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

93     Summary

93.1     Description

1-methoxy-2-propanol (2PG1ME) is a water soluble colourless volatile liquid with an ether like odour. 2PG1ME is the a-isomer of propylene glycol monomethyl ether (PGME) and makes out at least 95% of commercial PGME where the b-isomer is present in less than 5%.

93.2     Toxicokinetics

2PG1ME appears to be absorbed by all routes of exposure. Toxicological studies did not indicate that accumulation should occurr. The primary metabolic pathway was via demethylation and oxidation to CO₂, which is then exhaled. Conjugation and urinary excretion  played a minor role. The developmental toxicant methoxypropionic acid is not formed by 2PG1ME as it is a secondary alcohol, but only from the b-isomer 2-methoxy-1-propanol.

93.3     Human toxicity

93.3.1     Single dose toxicity

Groups of male volunteers were exposed by inhalation to different concentrations of PGME vapours for 1-7 hours.  Symptoms of slight CNS-depression (dizziness, headache) were reported from 1125-1500 mg/m³ in subjects exposed to rising concentration PGME. Overt CNS-impairment was seen in one of two subjects exposed to 3750 mg/m³

Volunteers exposed to 938 mg/m³ for 7 hours, complained of eye and nose irritation after 15-30 minutes, the irritation symptoms increasing and including complaints of throat irritation after 45 minutes. The symptoms were so strong that only four subjects remained in the chamber for 7 hours.

No reports of repeated dose toxicity, reproductive and developmental effects, mutagenic and genotoxic effects or carcinogenic effects in humans were found.

93.4     Animal toxicity

93.4.1     Single dose toxicity

Five out of 10 rats died following a 4 hour-exposure of 54600 mg/m³ PGME.. Dose-related CNS depression was reported in rats treated with single exposure from 25500 to 56600 for 1 to 8 hours, including unconsciousness in rats exposed to 54600 mg/m³ for 6 hours. Histopathological examination of rats dosed 10900-36400 mg/m³ for 6-7 hours showed slight granulation of liver cell cytoplasm and non-fatty liver deposits in half the rats exposed to 21800 mg/m³, while liver, kidney and lung weights increase.

Five out of 10 Guinea pigs died following 10 hours exposure to 54600 mg/m³PGME. One out of four rabbits died following 7 hours exposure to 54600 mg/m³.A monkey exposed to 36400 mg/m³ PGME for 6 hours showed CNS- symptoms including depressed respiration, excitation and lethargy.

Oral LD₅₀-values of 5000 to 6100 mg PGME/kg b.w. for rats, 10800 mg/kg b.w. for mice, 1840-5300 for rabbits and 9200 mg/kg for dogs were reported. In rats and dogs, general intoxication symptoms and symptoms of CNS depression were reported preceeding death.

Dermal application of 4600-13900 mg PGME /kg b.w. under occlusion for 24 hours caused narcosis in all animals, and 4 out of 5 rabbits at the high dose died. Dermal LD₅₀-values for rabbits of 13000 and 14200 mg/kg b.w were reported.

Respiratory tract irritation was reported from single 4 hour exposures of rats to 36400 or 54600 mg PGME /m³ . Slight irritation of the lungs was seen from a 7 hour exposure to 109000 mg PGME/m³, while no effects were reported at lower concentrations.

A monkey exposed to 36400 mg/m³ PGME for 6 hours showed eye and nose irritation. 

PGME was reported to be not irritating or slightly irritating to rabbits skin following single or repeated exposure. PGME was reported to be non-irritating or mildly irritating to the eyes of rabbits.

No sensitisation was seen in an adjuvant test in Guinea pigs.

93.4.2     Repeated dose toxicity

In an inhalation study including, rats, mice, rabbits and monkeys, the animals were exposed to PGME at different regimes, with concentrations from 300 to 10000 ppm (equivalent to 1125 - 37500 mg/m³), over 9 days to 6 months, 30 minutes to 7 hours daily. All species showed CNS-depression decreasing in studies of longer duration. Slight lung congestion and slight non-fatty degeneration and cytoplasma granulation of the liver in some of the studies. Overall, the effect level in rats and mice  was approximately 11000 mg/m³, while  rabbits showed effects in the liver and the lung at 5450 mg/m³..Guinea pigs appeared  slightly less sensitive, with showing CNS depression and slight liver effects at 22000 mg/m³, and monkeys showed CNS-depression at 36400 mg/m³. 

In a 90-day inhalation study in rats and rabbits exposed to 1090-10900 mg/m³, rats of the high concentration level exhibited CNS depression, increased liver weights and slight liver hypertrophy, while rabbits of the high exposure level showed CNS depression .

In dogs, oral ingestion of PGME over 14 weeks resulted in CNS-depression at 920 and 1850/2770 mg/kg b.w. Rats dosed 2.77 g/kg b.w. over 35 days showed increased liver and kidney weights.

Daily dermal doses of 6.47 and 9.24 g/kg b.w. over 13 weeks were toxic to rabbits. Occasional gastric retention and renal tubular necrosis were reported.

93.4.3     Toxicity to reproduction

Inhalation of up to 2250 mg/m³ PGME  for 10 days did not result in testicular effects in rats.

No effects on reproduction of female rats were reported from exposure up to 2250 mg/m³ PGME from days 6-17 of gestation.

No changes in testes or seminal vesicle weights were seen in male mice exposed to 2.5 g/kg b.w. PGME in drinking water for 25 days.Dogs exposed orally to 462-2772 mg/ kg b.w. for 14 weeks developed numerous spermiophages (macrophages) in the epididymis.

Delayed sternebral ossification was reported in pups of rats dosed 11250 mg/m³ from days 6-15 of gestation. Mild depression of the central nervous system and decreased body weight gain were seen in the dams of this treatment group, while no effect was seen on dams, reproduction parameters or pups at lower concentrations.

Pregnant rabbits exposed up to 11250 mg PGME/m³ had increased mortality, CNS depression and reduced weight gain at the high concentration, while there were no effects on reproduction or on development at this or lower concentration levels.

Delayed ossification of the skull was reported in pups of rats exposed orally to 739 mg/kg b.w. PGME on days 1-21 of gestation. No effect on the number of pups was seen. No details are given on maternal effects.

The F₁ and F₂-generation of mice exposed through the drinking water to approximately 3.3 g/kg b.w PGME in a continuous breeding study showed reduction in birth weights and reduced epididymis and prostate gland weights.

No evidence of foetotoxicity was seen from exposure of female mice by gavage to up to 1848 mg/kg b.w from days 1-18 of gestation.

No foetoxicity resulted from oral exposure of rabbits on days 6-18 of gestation to up to 924 mg/kg b.w.

93.4.4     Mutagenic and genotoxic effects

PGME was negative in an Ames test, in a unscheduled DNA synthesis test in rat hepatocytes and in a chromosome aberration test in Chinese hamster ovary cells. No in vivo studies were found.

93.4.5     Carcinogenic effects

Rats exposed by inhalation to 1125-11250 mg/m³ up to 24 months showed increased liver weights and incidence of eosinophilic heptocellular foci were increased in male of the high exposure group. Chronic progressive glomerulonephritis was more pronounced, and tubular epithelium damage in males treated at the high concentration compared to controls, but no there was no increase in tumour incidence. Levels of a_2u-globulin were elevated at 3 months in all the treated males compared to controls

Mice exposed to the same regime as the rats also had liver weights increase. No adverse effects on the kidney were seen, but females exposed for 3 months at the high concentration showed changes in the adrenal gland.

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