four) fairly distinct stages. The severity of these stages and the advance from one stage to the next depends greatly on the amount of ethylene glycol entering the body. (LaKind et al. 1999, Jacobsen & McMartin 1997, Cavender & Sowinski 1994, BUA 1991, ACGIH 2001).

The first stage consists primarily of “central nervous system (CNS) effects”. This stage usually occurs shortly after ingestion of ethylene glycol, within 30 minutes to 12 hours. The CNS effects are characterised by signs of drunkenness (but without the characteristic breath odour of alcohol), nausea, vomiting, and at large doses coma followed by convulsions and death in some cases. Mild hypotension, tachycardia, low-grade fever, depressed reflexes, generalised or focal seizures, myoclonic jerks, and titanic contractions can occur. Ocular signs (nystagmus, ophthalmoplegia, papilledema, and subsequent optic atrophy) have also been reported.

The second stage has been described as the “cardiopulmonary effects” stage that occurs 12 to 72 hours after ingestion. This stage may also be characterised by severe metabolic acidosis. Symptoms that occur include tachypnoea, tachycardia, mild hypotension, and cyanosis. In severe cases, pulmonary oedema, bronchopneumonia, cardiac enlargement, and congestive failure are present. Hypocalcaemia may occur secondary to precipitation of metabolically formed oxalate and calcium deposits. Death in this stage usually occurs between 24 and 72 hours after exposure and is attributed to pulmonary oedema, cardiac dilation, and bronchopneumonia.

The third stage is known as the “renal failure” stage and occurs 24 to 72 hours after ingestion. This stage is characterised by profound acidosis. The renal damage may vary from mild increase in blood urea nitrogen and creatinine followed by recovery, to complete anuria with acute tubular necrosis that can lead to death. Histological changes include tubular epithelial degeneration and necrosis and oxalate crystal deposition in the kidney, lower urinary tract, and other organs (e.g., the brain).

The three clinical stages of acute oral ethylene glycol toxicity may overlap with the different latency periods before each stage, depending on the amount of ethylene glycol ingested. Often, Stage II never develops, yet the patient shows symptoms of the third stage of intoxication. (LaKind et al. 1999).

Other neurological symptoms, effects on cranial nerves, have been identified six or more days after ingestion and constitute a possible fourth clinical stage. These delayed neurological effects have resulted in facial paralysis, facial palsy, hearing loss, elevated protein levels in the cerebrospinal fluid, and bilateral cranial nerve dysfunction. These symptoms are uncommon and the mechanism of injury is unknown, but is distinctly different from the pathological events of the first three stages. (LaKind et al. 1999).

The oral dose of ethylene glycol required to cause death in humans is not well defined in the literature (ATSDR 1997).

The minimal lethal dose has been estimated, based on poisonings from accidental or intentional ingestion, at about 100 ml (about 111 g corresponding to about 1.6 g/kg b.w. for an adult) (LaKind et al. 1999, ACGIH 2001, BUA 1991, Cavender & Sowinski 1994, ATSDR 1997, NTP 1993).

However, early diagnosis and appropriate therapeutic measures can significantly reduce mortality, so that even doses of 970 ml (about 1080 g corresponding to 15 g/kg b.w. for an adult) have been survived (Gaultier et al. 1976 – quoted from BUA 1991).

66.1.3     Dermal contact

The potential for subchronic human exposure to ethylene glycol (as well as other substances) to induce effects in motor-servicing workers who performed various tasks that brought them into contact with motor vehicle antifreeze has been studied by Laitinen et al. (1995 – quoted from LaKind et al. 1999). Individual exposures were intermittent, but the workers had been performing their jobs for up to 23 years. Exposures resulted in enhanced urinary excretion of ethylene glycol by workers compared with office worker controls, as well as enhanced ammonia excretion (typical of chronic acidosis associated with ethylene glycol exposure). Because measured airborne levels of ethylene glycol were below the detection limits, the authors concluded that exposure occurred primarily via dermal contact with ethylene glycol during extended contact with the antifreeze.

66.1.4     Skin irritation

In order to study the irritation and sensitisation potential, ethylene glycol was applied to infrascapular skin of 401 human volunteers nine times over a 3-week period, in 24-hour occluded and semioccluded patch tests. Sites were evaluated after 24 hours for local irritancy. Initial and challenge applications resulted in marginal erythematous reactions in 9.3 and 12.2% of the individuals, respectively. Definite erythema, seen in a smaller group during the induction period, suggested potential cumulative irritation. (Union Carbide 1990 – quoted from LaKind et al. 1999).

One-inch square gauze pads completely wetted with 0.11, 1.1, or 10% (v/v) ethylene glycol were applied to the backs of 13 volunteers with no known previous exposure to ethylene glycol. No skin reactions were reported from any of the patches after 1, 2, 4, or 8 hours. (Shupack et al. 1981 – quoted from LaKind et al. 1999 and from ACGIH 2001).

Out of 1556 dermatitis patients subjected to 20/24-hour closed patch tests, 3.9% (61) experienced an irritant response (of unspecified severity) to neat ethylene glycol (Hannuksela et al. 1975 – quoted from IUCLID 2000).

After treatment with a concentration of 5% ethylene glycol in water, one woman showed strong skin reactions while 10 other subjects showed no reactions (Hindson & Ratcliffe 1975 – quoted from IUCLID 2000).

The application of 3% ethylene glycol in ethanol (patch test) resulted in a positive reaction in 1 out of 9 persons (Dawson 1976  – quoted from IUCLID 2000).

Ethylene glycol produces no significant irritant effect on the skin. A slight maceration of the skin may result from prolonged exposures. (Rowe & Wolf 1982 – quoted from Cavender & Sowinski 1994 and from IUCLID 2000).

66.1.5     Eye irritation

Exposure of human eyes to vapour or spray of ethylene glycol for 4 weeks at 17 mg/m³ resulted in no effects (Grant 1986 – quoted from Cavender & Sowinski 1994 and from ACGIH 2001).

A splash of neat ethylene glycol into the eye of a worker produced marked inflammation, but no permanent damage (BIBRA 1993 – quoted from IUCLID 2000).

66.1.6     Skin sensitisation

Ethylene glycol was applied to infrascapular skin of 401 human volunteers nine times over a 3-week period, in 24-hour occluded and semioccluded patch tests. Sensitisation was assessed after a 3-week rest, by 24-hour patch test challenges at distal sites. Sensitisation was suggested in fewer than 1% of the volunteers, but this response was not confirmed after rechallenge. (Union Carbide 1990 – quoted from LaKind et al. 1999).

In 15 (1%) out of 1556 dermatitis patients subjected to 20/24 hour closed patch tests, the skin reaction was described as allergic in character (Hannuksela et al. 1975 – quoted from IUCLID 2000).

Allergic dermatitis have been reported in two workers handling a fluid containing ethylene glycol (25 or 33%) in the preparation of contact lenses for periods of 3 to 4 months. The sensitisation was confirmed by their positive reactions to 48-hour closed patch tests. The application of 3% ethylene glycol in ethanol or 5% in water to the skin of the two workers induced a positive reaction. (Dawson 1975, Hindson & Ratcliffe 1975 – both quoted from IUCLID 2000 and from BUA 1991).

66.2     Toxicity to reproduction

No data have been found.

66.3     Mutagenic and genotoxic effects

No data have been found.

66.4     Carcinogenic effects

No data have been found.

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