Registration Dossier

Administrative data

Description of key information

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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-guideline non-GLP study, published in peer-reviewed literature, with adequate and well described methods and detailed results.
Principles of method if other than guideline:
Groups of 30 male and 30 female weanling rats were fed for 2 years on diets containing 0, 6250, 12500, 25000 and 50000 ppm propylene glycol. Next to histopathological examinations and gross necropsy haematological examination and urinalysis were performed.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF-breeding colony, Charles River, France
- Age at study initiation: weanlings
- Weight at study initiation: males 120-150 g, females 120-140 g
- Diet: Spillers' Laboratory Small Animal Diet, ad libitum
- Water: ad libitum:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21± 1
- Humidity (%): 50-60
Route of administration:
oral: feed
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0, 6250, 12500, 25000 and 50000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0, 200, 400, 900 and 1700 mg/kg bw/day (males); 0, 300, 500, 1000 and 2100 mg/kg bw/day (females)
Basis:
actual ingested
No. of animals per sex per dose:
30/sex/dose
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: at 2 weeks intervals


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
The food intake was measured over the preceding 24 hr

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at weeks 13, 21, 52 and 80 of the study, blood was collected from the tail veins of eight males and eight females from each of the groups that had een fed on diets containing 0, 25000 and 5000 ppm propylene glycol. An additional bleed of eight rats from the control, 6250 and 12500 ppm was made at week 54.
- How many animals: groups of 8 males and 8 females
- Parameters examined: haemoglobin content, packed cell volume and counts of erythrocytes, total leucocytes and the individual types of leucocytes. Counts of reticulocytes were also carried out on the samples obtained after 52, 54 and 80 weeks. At week 104 the haematological investigations were limited to measurements of haemoglobin concentration and examination of a stained blood smear from all surviving rats.

URINALYSIS: Yes
- Time schedule for collection of urine: at weeks 13, 30 and 52, an urinary concentratio test was conducted on selected rats from the control and two highest treatment levels (25000 and 50000 ppm).
- Parameters examined: specific gravity and volume of urine produced during a 6-hr period of water deprivation, during a 2-hr period following a water load of 25 ml/kg and during a 4-hr period commencing 16 hr after the water load. Urinary cell counts were carried out on the 6-hr samples.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; brain, heart, liver, spleen, kidneys, adrenals, gonads, stomach, small intestine and caecum were weighed.
HISTOPATHOLOGY: Yes; next to the organs named above, salivary gland, trachea, aorta, thymus, lymph nodes, pituitary, urinary bladder, colon, rectum, pancreas, uterus, muscle and any tissue that appeared to be abnormal were examined.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No abnormalities were seen in the appearance or behavior of the rats. There were no statistically significant differences between treated and control rats in cumulative death rate.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant differences between treated and control rats in cumulative body-weight gain.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There were no statistically significant differences between treated and control rats in cumulative food consumption.

HAEMATOLOGY
There were no significant differences between treated and control rats in the results of the haematological examination.

URINALYSIS
There were no significant differences between treated and control rats in the results of the urinary cell excretion or renal concentration tests.

ORGAN WEIGHTS
Values of absolute organ weights and weights of organs relative to the terminal body weight were similar in all treated and control groups.

HISTOPATHOLOGY: NON-NEOPLASTIC
There was a wide range of histological abnormalities, particularly in kidney, liver and lung, though the incidence was similar in both test and control groups of rats. The kidney changes varied in severity and consisted of tubular degeneration, stromal and periglomerular fibrosis and inflammatory-cell infiltration mainly with lymphocytes. Occasional foci of calcification were also seen. The pigment in the kidneys of treated and control animals was found within the cells of the proximal tubule and resembled lipofuscin. The chronic changes found in the lungs were, generally, peribronchial and perivascualr lymphocyte cuffing and, in som cases, thickening and collapse of the alveili. The animals with pneumonia showed definite polymorphonuclear leucocyte infiltration of the alveoli. Most (86%) of the cases of pneumonia were found in animals which died due to ill health during the course of the study.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
there was a high incidence of mammary fibroadenomas and pituitary adenomas mainly affecting female rats, but the incidence was similar in test and control groups. Only a few of the neoplasms were malignant. The most numerous were subcutaneous fibrosarcomas but these occurred in both treated and control rats. The abdominal fibrosarcoma found in a control male rat was large and occupied the upper part of the abdomen involving the pancreas and liver but not the stomach or bile duct. Numerous small nodules (1-3 mm in diameter) were scattered in the remainder of the pancreatic tissue and mesentery. Larger masses (2 cm in diameter) were found in the lower abdominal cavity on the right vas deferens. The lung contained one metastasis.

Dose descriptor:
NOAEL
Effect level:
1 700 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: No adverse effects noted at the highest dose tested.
Dose descriptor:
NOAEL
Effect level:
2 100 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: No adverse effects noted at the highest dose tested.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study published in peer-reviewed literature, minor restrictions in reporting, but otherwise acceptable for assessment.
Principles of method if other than guideline:
Groups of 19 male and female rats were exposed by inhalation to 0.0, 0.16, 1.0 and 2.2 mg/l air propylene glycol for 6 hr/day, 5 days/week for 90 days. The clinical signs, body weights, food consumption, haematological parameters, clinical chemistry and gross and histopathological examinations were performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA-CREDO, L'Arbresle, France
- Age at study initiation: 3 months
- Weight at study initiation: males 355-365 g, females 255-265 g
- Housing: 2 per cage, Macrolon Type III cages
- Diet: pelleted feed (Specia Diet Services Rat and Mous No. 1, Shell Diet Services, Engand), ad libitum, except during the exposure
- Water: tap water, ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 / 12


Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: The MMADs of the diluted aerosol were less than2.22 and 1.96 μm for the medium- and high-concentration groups, respectively. The mean geometric diameter for the low-concentration group was not obtainable, possibly due to evaporation which occurred with large quantities of dilution air. No measurements were made of the particle size of the undiluted aerosol. The geometric standard deviations were 1.44 and 1,57, respectively for the medium- and high-dose groups.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Battelle nose-only exposure chambers
- System of generating particulates/aerosols: Battelle-designed nebulizers
- Air flow rate: 35-50 litre/minute

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatogarphy
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The aerosol concentrations were measured once per day by samples taken at animal ports with two gas washbottles (Aver & Co. AG, cat. No. 30852) in series, each containing l00 ml distilled water. Samples were routinely taken for about l0 min for the high, 30 min for the medium and 120 min for the low concentration. The air flow rates for sample collection were nominally 2 litre/min. During sampling, volumes were measured by calibrated
dry gasmeters (Compagnie des Compteurs, model G Ló, No. 160 525). Also, sampling flow-rates were obtained from calibrated rotameters. After
sampling, the contents of each washbottle were poured into a 150-ml volumetric flask, the sampling bottle was rinsed with distilled water and the flask was brought to volume. Samples were analysed daily for propylene glycol concentration by gas chromatography. The particle concentration was monitored continuously throughout exposures for the high concentration group. A dilution system (10;1) in connection with a Mini-RAM (GCA Corp., Bedford, MA) aerosol monitor was used. The Mini-RAM was calibrated against gravimetric measurements. The particle size distributions of the propylene glycol aerosol were determined once a week for each exposure group using a Mercer seven-stage cascade impactor (Model 02-100: IN-TOX Products, Albuquerque, NM). Isokinetic samples were taken at a flow-rate of I litre/min directly from an animal port for each exposure group, Impactor stages were weighed using a Mettler microbalance (Model AJ, Mettler, Zurich, Switzerland) with a sensitivity of 0.1 μg. The effective cutoff aerodynamic diameter (ECAD) values for lhe seven stages were: 0.325, 0.715, 1.06, 1.60,2.13,3.0 and 4.6 μm. Particle size distribution parameters (Raabe, l97l) were determined from the weight of material collected on each stage of the cascade impactor. The data were fltted using a probit model and the mass median aerodynamic diameter (MMAD) and geometric standard deviation were determined.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 160, 1000, 2200 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.16 ± 0.04, 1.01 ± 0.11 and 2.18 ± 0.31 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
19/sex/dose
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before starting exposures and before autopsy. The pre-study measurements were carried out over 4 days, 36 or 40 animals which comprised equal numbers of males and females were retro-orbitally bled each day. the measurements at the end of the study were carried out over 3 days. About 50 animals (approximately equal numbers of males and females from each treatment group) were retro-orbitally bled on each day of killing.
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- How many animals: all animals
- Parameters examined: haematocrit, haemoglobin concentration, red blood cell count, white blood cell count, mean read blood cell count, mean red blod cell corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets.


CLINICAL CHEMISTRY: Yes
before starting exposures and before autopsy. The pre-study measurements were carried out over 4 days, 36 or 40 animals which comprised equal numbers of males and females were retro-orbitally bled each day. the measurements at the end of the study were carried out over 3 days. About 50 animals (approximately equal numbers of males and females from each treatment group) were retro-orbitally bled on each day of killing.
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- How many animals: all animals
- Parameters examined: serum concentrations of glucose, urea nitrogen, total protein, albumin, total bilirubin, total cholesterol, calcium, inorganic phosphate, chloride, alkaline phosphatase, γ-glutamyltransferase, alanine aminotransferase, serum creatinine, 5'-nucleotidase, sorbitol dehydrogenase, sodium, potassium, creatine phosphokinase, triglycerides and total phospholipids.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Respiratory rates and tidal volumes were measured in four rats/group/sex on study day 7, and repeated on the same animals on study days 42 and 84. Four animals were measured simultaneously for 15 min preceding exposure and for the first 30 min of exposure while in exposure/plethysmograph tubes (Coggins et al., l98l).
Statistics:
Statistical analyses were conducted by one-way analysis of variance, Bartlett's tests for homogeneity, Dunnett's test for significance or a modified r-test (Gad and Weil, 1982).
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no significant differences in respiratory rates, tidal volumes or minute volumes between the control group and any of the treatment groups' nor did respiratory rates within groups decrease as the animals became acclimatized to the nose-only exposure conditions.
A treatment-related effect was reported nasal haemorrhaging which began during the second week of exposure and persisted throughout the study; recovery from clinical signs of nasal haemorrhaging occurred during the non-exposure weekend periods. This haemorrhaging was reduced to less than 4% in the low-exposure female group after the fourth week of exposure. From week 2 to 13, the average incidences of nasal haemorrhaging in males were less than 1% in controls, 64% in the low-exposure group, 74% in the medium-exposure group and 75% in the high exposure group. In females, the average incidences were less than 1% in controls, l4% in the low exposure group and 7l% in the medium- and high exþosure groups. Similar trends were observed for ocular discharge, with incidences of 16% in low exposure males, 40% in medium- and high-exposure males, and 570 in controls. There was generally less ocular discharge in females, who had incidences of 8% in controls, l4% in the low exposure group, 28% in the medium-exposure group and 35% in the high exposure group.

BODY WEIGHT AND WEIGHT GAIN
The high-exposure female rats showed a significant reduction in body weight, approximately 5-7%,starting on day 50 and continuing until the end ofthe study. The medium-exposure females also had reduced body weights beginning on study day 64 which continued until the end of the study. There were no signiflcant differences between the body weights of control and treated males; however, a trend was established by day 56; the control animals were heaviest, the low-exposure group were lighter than the medium-exposure group and the high-exposure group were the lightest. The differences between the control and high-exposure mean body weights were only 4%o for males and 6% for females on the flnal day of the study. The sudden drop in body weight for the final day of the study was due to a 6-hr fast; the animals were weighed after the flnal exposure. On previous weighings, the animals were weighed before they were placed in the nose-only chambers.

FOOD CONSUMPTION
The reduction in the females body weights during the study was correlated with a significant reduction in feed consumption beginning on study day 43 for the high-exposure females and on study day 50 for the medium-exposure females. The mean feed consumption was also significantly reduced on study day 50 for the low-exposure females. High-exposure male rats had significantly reduced feed consumption on study days 57, 64 and 88. There were no trends or significant differences from the controls in feed consumption for the low-exposure or medium-exposure male rats.

HAEMATOLOGY
Pre-study measurements of selected haematology components revealed statistically significant (P < 0.05) diflerences between animals assigned to
treated groups and control groups. However, the changes showed no consistent trends with respect to treatment group or sex and were not considered to be biologically significant.
The only statistically significant change in the erythrocytic profile at the end of the study occurred in the high-exposure females. The mean corpuscular haemoglobin concentration was reduced when compared with that lor the female control group. There were significant decreases in white blood cell count, banded neutrophil count and lymphocyte count in medium- and high-exposure females. High-exposure male rats also showed a significantly reduced banded neutrophil count which was not considered relevant to propylene glycol exposure.

CLINICAL CHEMISTRY
There were no statistically signiflcant changes in pre-study concentrations of serum enzymes, serum chemistries or serum electrolytes in the male rats. In the pre-study only serum phosphate was significantly increased (P < 0.05) in females of the high-exposure group (2.84 + 0.48 mmol/litre) compared with the control group (2.49 + 0.40 mmol/litre).
There were statistically significant decreases in serum sorbitol dehydrogenase and γ-glutamyl transferase in the medium- and high-exposure male rats, respectively. Sporadic statistically significant changes also were reported for serum glucose, albumin and creatinine in medium-exposure males and for serum protein, albumin and cholesterol in high-exposure males. In the female rats, serum protein was elevated only in the medium-exposure
animals. There were no changes in serum electrolytes in males of any group but serum chloride was elevated in the low-exposure females. As propylene glycol levels increased, decreasing trends in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and γ-glutamyl
transferase, serum protein, albumin, cholesterol and inorganic phosphate were observed in male rats, but were not observed in the female rats.

ORGAN WEIGHTS
Absolute organ weights were significantly decreased for the lungs of high-exposure females, spleens of low- and high-exposure males, livers of
medium- and high-exposure males, kidneys of highand medium-exposure males and females. Lung weights were signiflcantly increased in low-exposure males. When organ weights were expressed relative to terminal body weights or brain weights, high-exposure male spleen weights were signiflcantly decreased and low-exposure male lung weights remained increased. There were no significant changes in absolute weights of adrenal glands, testes, brain, thymus, heart, prostate, uterus, urinary bladder or ovaries nor in these organ weights when expressed relative to body or brain weight.

GROSS PATHOLOGY
There were no treatment-related changes in gross pathology when the animals were killed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic evaluation of the nasal cavity revealed a thickening of the respiratory epithelium, noted as an increase in the numbers of goblet cells or as an increase in the mucin content of the goblet cells in the medium and high-exposure male and female rats. The increased number of goblet cells was observed in the posterior portion of the nasal cavity, lining of the septum, the lateral walls, the anterior turbinates and in selected cases the ethmoid turbinates. The subjective judgement of the proliferation of goblet cells in the posterior nasal cabity was accompanied by an increased volume of mucus in the individual goblet cells. There were no histological changes in the trachea, lungs or larynx.
Dose descriptor:
NOAEC
Effect level:
1 000 mg/m³ air
Sex:
female
Basis for effect level:
other: Based on the decreased body weights of the high-dose females
Dose descriptor:
NOAEC
Effect level:
2 200 mg/m³ air
Sex:
male
Basis for effect level:
other: No adverse effects observed at the highest tested dose.
Dose descriptor:
LOEC
Effect level:
160 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Based on reported nasal haemorrhaging in all test groups
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Aerosol exposure. Female body weight changes only - no effect on males.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study published in peer-reviewed literature, minor restrictions in reporting, but otherwise acceptable for assessment.
Principles of method if other than guideline:
Groups of 19 male and female rats were exposed by inhalation to 0.0, 0.16, 1.0 and 2.2 mg/l air propylene glycol for 6 hr/day, 5 days/week for 90 days. The clinical signs, body weights, food consumption, haematological parameters, clinical chemistry and gross and histopathological examinations were performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: IFFA-CREDO, L'Arbresle, France
- Age at study initiation: 3 months
- Weight at study initiation: males 355-365 g, females 255-265 g
- Housing: 2 per cage, Macrolon Type III cages
- Diet: pelleted feed (Specia Diet Services Rat and Mous No. 1, Shell Diet Services, Engand), ad libitum, except during the exposure
- Water: tap water, ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 / 12


Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: air
Remarks on MMAD:
MMAD / GSD: The MMADs of the diluted aerosol were less than2.22 and 1.96 μm for the medium- and high-concentration groups, respectively. The mean geometric diameter for the low-concentration group was not obtainable, possibly due to evaporation which occurred with large quantities of dilution air. No measurements were made of the particle size of the undiluted aerosol. The geometric standard deviations were 1.44 and 1,57, respectively for the medium- and high-dose groups.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Battelle nose-only exposure chambers
- System of generating particulates/aerosols: Battelle-designed nebulizers
- Air flow rate: 35-50 litre/minute

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatogarphy
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The aerosol concentrations were measured once per day by samples taken at animal ports with two gas washbottles (Aver & Co. AG, cat. No. 30852) in series, each containing l00 ml distilled water. Samples were routinely taken for about l0 min for the high, 30 min for the medium and 120 min for the low concentration. The air flow rates for sample collection were nominally 2 litre/min. During sampling, volumes were measured by calibrated
dry gasmeters (Compagnie des Compteurs, model G Ló, No. 160 525). Also, sampling flow-rates were obtained from calibrated rotameters. After
sampling, the contents of each washbottle were poured into a 150-ml volumetric flask, the sampling bottle was rinsed with distilled water and the flask was brought to volume. Samples were analysed daily for propylene glycol concentration by gas chromatography. The particle concentration was monitored continuously throughout exposures for the high concentration group. A dilution system (10;1) in connection with a Mini-RAM (GCA Corp., Bedford, MA) aerosol monitor was used. The Mini-RAM was calibrated against gravimetric measurements. The particle size distributions of the propylene glycol aerosol were determined once a week for each exposure group using a Mercer seven-stage cascade impactor (Model 02-100: IN-TOX Products, Albuquerque, NM). Isokinetic samples were taken at a flow-rate of I litre/min directly from an animal port for each exposure group, Impactor stages were weighed using a Mettler microbalance (Model AJ, Mettler, Zurich, Switzerland) with a sensitivity of 0.1 μg. The effective cutoff aerodynamic diameter (ECAD) values for lhe seven stages were: 0.325, 0.715, 1.06, 1.60,2.13,3.0 and 4.6 μm. Particle size distribution parameters (Raabe, l97l) were determined from the weight of material collected on each stage of the cascade impactor. The data were fltted using a probit model and the mass median aerodynamic diameter (MMAD) and geometric standard deviation were determined.
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
0, 160, 1000, 2200 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 0.16 ± 0.04, 1.01 ± 0.11 and 2.18 ± 0.31 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
19/sex/dose
Control animals:
yes, sham-exposed
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before starting exposures and before autopsy. The pre-study measurements were carried out over 4 days, 36 or 40 animals which comprised equal numbers of males and females were retro-orbitally bled each day. the measurements at the end of the study were carried out over 3 days. About 50 animals (approximately equal numbers of males and females from each treatment group) were retro-orbitally bled on each day of killing.
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- How many animals: all animals
- Parameters examined: haematocrit, haemoglobin concentration, red blood cell count, white blood cell count, mean read blood cell count, mean red blod cell corpuscular haemoglobin, mean corpuscular haemoglobin concentration and platelets.


CLINICAL CHEMISTRY: Yes
before starting exposures and before autopsy. The pre-study measurements were carried out over 4 days, 36 or 40 animals which comprised equal numbers of males and females were retro-orbitally bled each day. the measurements at the end of the study were carried out over 3 days. About 50 animals (approximately equal numbers of males and females from each treatment group) were retro-orbitally bled on each day of killing.
- Anaesthetic used for blood collection: Yes (carbon dioxide)
- How many animals: all animals
- Parameters examined: serum concentrations of glucose, urea nitrogen, total protein, albumin, total bilirubin, total cholesterol, calcium, inorganic phosphate, chloride, alkaline phosphatase, γ-glutamyltransferase, alanine aminotransferase, serum creatinine, 5'-nucleotidase, sorbitol dehydrogenase, sodium, potassium, creatine phosphokinase, triglycerides and total phospholipids.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
Respiratory rates and tidal volumes were measured in four rats/group/sex on study day 7, and repeated on the same animals on study days 42 and 84. Four animals were measured simultaneously for 15 min preceding exposure and for the first 30 min of exposure while in exposure/plethysmograph tubes (Coggins et al., l98l).
Statistics:
Statistical analyses were conducted by one-way analysis of variance, Bartlett's tests for homogeneity, Dunnett's test for significance or a modified r-test (Gad and Weil, 1982).
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no significant differences in respiratory rates, tidal volumes or minute volumes between the control group and any of the treatment groups' nor did respiratory rates within groups decrease as the animals became acclimatized to the nose-only exposure conditions.
A treatment-related effect was reported nasal haemorrhaging which began during the second week of exposure and persisted throughout the study; recovery from clinical signs of nasal haemorrhaging occurred during the non-exposure weekend periods. This haemorrhaging was reduced to less than 4% in the low-exposure female group after the fourth week of exposure. From week 2 to 13, the average incidences of nasal haemorrhaging in males were less than 1% in controls, 64% in the low-exposure group, 74% in the medium-exposure group and 75% in the high exposure group. In females, the average incidences were less than 1% in controls, l4% in the low exposure group and 7l% in the medium- and high exþosure groups. Similar trends were observed for ocular discharge, with incidences of 16% in low exposure males, 40% in medium- and high-exposure males, and 570 in controls. There was generally less ocular discharge in females, who had incidences of 8% in controls, l4% in the low exposure group, 28% in the medium-exposure group and 35% in the high exposure group.

BODY WEIGHT AND WEIGHT GAIN
The high-exposure female rats showed a significant reduction in body weight, approximately 5-7%,starting on day 50 and continuing until the end ofthe study. The medium-exposure females also had reduced body weights beginning on study day 64 which continued until the end of the study. There were no signiflcant differences between the body weights of control and treated males; however, a trend was established by day 56; the control animals were heaviest, the low-exposure group were lighter than the medium-exposure group and the high-exposure group were the lightest. The differences between the control and high-exposure mean body weights were only 4%o for males and 6% for females on the flnal day of the study. The sudden drop in body weight for the final day of the study was due to a 6-hr fast; the animals were weighed after the flnal exposure. On previous weighings, the animals were weighed before they were placed in the nose-only chambers.

FOOD CONSUMPTION
The reduction in the females body weights during the study was correlated with a significant reduction in feed consumption beginning on study day 43 for the high-exposure females and on study day 50 for the medium-exposure females. The mean feed consumption was also significantly reduced on study day 50 for the low-exposure females. High-exposure male rats had significantly reduced feed consumption on study days 57, 64 and 88. There were no trends or significant differences from the controls in feed consumption for the low-exposure or medium-exposure male rats.

HAEMATOLOGY
Pre-study measurements of selected haematology components revealed statistically significant (P < 0.05) diflerences between animals assigned to
treated groups and control groups. However, the changes showed no consistent trends with respect to treatment group or sex and were not considered to be biologically significant.
The only statistically significant change in the erythrocytic profile at the end of the study occurred in the high-exposure females. The mean corpuscular haemoglobin concentration was reduced when compared with that lor the female control group. There were significant decreases in white blood cell count, banded neutrophil count and lymphocyte count in medium- and high-exposure females. High-exposure male rats also showed a significantly reduced banded neutrophil count which was not considered relevant to propylene glycol exposure.

CLINICAL CHEMISTRY
There were no statistically signiflcant changes in pre-study concentrations of serum enzymes, serum chemistries or serum electrolytes in the male rats. In the pre-study only serum phosphate was significantly increased (P < 0.05) in females of the high-exposure group (2.84 + 0.48 mmol/litre) compared with the control group (2.49 + 0.40 mmol/litre).
There were statistically significant decreases in serum sorbitol dehydrogenase and γ-glutamyl transferase in the medium- and high-exposure male rats, respectively. Sporadic statistically significant changes also were reported for serum glucose, albumin and creatinine in medium-exposure males and for serum protein, albumin and cholesterol in high-exposure males. In the female rats, serum protein was elevated only in the medium-exposure
animals. There were no changes in serum electrolytes in males of any group but serum chloride was elevated in the low-exposure females. As propylene glycol levels increased, decreasing trends in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and γ-glutamyl
transferase, serum protein, albumin, cholesterol and inorganic phosphate were observed in male rats, but were not observed in the female rats.

ORGAN WEIGHTS
Absolute organ weights were significantly decreased for the lungs of high-exposure females, spleens of low- and high-exposure males, livers of
medium- and high-exposure males, kidneys of highand medium-exposure males and females. Lung weights were signiflcantly increased in low-exposure males. When organ weights were expressed relative to terminal body weights or brain weights, high-exposure male spleen weights were signiflcantly decreased and low-exposure male lung weights remained increased. There were no significant changes in absolute weights of adrenal glands, testes, brain, thymus, heart, prostate, uterus, urinary bladder or ovaries nor in these organ weights when expressed relative to body or brain weight.

GROSS PATHOLOGY
There were no treatment-related changes in gross pathology when the animals were killed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic evaluation of the nasal cavity revealed a thickening of the respiratory epithelium, noted as an increase in the numbers of goblet cells or as an increase in the mucin content of the goblet cells in the medium and high-exposure male and female rats. The increased number of goblet cells was observed in the posterior portion of the nasal cavity, lining of the septum, the lateral walls, the anterior turbinates and in selected cases the ethmoid turbinates. The subjective judgement of the proliferation of goblet cells in the posterior nasal cabity was accompanied by an increased volume of mucus in the individual goblet cells. There were no histological changes in the trachea, lungs or larynx.
Dose descriptor:
NOAEC
Effect level:
1 000 mg/m³ air
Sex:
female
Basis for effect level:
other: Based on the decreased body weights of the high-dose females
Dose descriptor:
NOAEC
Effect level:
2 200 mg/m³ air
Sex:
male
Basis for effect level:
other: No adverse effects observed at the highest tested dose.
Dose descriptor:
LOEC
Effect level:
160 mg/m³ air
Sex:
male/female
Basis for effect level:
other: Based on reported nasal haemorrhaging in all test groups
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
160 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Aerosol exposure. Effects on nose.

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study predates GLP and OECD guideilnes, published in peer-reviewed literature, restrictions in design and reporting, but contributing to the overall assessment.
Principles of method if other than guideline:
0.02 ml of the test substance (neat, 50% and 10% solution in acetone) were dropped on the dorsal skin between the flanks of 50 mice/group twice a week on a 1-inch square area which was shaved regularly. The animals were checked weekly, and all lesions and tumors were recorded. Animals were allowed to die spontaneously or were killed when moribund. Complete autopsies were performed on all animals. The skin from all animals, all grossly observed tumors and other lesions in the lungs, livers, kidneys etc., from treated as well as control groups were studied histologically.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
Swiss
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Eppley colony
- Age at study initiation: 7 weeks
- Housing: in plastic cages with commercial bedding, 10/cage
- Diet: commercal diet, ad libitum
- Water: libitum

Type of coverage:
open
Vehicle:
acetone
Details on exposure:
TEST SITE
- Area of exposure: 1-inch square
- % coverage: 0
- Type of wrap if used: none
- Time intervals for shavings or clipplings: regularly


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.02 ml
- Concentration (if solution): 100, 50 and 10%
- Constant volume used: yes


VEHICLE
- Amount(s) applied (volume or weight with unit): 0.02 ml
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Lifespan
Frequency of treatment:
Twice a week
Remarks:
Doses / Concentrations:
10%, 50% and 100% in 0.02 ml acetone
Basis:

No. of animals per sex per dose:
50 females/dose
Control animals:
other: 135 untreated animals served as controls, 50 animals were treated with the solvent alove; 50 were treated with 7,12-dimethylbenzanthracene as a positive control
Details on study design:
- Rationale for animal assignment (if not random): the animals were randomized prior to the start of the experiments; the littermates were separated.
Positive control:
7,12-dimethylbenzanthracene
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly; all lesions and tumors were recorded.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. The skin from all animals, all grossly observed tumors and other lesions in the lungs, livers, kidneys etc. from treated as well as control groups were studied histologically.
Statistics:
The statistical significance of the results was evaluated using the methods presented by Armitage (1971).
Clinical signs:
not specified
Dermal irritation:
not specified
Mortality:
not specified
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
No substance-related tumor increases were evidenced in mice treated with monopropylene glycol at different concentrations.
Dose descriptor:
NOAEL
Effect level:
0.02 other: ml/twice a week
Sex:
female
Basis for effect level:
other: No substance-related tumor increases were evidenced with neat monopropylene glycol.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study predates GLP and OECD guideilnes, published in peer-reviewed literature, restrictions in design and reporting, but contributing to the overall assessment.
Principles of method if other than guideline:
0.02 ml of the test substance (neat, 50% and 10% solution in acetone) were dropped on the dorsal skin between the flanks of 50 mice/group twice a week on a 1-inch square area which was shaved regularly. The animals were checked weekly, and all lesions and tumors were recorded. Animals were allowed to die spontaneously or were killed when moribund. Complete autopsies were performed on all animals. The skin from all animals, all grossly observed tumors and other lesions in the lungs, livers, kidneys etc., from treated as well as control groups were studied histologically.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
Swiss
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Eppley colony
- Age at study initiation: 7 weeks
- Housing: in plastic cages with commercial bedding, 10/cage
- Diet: commercal diet, ad libitum
- Water: libitum

Type of coverage:
open
Vehicle:
acetone
Details on exposure:
TEST SITE
- Area of exposure: 1-inch square
- % coverage: 0
- Type of wrap if used: none
- Time intervals for shavings or clipplings: regularly


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.02 ml
- Concentration (if solution): 100, 50 and 10%
- Constant volume used: yes


VEHICLE
- Amount(s) applied (volume or weight with unit): 0.02 ml
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Lifespan
Frequency of treatment:
Twice a week
Remarks:
Doses / Concentrations:
10%, 50% and 100% in 0.02 ml acetone
Basis:

No. of animals per sex per dose:
50 females/dose
Control animals:
other: 135 untreated animals served as controls, 50 animals were treated with the solvent alove; 50 were treated with 7,12-dimethylbenzanthracene as a positive control
Details on study design:
- Rationale for animal assignment (if not random): the animals were randomized prior to the start of the experiments; the littermates were separated.
Positive control:
7,12-dimethylbenzanthracene
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly; all lesions and tumors were recorded.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes. The skin from all animals, all grossly observed tumors and other lesions in the lungs, livers, kidneys etc. from treated as well as control groups were studied histologically.
Statistics:
The statistical significance of the results was evaluated using the methods presented by Armitage (1971).
Clinical signs:
not specified
Dermal irritation:
not specified
Mortality:
not specified
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
No substance-related tumor increases were evidenced in mice treated with monopropylene glycol at different concentrations.
Dose descriptor:
NOAEL
Effect level:
0.02 other: ml/twice a week
Sex:
female
Basis for effect level:
other: No substance-related tumor increases were evidenced with neat monopropylene glycol.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
chronic
Species:
mouse

Additional information

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.

For systemic effects, the NOAEL of 1000 mg/m3 was established, based on the reduced body weight and decreased food consumption in high-dose females.

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

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. However, this reported nasal “hemorrhage” observed in the study was not supported by microscopic evidence of tissue damage and hemorrhage. An alternative explanation is that this “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, while the increased number of goblet cells and/or increased mucin content in the mid- and high dose groups appears to be an adaptive response. Nevertheless, the lowest dose level of 160 mg/m3is considered a LOAEL for local effects. For systemic effects, a NOAEL of 1000 mg/m3was established, based on the reduced body weight and decreased food consumption in high-dose females

Justification for classification or non-classification

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.