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EC number: 200-338-0 | CAS number: 57-55-6
The repeated dose toxicity of monopropylene glycol by oral and inhalatory exposure routes is low. The lowest NOAEL of 1700 mg/kg bw/day was obtained in a chronic study with rats receiving monopropylene glycol in diet. In the subchronic inhalation study with rats, exposed to aerosol of monopropylene glycol at concentration levels of 160-2200 mg/m3, reported nasal haemorraghic discharge and ocular discharge occurred in all dose groups; this was accompanied by microscopically observed prominent goblet cell and/or mucus production in mid- and high-concentration groups. Based on these findings, the lowest dose level of 160 mg/m3 is considered a LOAEL for local effects. For systemic effects, a NOAEL of 1000 mg/m3 was established, based on the reduced body weight and decreased food consumption in high-dose females.
Oral route of exposure
Two chronic studies with rats and one subchronic study with dogs administered monopropylene glycol either in diet or in drinking water were available for assessment. Gaunt et al., 1972, administered diets containing 0, 6250, 12500, 25000 and 50000 ppm monopropylene glycol to groups 30 male and 30 female weanling rats for 2 years. Next to histopathological examinations and gross necropsy haematological examination and urinalysis were performed. No adverse effects were noted at the highest tested dose, resulting in NOAELs of 1700 mg/kg bw/day and 2100 mg/kg bw/day for male and female rats, respectively, based on the determined daily average food intake.
In the old study of Seidenfeld et al., 1932, with only limited parameters examined, groups of 5 rats were administered propylene glycol in drinking water as 0, 1, 2, 5, 10, 25 and 50% solutions for 140 days, corresponding to average daily doses of 1600, 3680, 7700, 13200, 21000 and 37000 mg/kg bw/day, respectively. The consumption of food, propylene glycol, and body weight were recorded. At the end of the experiment the rats were placed in cages and their urines were collected and examined. Thereafter the animals were killed and autopsied and their kidneys, hearts, spleens and livers were examined histologically. All animals given 25% or 50% propylene glycol in water died within the first 9 days of treatment. No adverse effects were noted in other dose groups, resulting in NOAEL of 13200 mg/kg bw/day.
In the subchronic study with dogs reported by Weil et al., 1971, groups of 5 male and 5 female beagle dogs were fed diets containing propylene glycol at dosage levels of 5000 and 2000 mg/kg bw for 2 years. The dietary concentration of propylene glycol necessary to produce a dosage level of 5000 mg/kg bw/day averaged about 20%, while for the 2000 mg/kg bw/day group it approximated 8%. A second series of animals was given an isocaloric amount of dextrose mixed with food (2540 and 6350 mg/kg bw/day) and served as another set of controls. Mortality, body-weight change, diet utilization and water consumption, liver, kidney and spleen weights were examined and micropathology was performed. In addition, measurements of blood, urine and biochemical parameters were performed. In the group receiving 5000 mg/kg bw/day of propylene glycol, an effect upon erythrocytes was evident in comparison with the nutritionally equivalent group receiving dextrose. Haemoglobin, haematocrit and total erythrocyte count were slightly low while increases were seen in anisocystosis, poikilocytes and reticulocytes. These changes are indicative of some erythrocyte destruction with replacement from bone marrow. All of the dose-related significant haematological findings were consistent with an increased rate of erythrocyte haemolysis associated with the high concentrations of propylene glycol in the blood. However, even at a propylene glycol concentration of 20% in the diet, this effect was not sufficient to result in any changes that appeared to be irreversible and there was no evidence of damage to bone marrow or spleen. The NOAEL was established to correspond to 2000 mg/kg bw/day based on haemolysis at the next dose level.
Cats appear to be more sensitive to monopropylene glycol. The study of Toxicology Research Laboratory (1979) reported a species-specific increase in Heinz bodies after dietary administration of monopropylene glycol at actual ingested doses of 0, 443 or 4239 mg/kg bw/day for 94 days, or 0, 80, 675 and 1763 mg/kg bw/day for 69 days to male cats. Increased hemosiderin deposits were also noted in liver and spleen, but appeared secondary to Heinz body formation. The formation of Heinz bodies and increased hemosiderin occured in a dose-related manner at doses of 675 mg/kg bw/day and higher. Although a daily dose level of 443 mg/kg bw/day appeared to cause a slight increase in Heinz body formation (without detectable increased hemosiderin present in the liver or spleen), the levels of Heinz body formation in this group of cats was comparable to levels observed in one of the four control cats; therefore a NOAEL of 443 mg/kg bw/day was set in the study.
Inhalation route of exposure
A subchronic inhalation toxicity study with rats exposed to propylene glycol aerosol at dose levels of 0.0, 0.16, 1.0 and 2.2 mg/L air for 6 hr/day, 5 days/week for 90 days was reported by Suber et al., 1989. A treatment-related effect was reported as nasal haemorrhaging which began during the second week of exposure and persisted throughout the study; recovery from these clinical signs occurred during the non-exposure weekend periods. The frequency of this reported nasal haemorrhaging remained constant throughout the study and was highest (65-75%) in the medium-and high-concentration groups. Similar trends were observed for ocular discharge, with incidences of 16% in low-exposure males, 40% in medium and high exposure males and 5% in controls. There was generally less ocular discharge in females, who had incidences of 8% in controls, 14% in the low-exposure group, 28% in the medium-exposure group and 35% in the high-exposure group. Minute volume, tidal volume and respiratory rates were not significantly altered at any dose levels.
A reduction in mean body weight by 5-7% was observed in the high-exposure female rats. This reduction correlated with the observed reduction in feed consumption. There was no trend towards reduced feed consumption among male rats, but reduced consumption on selected days for the high-exposure male rats was seen. Inconsistent but statistically significant changes were observed with absolute organ weights, but these changes were not considered to be biologically significant by the authors when the weights for all of the treatment groups were compared and when the gross histological findings were taken into account. No adverse changes in gross pathological and histopathological variables were noted, except of an increase in the number of goblet cells or an increase in the mucin content of the goblet cells present, observed in the nasal turbinates of both male and female rats. In addition, white blood cell counts revealed a concentration-related decrease in total white blood cells in mid- and high-concentration females, a decrease in banded neutrophils in mid-concentration females and high-concentration males and females, and finally a decrease in lymphocytes in mid- and high-concentration females.
Based on the reported nasal hemorrhaging and ocular discharge at all dose levels, accompanied by the lowest dose level of 160 mg/m3 is considered to be a LOAEL for local effects and shall be used for the risk assessment. However, it should be noted that the reported nasal “hemorrhage” observed in the study was not supported by microscopic evidence of tissue damage and hemorrhage. An alternative explanation is that the reported “hemorrhage” was pigment/porphyrin staining following an increase in lacrimal secretion caused by the mildly irritating or drying effect of propylene glycol aerosols on mucous membranes. The increased number of goblet cells and/or increased mucin content in the mid- and high dose groups appears to be an adaptive response.
Dermal route of exposure
In a limited study of Stenbäck et al. (1974), groups of 50 female Swiss mice were treated twice a week with 0.02 ml of either neat monopropylene glycol or its 50% or 10% solution in acetone, by dropping the liquid on the dorsal skin between the flanks on a 1-inch square area which was shaved regularly. Mice were allowed to die spontaneously or killed when moribound. Complete autopsies were performed on all animals and the skin and all grossly observed tumors and other lesions were examined histopathologically. The authors concluded that no substance-caused increase in tumor evidence was evidenced in any group; however, no further data on toxicity are presented.
The following information is taken into account for any hazard / risk assessment
Based on the NOAEL of 1700 mg/kg bw/day and 1000 mg/m3, obtained in oral chronic and inhalatory subchronic studies with rats, respectively, classification of monopropylene glycol for repeated dose toxicity is not warranted in accordance with Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.
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