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

82     Human toxicity

Haematological effects have been identified as the critical end-point in toxicological studies on EGBE. Humans appear to be less sensitive to the haematological effects of EGBE than are rats, mice, rabbits, and guinea pigs. (EPA 1999).

82.1     Single dose toxicity

82.1.1     Inhalation

Three controlled studies have been conducted by Carpenter et al. (1956 – quoted from EPA 1999, ATSDR 1998, NTP 2000).

In the first study, two men were exposed for 4 hours to an EGBE concentration of 113 ppm (555 mg/m³). Effects observed included nasal and ocular irritation, a metallic taste in the mouth, and belching. Erythrocyte osmotic fragility was not affected.

In a second study, two men and one woman were exposed to 195 pm (957 mg/m³) for two 4-hour periods, separated by a 30-minute recess. There was no change in the blood pressure, erythrocyte fragility, or pulse rate. Irritation of the nose and throat followed by ocular irritation and disturbed taste was noted.

In the third study, two men and two women were exposed for 8 hours to an EGBE concentration of 100 ppm (490 mg/m³). No changes in blood pressure, erythrocyte fragility, or pulse rate were observed. Irritation of the nose and throat followed by ocular irritation and a disturbing metallic taste were noted.

When seven male volunteers were exposed to EGBE (20 ppm (98 mg/m³)) for 2 hours during light physical exercise (bicycle ergometer), none of the subjects complained of or showed any signs of adverse effects (pulmonary ventilation, respiratory frequency, heart rate, electrocardiograms) (Johanson et al. 1986 – quoted from ECETOC 1995b, ATSDR 1998, NTP 2000).

82.1.2     Oral intake

In twenty-four children (aged 7 months to 9 years) observed subsequent to oral ingestion of at least 5 ml of glass window cleaner containing EGBE (0.5-9.9%), no symptoms of EGBE poisoning and no haemolysis were observed in any of the children (Dean & Krenzelok 1991 – quoted from EPA 1999, ATSDR 1998).

Poisoning cases by ingestion of household products containing EGBE have been reported (Rambourg-Schepens et al. 1988, Gijsenbergh et al. 1989, Bauer et al. 1992, Gualtieri et al. 1995  – quoted from EPA 1999, ECETOC 1995b, ATSDR 1998, NTP 2000). The intakes of EGBE were 30-60 ml, 25-30 g (corresponding to 400-500 mg/kg b.w.), ca. 46 ml, and 79-105 ml (corresponding to 1130-1500 mg/kg b.w.) in the four case reports, respectively. The symptoms observed in various studies included cardiovascular effects (increased heart rate, decreased blood pressure), haematological effects (decreased haemoglobin concentration and haematocrit, and thrombocytopenia), metabolic acidosis, haematuria, and haemoglobinuria.

82.1.3     Dermal contact

No data have been located.

82.1.4     In vitro studies

Blood from male and female young volunteers was unaffected by 4-hour incubations with 2-butoxyacetic acid (2-BAA, the toxic metabolite of EGBE) at concentrations up to 4.0 mM (470 mg/l) (60-235 mg/l produced total rat erythrocyte haemolysis). There was a slight increase in haemolysis of human erythrocytes incubated with 8 mM (945 mg/l) of 2-BAA with female erythrocytes showing a slightly greater sensitivity than male erythrocytes. (Ghanayem 1989, Ghanayem 1989 et al. 1989 – quoted from EPA 1999, ECETOC 1995b, ATSDR 1998).

Using a sensitive assay for erythrocyte deformability and haemolysis, human erythrocytes were unaffected following exposure to 2-BAA at concentrations up to 2mM (235 mg/l) for up to 4 hours (rat erythrocytes were haemolysed and showed decreased deformability). The possibility that certain human subpopulations, including the aged and those predisposed to haemolytic disorders, might be at an increased risk from exposure to EGBE has been investigated using blood from the elderly (mean age 71.9 years; range 64-79 years, five men and four women), from patients with sickle cell disease (seven patients), and from patients with spherocytosis (three individuals). Erythrocytes from these potentially sensitive groups were unaffected by incubations with 2-BAA at concentrations up to 2.0 mM (235 mg/l) for up to 4 hours. (Udden 1994, Udden & Patton 1994 – quoted from EPA 1999, NTP 2000; Udden 1992 – quoted from ECETOC 1995b).

The deformability of human erythrocytes incubated at 2-BAA concentrations of 7.5-10 mM (885-1180 mg/l) displayed a slight but significant decrease that was accompanied by slight increases in osmotic fragility and MCV. These effects were judged pre-haemolytic and corresponded to similar changes reported in rat erythrocytes, but at approximately 15-fold lower concentrations (0.5 mM) in rat erythrocytes than in human erythrocytes. (Udden 1995 – quoted from EPA 1999).

82.2     Irritation

Irritation of nose and throat, and eyes have been reported following exposure to airborne EGBE at concentrations from 490-957 mg/m³ for 4-8 hours; irritation was not reported following exposure to EGBE (98 mg/m³) for 2 hours. See 3.1.1 for further details.

82.3     Sensitisation

Volunteers (214 men and women) were given 0.2 ml 10% EGBE in patches applied to the intra-scapular area of the back. The dosed area was occluded. Testing included dosing, removal of the patch within 24 hours, evaluating the exposed area at 48 hours, and application of an identical patch to the same location. The subjects received nine such applications over a 6-week period. By the end of the 6 weeks, 25% of the subjects showed slight or definite erythema. Following application to a naïve area at 6 weeks, slight erythema was observed in seven subjects at 48 hours and 12 at 72 hours; one subject had definite erythema at 72 hours. No other effects were noted. It was concluded that there were no dermal effects of 10% EGBE under the conditions of the study. (Greenspan et al. 1995 – quoted from ATSDR 1998, NTP 2000).

82.4     Repeated dose toxicity

In a cross-section study, 31 male workers (22-45 years old, employed for 1-6 years) exposed to low levels of EGBE were monitored by Haufroid et al. (1997 – quoted from EPA 1999, ATSDR 1998). The average airborne concentration of EGBE was 2.9 mg/m³ (20 workers were exposed to an average concentration of 3.7 mg/m³ and 11 workers to 2.3 mg/m³). Red blood cell (RBC) count, haemoglobin (Hgb), haematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), haptoglobin (Hp), reticulocyte numeration (Ret), and osmotic resistance (OR, a measure of osmotic fragility) as well as hepatic and renal creatinine and urinary retinal binding protein parameters was investigated. Single determinations of 2-BAA (toxic metabolite of EGBE) in post-shift urine samples were used to assess exposure to EGBE. A significant correlation was observed between post-shift free urinary 2-BAA concentrations and EGBE in air. No difference between exposed and control workers was observed for RBC counts, Hgb, MCV, MCH, Hp, Ret, and OR. Statistically significant changes were observed for Hct (3.3% decrease) and MCHC (2.1% increase). No significant differences were observed in hepatic and renal biomarkers. According to ATSDR (1998), the differences in Hct and MCHC may be consistent with haemolysis and may be early indicators of potential adverse effects, but because the changes were in the range of normal clinical values, the concentration in the air of EGBE (2.9 mg/m³) was considered as a NOAEC.

82.5     Toxicity to reproduction

No data have been located regarding toxicity to reproduction in humans following exposure to EGBE.

82.6     Mutagenic and genotoxic effects

No increases in the frequencies of micronuclei or sister chromatid exchanges were observed in peripheral blood lymphocytes of varnish production workers exposed to both EGBE and to 2-ethoxyethanol (EGEE) (Söhnlein et al. 1993 – quoted from ATSDR 1998, NTP 2000).

82.7     Carcinogenic effects

No data have been located regarding carcinogenic effects in humans following exposure to EGBE.

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