| Front page | | Contents | | Previous | | Next |

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

85     Summary

85.1     Description

EGBE is a colourless liquid with a low vapour pressure (0.76 mmHg at 20°C); it is miscible with water.

85.2     Toxicokinetics

EGBE is rapidly absorbed and distributed throughout the body (humans and rats) following inhalation, oral administration and dermal contact. Following inhalation, peak blood levels were observed in humans within 1-2 hours following exposure; one study in human volunteers indicates an uptake of about 60% of the inspired amount during light physical exercise.

In humans, EGBE is eliminated primarily as 2-butoxyacetic acid (2-BAA) in the urine either free or conjugated to glutamine and, to a lesser extent, glycine. In rats, EGBE can also be converted to ethylene glycol or conjugated to glucuronide and sulphate to some extent. Excretion also takes place via expired air in form of carbon dioxide.

85.3     Human toxicity

85.3.1     Single dose toxicity, irritation

In human volunteers exposed by inhalation to EGBE at concentrations from 490-957 mg/m³ for 4-8 hours, irritation of the nose and throat, and eyes was noted; no haematological effects were observed. When seven male volunteers were exposed to EGBE (98 mg/m³) for 2 hours, none of the subjects complained of or showed any signs of adverse effects.

Poisoning cases are available reporting haematological changes and metabolic acidosis following acute ingestion of large doses of EGBE in household products and combined with other solvents.

85.3.2     Irritation, sensitisation

In a patch test, human volunteers showed no dermal effects following application of 10% aqueous EGBE.

85.3.3     Repeated dose toxicity

No differences between exposed and control workers (average airborne concentration of EGBE: 2.9 mg/m³) were observed for haematological parameters except for small changes for haematocrit (3.3% decrease) and mean corpuscular haemoglobin concentration (MCHC) (2.1% increase).

85.3.4     Toxicity to reproduction

No data have been located.

85.3.5     Mutagenic and genotoxic effects

No increases in micronuclei or sister chromatid exchanges were observed in workers exposed to both EGBE and to 2-ethoxyethanol (EGEE).

85.3.6     Carcinogenic effects

No data have been located.

85.4     Animal toxicity

85.4.1     Single dose toxicity

LC₅₀-values (4-hour exposure) of 2200-2400 mg/m³ have been reported for rats and of 3440 mg/m³ (7-hour exposure) for mice. One of six guinea pigs died after 4 hours of exposure to saturated vapour (ca. 4900 mg/m³).

Oral LD₅₀-values of 530-3000 mg/kg have been reported for rats, of 1230 and 1519 mg/kg for mice, of 950-1415 for guinea pigs, and of 320-3100 for rabbits.

Dermal LD₅₀-values of 406 to 1804 mg/kg have been reported for rabbits, of 255-4800 mg/kg for guinea pigs, and of 2273 mg/kg for rats.

Following inhalation, increased erythrocyte fragility was seen in rats exposed to 305 mg/m³ for 4 hours and haemoglobinuria was observed in rats and mice exposed to about 1000 mg/m³ for 7 hours; no such effects were observed in monkeys exposed to about 1000 mg/m³ for 7 hours.

Following oral administration to rats, haemoglobinuria was observed at 3000 and 1500 mg/kg in male and female rats, respectively. Haemolysis of erythrocytes accompanied by haemoglobinuria have been observed following a single dose of 500 mg/kg, and at 125 mg/kg although to a lesser degree. Guinea pigs dosed once with 250 mg/kg showed no adverse haematological effects. The haematological effects in rats were found to be dose- and age-dependent, with older rats being more sensitive than younger rats.

Following dermal exposure, haemolytic effects have been observed in rats by application of 260 mg/kg to the shaved skin.

85.4.2     Irritation

In rabbits, EGBE has been considered a severe irritant by the Draize protocol and an irritant by the EU protocol. Several other studies have also reported EGBE to be a skin irritant in rabbits. Severe skin irritation has been noted in guinea pigs after application of EGBE.

Female rabbits exposed to EGBE (³72 mg/kg, 8 hours) developed cutaneous lesions accompanied by necrosis of epidermis and dermis on the 4^th day after exposure; skin lesions healed within a 2-week period.

EGBE has in several studies been reported to be severely irritating when instilled (undiluted) in the eyes of rabbits. Moderate corneal injury was observed in rabbits in which 0.5 ml of a 15% dilution of EGBE was placed in the conjunctival sac; no effects were observed with a dilution of 5%. In a Draize test performed in rabbits, undiluted EGBE caused severe irritation, dilutions at 70 and 30% caused moderate irritation, and dilutions of 20 and 10% caused mild irritation.

Male mice exposed to 750-8200 mg/m³ EGBE for 10-15 minutes exhibited a 20% decreased in respiratory rate at the lowest concentration and a 40% decrease at the highest concentration.

85.4.3     Sensitisation

EGBE did not result in dermal sensitisation when tested in the guinea pig maximisation test.

85.4.4     Repeated dose toxicity

Following repeated inhalation exposure to EGBE vapours, haematological effects (decreased RBC counts and Hgb levels, increased MCH) have been observed in rats exposed for 90 days to 378 mg/m³; these effects had either decreased or returned to the range of the control values. The NOAEC was 123 mg/m³.

In 14-week NTP studies in rats and mice, haematological evaluations showed an exposure concentration-related anaemia (in female rats and mice from 152 mg/m³; in male rats and mice from 614 mg/m³). Histopathological effects were observed in the spleen, bone marrow (rats only), liver, kidneys, and forestomach from 307 mg/m³ in female rats, and from 614 mg/m³ in male rats and mice (both sexes). The lowest concentration used in the study, 152 mg/m³, was a LOAEC for haematological changes in female rats and mice; the NOAEC for male rats and mice was 307 mg/m³.

In chronic NTP-studies in rats and mice, exposure-related  anaemia was observed in both species; female animals were generally more sensitive than male animals. The LOAEC for haematological changes was 152 mg/m³ for rats and 307 mg/m³ for mice, the lowest concentrations tested in the studies of rats and mice, respectively.

Following oral administration of EGBE by gavage to male rats for 6 weeks, dose-related changes (decreased RBC counts and Hgb concentration, and increased MCH and haemoglobinuria) were observed from 222 mg/kg b.w./day, the lowest dose level used in the study. Histopathological changes were noted in the spleen from 222 mg/kg b.w./day, and in the liver and kidneys from 443 mg/kg b.w./day.

In a 13-week NTP drinking water study, haematological effects were observed in female rats from 82 mg/kg b.w./day and in male rats from 281 mg/kg b.w./day. Histopathological changes were observed in the spleen from 129 and 151 mg/kg b.w./day in males and females, respectively; and in the liver from 69 and 82 mg/kg b.w./day in males and females, respectively. The lowest dose level tested (69/82 mg/kg b.w./day in males/females, respectively) was a LOAEL for haematological effects.

When EGBE was administered by gavage to male mice for 6 weeks, the LOAEL for haematological effects was 357 mg/kg b.w./day, the lowest dose tested.

In a 13-week study, occluded dermal administration of EGBE to rabbits at dose levels up to 150 mg/kg produced no observable haematological effects.

The immune system did not appear to be a sensitive target of EGBE in rats exposed to EGBE in the drinking water at doses up to 506/444 mg/kg b.w./day in males and females, respectively, for 21 days.

85.4.5     Toxicity to reproduction

The reproductive toxicity of EGBE has been studied in a variety of studies in rats, mice and rabbits following inhalation or oral administration. EGBE did not cause adverse effects in any reproductive organ, including testes, in any of the studies. In a two-generation reproductive toxicity study, fertility was reduced in mice only at maternally toxic doses (above 1000 mg/kg b.w./day) when EGBE was administered in the drinking water.

In addition, several developmental toxicity studies have addressed the potential of EGBE to induce embryo- and/or foetotoxicity following oral, inhalation, and dermal exposures to rats, mice, and rabbits. Toxicity to embryos and/or foetuses was observed only at dose levels, which also resulted in maternal toxicity. No malformations were observed in any of the studies.

85.4.6     Mutagenic and genotoxic effects

EGBE was negative for mutation in Salmonella typhimurium strains TA97, TA98, TA100, TA102, TA1535, and TA1537 both with and without metabolic activation. A weak mutagenic response was seen in one test in strain TA97a both with and without metabolic activation. When this test was repeated, a negative response was obtained.

No mutagenic activity was observed when EGBE was investigated using bacteriophage T4D with Escherichia coli B, CR63, and K12, and in a test with Escherichia coli WP2uvrA in the presence and absence of Arochlor-induced rat liver S9 mix.

EGBE or its metabolite 2-butoxyacetaldehyde (BAL) were not found to be mutagenic in an in vitro gene mutation assay using Chinese hamster ovary (CHO) cells, whereas both EGBE and BAL weakly induced gene mutations in Chinese hamster V79 cells at high concentrations.

EGBE did not induce sister chromatid exchanges (SCEs) or chromosomal aberrations in CHO cells with or without liver S9 mix or in Chinese hamster V79 fibroblast cells. At high concentrations, however, EGBE weakly induced aneuploidy (numerical chromosomal anomalies), SCEs and micronuclei, and potentiated the clastogenicity induced by methyl methanesulfonate.

EGBE did not increase the incidence of micronuclei in the bone marrow cells of male rats or mice given three intraperitoneal injections of EGBE.

85.4.7     Carcinogenic effects

NTP has performed 2-year inhalation studies in rats and mice. No evidence of carcinogenic activity was found in male rats and equivocal evidence of carcinogenic activity in female rats based on increased combined incidences of benign and malignant pheochromocytoma of the adrenal medulla. In mice, some evidence of carcinogenic activity was found based on increased incidences of forestomach squamous cell papillomas and carcinomas in female mice and increased incidences of hemangiosarcoma of the liver in male mice.

| Front page | | Contents | | Previous | | Next | | Top |