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

69     Summary

69.1     Description

Ethylene glycol (EG) is a clear, colourless, slightly viscous, hygroscopic liquid with a sweet taste. It is miscible with water and has a low vapour pressure (0.06 mmHg at 20 °C).

69.2     Toxicokinetics

EG is rapidly absorbed and distributed following inhalation, oral and dermal administration. In one inhalation study in rats, 75-80% of inhaled EG (vapour or aerosol) was distributed immediately after exposure. Total recovery of oral doses in rats and mice is approximately 90-100%, indicating substantial absorption. After dermal application, approximately 30% of a dose was absorbed through rat skin, whereas mice absorbed 85-100% of the administered dose.

The metabolism of EG occurs in the liver and kidney. The initial step is a conversion of the parent compound to glycolaldehyde, which is further oxidised to glycolic acid. Glycolic acid is then converted to glyoxylic acid, which is converted either to carbon dioxide or to oxalic acid. Generally, metabolism begins immediately after administration of EG, and excretion of most of the parent compound and metabolites is complete 12 to 48 hours after dosing. The major excretory end products are carbon dioxide in exhaled air, and glycolate and unchanged EG in the urine.

69.3     Human toxicity

Twenty male volunteers exposed for 30 days, 20-22 hours a day, to EG atmospheres (aerosol, diameters of droplets 1-5 µm) containing mean concentrations of 17 to 49 mg/m³ did not experience any serious signs of toxicity, but there were complaints of irritation of the throat. The irritation became common when the volunteers re-entered the chamber in which the concentration of EG (during the absence of volunteers) was raised to about 140 mg/m³ and concentrations greater than about 200 mg/m³ were intolerable due to strong irritation of the upper respiratory tract. 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 were observed.

Several deaths due to accidental or intentional ingestion of EG have been reported; the minimal lethal oral dose for humans has been estimated to be about 1.6 g/kg b.w. (adults). The clinical signs which follow acute poisoning after ingestion of EG can be divided into three (possibly four) stages: 1) effects on the central nervous system, which occur 30 minutes to 12 hours after ingestion; 2) effects on the cardiopulmonary system occurring 12 to 72 hours after ingestion, this stage may also be characterised by severe metabolic acidosis; 3) effects on the kidneys, which occur 24 to 72 hours after ingestion, this stage is characterised by profound metabolic acidosis; and 4) degenerative effects on the central nervous system occurring 6 or more days after ingestion, symptoms which are uncommon.

EG has not shown a particularly irritating potential to eyes or skin and was not shown to have a strong sensitising potential although some case reports are available. Prolonged dermal exposure can result in skin maceration.

No data on toxicity to reproduction, mutagenic and genotoxic effects, or carcinogenic effects of EG in humans have been found.

69.4     Animal toxicity

69.4.1     Single dose toxicity

An LC₅₀-value (one hour) of 10.9 g/m³ has been reported in rats. In a study of rats, all animals survived an 8-hour exposure to a saturated atmosphere (ca. 200 mg/m³ (calculated)).

The reported oral LD₅₀-values ranged from >2.0 to 11.3 g/kg b.w. in rats, from 5.89 to 15.4 g/kg b.w. in mice, from 7.0 to 9.3 g/kg b.w. in rabbits, from 4.0 to 8.2 g/kg b.w. in guinea pigs, from 4 to 8.2 g/kg b.w. in dogs, and of 1.67 and 4.7 g/kg b.w. in cats. A minimal lethal dose of 3.8 g/kg b.w. has been reported for rats, of 1 g/kg b.w. for cats, and of 6.7/7.3 g/kg b.w. for dogs.

Dermal LD₅₀-values of 9.53 and 10.6 g/kg b.w. have been reported for the rabbit.

EG did not show irritating properties when applied to the skin of rabbits.

Moderate to severe eye irritation has been observed in rats and rabbits exposed continuously for 90 days to EG (vapour) at a concentration of 12 mg/m³; guinea pigs, dogs, and monkeys exposed similarly showed no effects on the eyes. Following exposure to a concentration of 57 mg/m³ of EG (vapour, 8 hours a day, 5 days per week for 6 weeks), rats, guinea pigs, rabbits, dogs, and monkeys did not show any signs of ocular irritation.

EG (10, 20, or 50 % solution in water) caused slight oedema and erythema under occlusive conditions in the eyes of rabbits whereas instillation of neat EG produced moderate to severe oedema and erythema. Irritation consisting of chemosis, swelling, and conjunctival redness has also been observed in rabbit eyes following instillation of 4 and 40% EG in balanced salt solutions. The lowest non-irritating concentration of EG has been reported to be 20% when applied as 0.1 ml solution 5 times a day for 21 consecutive days. In other studies, neat EG has been reported to be only slightly irritating one hour after instillation of 0.1 ml of the fluid or to show an extremely low potential for eye irritation.

No data on sensitisation in experimental animals have been found.

69.4.2     Repeated dose toxicity

Rats, guinea pigs, rabbits, dogs and monkeys were exposed to EG (vapour) either continuously at a concentration of 12 mg/m³ for 90 days (continuous study), or at concentrations of 10 or 57 mg/m³ for 8 hours a day, 5 days per week for 6 weeks (repeated study). In the continuous study, one rat, one rabbit and 3 guinea pigs died during exposure as well as four control rats; moderate to severe eye irritation was observed in rats and rabbits; and histopathological examination showed inflammatory changes in the lungs of exposed animals and to a lesser degree in controls. In the repeated study, at 10 mg/m³, histopathological examination revealed mild congestion in the spleens of both dogs, hepatic fatty changes in 2/8 guinea pigs and in 1/8 rats, and focal necrosis in the liver of 1/8 guinea pigs and of 1/8 rats; focal necrosis of the liver was also seen in 1 of 3 control guinea pigs; at 57 mg/m³, histopathological examinations revealed non-specific inflammatory changes in the lungs and occasionally the hearts of exposed animals.

In a 90-day drinking water study, a dose-dependent increase in the incidence and severity of kidney damage (dilation, degeneration, and inflammation of the renal tubules, and renal pelvis) were observed in male rats at concentrations from 1% EG in the drinking water and in female rats from 2%; the NOAEL for renal effects (in males) in this study was 0.5% EG in the drinking water (corresponding to about 550 mg/kg b.w./day).

In a 13-week feeding study in rats, kidney lesions were observed at dose levels from 2.5% in male rats (toxic nephrosis) and at 5% in female rats; the relative kidney weight was significantly increased in both male and female rats from 2.5% and serum urea nitrogen and serum creatinine levels were significantly elevated in male animals from 2.5%. The NOAEL for renal effects (in males) in this study was 1.25% (equivalent to 625 mg/kg b.w./day, or according to the author: 600-1000 mg/kg b.w./day). In another dietary study in rats of similar duration (16 weeks), damage to the kidneys were observed from 0.25% in male rats and at 1% in female rats; the NOAEL for renal effects (in males) in this study was 0.1% (corresponding to about 70 mg/kg b.w./day).

In a 2-year feeding study in rats, kidney lesions were observed at a dose level of 2.5% in male rats and all male rats at this dose level had died after 16 months of exposure due to oxalate nephrosis; kidney lesions were not observed in female rats at dose levels up to 2.5%. Kidney weights were increased in both male and female rats at 2.5%. The NOAEL for renal effects (in males) in this study was 0.5% (corresponding to 200 mg/kg b.w./day). Mild fatty metamorphosis of the liver was observed in female rats at 2.5% (corresponding to 1000 mg/kg b.w./day); a NOAEL of 0.5% (corresponding to 200 mg/kg b.w./day) can be considered for liver effects in female rats. In another 2-year dietary study in rats, kidney damage was observed from 0.5% in male rats (crystal deposition in the kidney, degeneration of the tubular epithelium in 1/11 animals) and in female rats at 4%; the NOAEL for renal effects (in males) in this study was 0.2% (equivalent to 100 mg/kg b.w./day).

In mice, mild toxic nephrosis (only one animal) and a degenerative change in the livers were observed in male mice from a dietary level of 2.5% EG for 13 weeks; no effects were seen in female mice. The NOAEL in this study was 1.25% (equivalent to 1875 mg/kg b.w./day).

In a 2-year feeding study in mice, hepatocellular hyaline degeneration was seen in female mice at dietary levels from 2.5%. Incidence and severity of nephropathy were not affected in either sex at dietary levels of up to 2.5% in males and of up to 5% in females. The NOAEL in this study was 1.25% (equal to 3000 mg/kg b.w./day). In another 2-year feeding study in mice, no adverse effects on the kidneys were observed at dietary levels up to 1000 mg/kg b.w./day (the highest dose level in the study).

69.4.3     Toxicity to reproduction

When rats were exposed to a respirable EG aerosol by whole-body exposures (6 hours a day, gestational days 6 to 15), there was some evidence of treatment-related reductions in ossification of the foetal skeleton at 2500 mg/m³ and an increase in the incidence of poorly ossified metatarsals and proximal phalanges of the hindlimb at 1000 mg/m³; the only maternal effect observed was a significant increase in liver weight (absolute and relative) at 2500 mg/m³. The NOAEL was 1000 mg/m³ for maternal and 150 mg/m³ for developmental toxicity.

In mice exposed similarly as the rats, several gestational parameters were affected from 1000 mg/m³ and there was a significant increase in the incidence of a number of external, visceral, and skeletal malformations. The incidences of many foetal variations were also increased from 1000 mg/m³, but only a few at the lowest dose level (150 mg/m³). Reduced maternal body weight and body weight gain and reduced gravid uterine weight were observed from 1000 mg/m³. The NOAEL was 150 mg/m³ for maternal and at or below 150 mg/m³ for developmental toxicity.

In a subsequent nose-only study (aerosol, 6 hours a day, gestational days 6 to 15) in mice, foetal body weights per litter were significantly reduced and the incidences of one skeletal malformation (fused ribs) and 18 skeletal variations were increased at 2500 mg/m³; maternal kidney weights were increased from 1000 mg/m³. The NOAEL was 500 mg/m³ for maternal and 1000 mg/m³ for developmental toxicity.

In a three-generation dietary reproduction study in rats, no treatment-related effects were observed in the F₂ parents and in the F₃ weanlings, including kidney damage; the NOAEL for reproductive toxicity was 1000 mg/kg b.w./day (the highest dose level in the study). In a continuous breeding study in mice, EG was administered in the drinking water for 14 weeks; the NOAEL for reproductive effects was 0.5% (corresponding to an average dose of 840 mg/kg b.w./day) with foetotoxic effects, including malformations, being observed at the higher concentration of 1%.

In Fischer 344 rats, the NOAEL for developmental toxicity as well as for maternal toxicity (only body weights of the dams were examined) was 1000 mg/kg b.w./day (the highest dose level in the study) when EG was administered in the diet from gestation day 6 to 15. When EG was administered by gavage (from gestation day 6 to 15) to CD rats, the NOAEL for developmental toxicity was 500 mg/kg b.w./day with effects (reduced body weights; duplicated or missing ribs, centra, and arches; and poor ossification) being observed at 1000 mg/kg b.w./day; maternal effects (increased relative liver weight) was observed as well at this dose level. Similarly, another gavage study in CD rats showed that administration of EG (from 1250 mg/kg b.w./day, the lowest dose level in the study) during organogenesis produced severe dose-related developmental toxicity, including malformations, at dose levels where no serious maternal effects (reduced maternal body weight gain at 1250 mg/kg b.w./day) were observed. However, in a third gavage study, where EG was administered to CD rats from gestation day 6 to 20, no toxicity were observed in offspring at dose levels up to 1250 mg/kg b.w./day; maternal effects at this dose level included kidney damage. In Wistar rats, a NOAEL of 638 mg/kg b.w./day for developmental toxicity (foetotoxicity as well as malformations) was observed following administration of EG by a stomach tube from gestation day 6 to 15; no information was given with regard to maternal effects.

When EG was administered by gavage (from gestation day 6 to 15) to CD-1 mice, the NOAEL for developmental toxicity was 150 mg/kg b.w./day with effects (slight reductions in foetal body weight and increased incidences of extra ribs) being observed at 500 mg/kg b.w./day; no maternal effects were observed at any dose level (up to 1500 mg/kg b.w./day). Another gavage study in CD-1 mice showed that administration of EG (from 750 mg/kg b.w./day, the lowest dose level in the study) during organogenesis produced severe dose-related developmental toxicity, including malformations, a dose level where no maternal effects were observed.

In New Zealand White (NZW) rabbits, the NOAEL for maternal toxicity was 1000 mg/kg b.w./day and the NOAEL for developmental toxicity was 2000 mg/kg b.w./day (the highest dose level in the study), when EG was administered by gavage on gestational day 6 through 19.

Following occluded cutaneous application of EG to CD-1 mice on gestation days 6 to 15 (6 hours per day),  the NOAEL for maternal and developmental toxicity was the highest exposure level (approximately 3550 mg/kg b.w./day).

69.4.4     Mutagenic and genotoxic effects

EG has shown negative results in the following in vitro test systems: in the Ames test (several tests in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537; TA1538), in the SOS chromotest in Escherichia coli PQ37, in the DNA damage and repair assay in Escherichia coli (WP2, WP2uvrA, WP67, CM611, WP100, W3100polA+, p3478polA-), for gene conversion in Saccharomyces cerevisiae, for aneuploidy induction in the fungus Neurospora crassa, in a cytogenetic assay in Chinese Hamster Ovary (CHO) cells, for gene mutation in the HGPRT assay in CHO cells, in the mouse lymphoma assay, for sister chromatid exchanges and chromosome aberrations in CHO cells, and for unscheduled DNA synthesis in rat hepatocytes. In one HGPRT assay and in one test for chromosome aberration, both in CHO cells, the result of the assay was reported as being ambiguous. Most of the assays were performed both with and without metabolic activation.

Negative results have also been reported in in vivo studies: in the dominant lethal assay following oral administration in the feed to Fischer 344 rats and for chromosome aberrations in mice following intraperitoneal injection. In a micronucleus assay in mice, an increase in the numbers of micronuclei was observed following oral administration of very high doses (2.8 to 13.9 g/kg b.w.), except at the lowest dose level, and following intraperitoneal injection (doses of 1.4 to 7.0 g/kg b.w.).

69.4.5     Carcinogenic effects

No evidence of a carcinogenic effect of EG was observed in Fischer 344 rats administered diets yielding dosages of up to approximately 1000 mg/kg b.w./day for 24 months, in Sprague-Dawley rats receiving dietary concentrations of up to 4% (equivalent to 2000 mg/kg b.w./day) for 2 years, in B6C3F1 mice fed diets containing EG for 103 weeks (male mice: up to 2.5% equivalent to approximately 6000 mg/kg b.w./day; female mice: up to 5% equivalent to approximately 12000 mg/kg b.w./day), or in CD-1 mice administered diets yielding dosages of up to approximately 1000 mg/kg b.w./day for 24 months.

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