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

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

86 Evaluation

EGBE is absorbed and distributed throughout the body (humans and rats) following inhalation, oral administration and dermal contact. EGBE is metabolised to 2-butoxyacetic acid (2-BAA), which probably is responsible for the haemolytic effect identified as the critical end-point in toxicological studies on EGBE.

Only limited data on the toxic effects of EGBE in humans are available. These data comes largely from case reports dealing with accidental poisonings and/or workplace exposure. EGBE seems of low acute toxicity in humans. The available data show that after acute oral ingestion of large doses of EGBE (combined with other solvents), haematological changes and metabolic acidosis are the primary effects. The only indication of haemolysis (small changes for haematocrit and MCHC) following repeated inhalation was observed in workers exposed to an average airborne concentration of EGBE of 2.9 mg/m³; however, the changes were within the range of normal clinical values and are not considered as being adverse.

EGBE is of moderate acute toxicity whether animals are exposed via the oral, dermal, or respiratory routes with oral LD₅₀-values ranging from 320 to 3100 mg/kg (rats, mice, guinea pigs, rabbits), dermal LD₅₀-values ranging from 406 to 4800 mg/kg (rabbits, guinea pigs, rats), and LC₅₀-values of 2200-2400 mg/m³ (4-hour exposure) for rats and of 3440 mg/m³ (7-hour exposure) for mice.

Irritation of the nose and throat, and eyes has been noted in human volunteers exposed by inhalation to EGBE at concentrations from 490-957 mg/m³ for 4-8 hours, but not in volunteers exposed to EGBE (98 mg/m³) for 2 hours. The NOAEC for irritative effects of EGBE in humans is above 100 mg/m³.

In rabbits, EGBE is severely irritating when instilled (undiluted) in the eyes; dilutions at 70 and 30% caused moderate irritation, and dilutions of 20 and 10% caused mild irritation. In rabbits, EGBE has been considered a severe irritant by the Draize protocol and an irritant by the EU protocol. Severe skin irritation has also been noted in guinea pigs. 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.

Human volunteers showed no dermal effects of 10% EGBE in a patch test and EGBE did not result in dermal sensitisation when tested in the guinea pig maximisation test.

Intravascular haemolysis is the primary response elicited in sensitive animal species following inhalation, oral, and dermal exposure to EGBE.

Changes in haematological parameters have been observed in rats and mice following acute inhalation exposure (increased erythrocyte fragility in rats at 305 mg/m³ for 4 hours; haemoglobinuria in rats and mice at about 1000 mg/m³ for 7 hours). Following oral administration, haemolysis of erythrocytes accompanied by haemoglobinuria was observed in rats following a single dose at dose levels from about 125 mg/kg. Following dermal exposure, haemolytic effects have been observed in rats by application of 260 mg/kg to the shaved skin.

Following repeated inhalation exposure to EGBE vapours, the NOAEC for haematological changes was 123 mg/m³ in a 90-day study in rats; in the 2-year NTP-study, 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. In the 14-week NTP-study, the lowest concentration used in the study, 152 mg/m³, was a LOAEC for haematological changes in female rats and mice; the NOAEC for haematological changes in male rats and mice was 307 mg/m³. Following oral administration of EGBE by gavage to male rats for 6 weeks, the LOAEL for haematological changes was 222 mg/kg b.w./day, the lowest dose level used in the study. In a 13-week NTP drinking water study, 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 available data indicate that certain species are more susceptible to the haemolytic effects of EGBE. The sensitivities range from that of guinea pigs, which displayed no haemolytic effects following a single oral administration of 1000 mg/kg b.w EGBE, to that of rats, which displayed increased osmotic fragility of erythrocytes at a single-inhalation exposure to 305 mg/m³ and haemolysis of erythrocytes following a single oral dose at dose levels from about 125 mg/kg. Humans appear to be less sensitive than rats are to the haemolytic effect of EGBE as haemolysis has not been observed in acute inhalation exposures of human volunteers to up to about 950 mg/m³; reversible haemolytic effects have been observed in cases where humans consumed single oral doses of 400 to 1500 mg/kg b.w. This difference in sensitivity between rats and humans is supported by in vitro studies, which have shown that erythrocytes from humans were unaffected by incubations with 2-butoxyacetic acid (2-BAA, the toxic metabolite of EGBE) at concentrations, which produced total rat erythrocyte haemolysis.

With respect to gender sensitivity, the available data consistently showed that female rats are more sensitive to EGBE-induced haemolysis than male rats are. Female mice also appeared to be slightly more sensitive than male mice. In vitro, female erythrocytes have shown a slightly greater sensitivity than male erythrocytes following incubation with 2-BAA.

Several studies have assessed the effect of age on the haemolytic effects in young and adult rats. Older rats appeared to be more sensitive than the younger rats following acute doses of EGBE; however, chronic exposures appear to impart a certain level of tolerance to rats and mice over time as apparent tolerance to EGBE-induced haemolysis in rats and mice was observed in the 2-year NTP inhalation studies.

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, from patients with sickle cell disease, and from patients with spherocytosis. Erythrocytes from these potentially sensitive groups were unaffected by incubations with 2-BAA at concentrations, which produced total rat erythrocyte haemolysis.

Effects have also been observed in the liver (hepatocellular degeneration and haemosiderin pigmentation of Kupffer cells), kidneys (haemosiderin accumulation, renal tubular degeneration, and intracytoplasmic haemoglobin), bone marrow (hyperplasia), and spleen (haematopoietic cell proliferation, congestion, and increased haemosiderin pigmentation) following exposure to EGBE. These effects, which generally occur at higher exposure levels than those causing haemolysis, are secondary to the haematotoxicity of EGBE and a result of a compensatory response to the haemolysis.

The reproductive and developmental toxicity of EGBE has been studied in several studies in rats, mice and rabbits following inhalation, oral administration, or dermal application (developmental toxicity only). It can be concluded from these studies that EGBE does not affect the reproductive organs of parents (both males or females), and only results in adverse reproductive and developmental effects at dose levels, which also result in parental toxicity. No malformations were observed in any of the studies.

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

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

EGBE has been tested for its potential to induce gene mutations in in vitro systems and cytogenetic damage in both in vitro and in vivo systems. In most of the tests, EGBE has given negative results. One laboratory, however, has reported weak genotoxicity responses, but only at toxic doses. Overall, the available data do not support a mutagenic or clastogenic potential for EGBE.

In 2-year NTP inhalation studies, no evidence of carcinogenic activity was found in male F344 rats, equivocal evidence in female F344 rats based on increased combined incidences of benign and malignant pheochromocytoma of the adrenal medulla, and some evidence in B6C3F1 mice 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. These tumour increases are, according to EPA (1999), of uncertain relevance to humans. As EGBE is generally negative in the genotoxicity tests and as glycol ethers generally appear unlikely to be carcinogenic, the concern for a carcinogenic potential of EGBE is low.

No data have been located regarding carcinogenic effects in humans.

86.1.1 Conclusion

The critical effects following exposure to EGBE are the irritative effects on the respiratory tract and eyes observed in humans and in experimental animals and the haemolytic effect observed in experimental animals and probably also indicated by the sparse human data available.

Irritation of the nose and throat, and eyes was noted in human volunteers exposed by inhalation to EGBE at concentrations from 490-957 mg/m³ for 4-8 hours, but not in volunteers exposed to EGBE (98 mg/m³) for 2 hours. The NOAEC for irritative effects of EGBE in humans is thus above 100 mg/m³. 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. EGBE is irritating to the eyes and skin of experimental animals.

Haemolysis has been identified as the critical end-point in toxicological studies of EGBE. Certain species differences in sensitivity have been observed regarding the haemolytic effects of EGBE, with rats being particularly sensitive, mice sensitive, and guinea pigs appearing relative insensitive. The only indication of haemolysis (small changes for Hct and MCHC) following repeated inhalation was observed in workers exposed to an average airborne concentration of EGBE of 2.9 mg/m³; however, the changes were within the range of normal clinical values and are not considered as being an adverse effect.

Data indicate that humans are less sensitive to the haemolytic toxicity of EGBE than are rats as no or very slight haemolytic effects were observed in the poisoning cases after acute oral ingestion of large doses. This difference in sensitivity between rats and humans is supported by in vitro studies, which have shown that erythrocytes from humans were unaffected by incubations with 2-butoxyacetic acid (2-BAA, the toxic metabolite of EGBE) at concentrations, which produced total rat erythrocyte haemolysis.