1-propoxypropan-2-ol

Endpoint summary

Description of key information

A GLP-study according to OECD guideline 413 and several GLP-studies according to or equivalent to OECD guideline 412 are available for propylene glycol n-propyl ether.

Key value for chemical safety assessment

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

Study period:

March 1988 - July 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

other: Fischer 344 & CD Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley Inc. Indianapolis (Fischer 344) & Charles River Breeding Laboratories Inc. Kingston (CD Sprague-Dawley)
- Age at study initiation: 56 days
- Weight at study initiation: ca. 180 g (Fischer 344 males); ca. 130 g (Fischer 344 females); ca. 320 g (Sprague-Dawley males); ca. 190 g (Sprague-Dawley females)
- Fasting period before study: n.a.
- Housing: two animals per cage (during recovery period: one per cage) in stainless steel wire-mesh cages in a Relocatable Containment System
- Diet (e.g. ad libitum): ad libitum (during non-expsoure periods)
- Water (e.g. ad libitum): ad libitum (during non-exposure periods)
- Acclimation period (to expsoure chamber): 2 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-23.9°C
- Humidity (%): 45-78%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hour photoperiod

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: n.a.

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel cages with glass windows (volume 4320 l)
- Method of conditioning air: For all target concentrations, liquid PROPASOL Solvent P was metered from a piston pump into a glass evaporator. The temperature in the evaporator was maintained at a level sufficient to vaporize the test material. The resultant vapor was carried into the chamber by a countercurrent air stream that entered the bottom of the evaporator.
- Air flow rate: 1000 l/min
- Air change rate: 14 changes per hour

TEST ATMOSPHERE
- Brief description of analytical method used: Chamber concentrations of PROPASOL Solvent P vapor were analyzed at least twelve times a day by gas chromatography. The chamber probe wa placed in the breathing zone of the animals. The daily nominal (estimated) concentration was also determined.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations of PROPASOL Solvent P vapor were analyzed at least twelve times a day by gas chromatography.

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

5 days per week

Remarks:

Doses / Concentrations:
30 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
100 ppm
Basis:
nominal conc.

Remarks:

Doses / Concentrations:
300 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

20

Control animals:

yes, concurrent no treatment

Details on study design:

- Post-exposure recovery period : After the 14-week exposure regimen, half the animals (10/sex/strain/group) were kept for an additional 3-month recovery period.

Positive control:

none

Observations and examinations performed and frequency:

ANIMAL OBSERVATIONS: Yes
All animals were individually observed for signs of toxic effects. During the exposures, observations were recorded on a group basis. Preceding and following each exposure, on weekends, and each weekday during the postexposure recovery period, observations were recorded for animals exhibiting overt clinical signs. At the time of body weight collection and just preceding sacrifice, detailed observations were performed on all animals.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on the morning prior to the initiation of the first exposure. The animals were weighed weekly during the 14-week exposure regimen and immediately preceding sacrifice. The animals held during the 13-week recovery period were weighed once a week and immediately prior to sacrifice.

FOOD AND WATER CONSUMPTION:
Food and water consumption were measured over approximately a 14-hour period following 65 exposures for the male and female F-344 rats and for approximately 15-hours following 66 exposures for the male and female SD rats. (10 animals/sex/strain/group)
Food and water consumption were not evaluated for the animals maintained during the recovery period.

OPHTHALMOSCOPIC EXAMINATION: Yes
Prior to the first exposure and following the exposures on May 26 (week 7) and July 7 (week 13), 1988, the eyes of all rats were examined by a veterinary ophthalmologist. The examination included indirect ophthalmoscopy following dilation of the rats eyes with a 1 % Mydriacyl (tropicamide) solution. An ophthalmic examination was perfomed September 22 (week 24), 1988, for the recovery animals.

CLINICAL CHEMISTRY AND HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 14-weeks of exposure, just prior to sacrifice (10 animals/sex/strain/group) & after approximately 13 weeks postexposure (recovery) period, just prior to sacrifice (10 animals/sex/strain/group)
- Anaesthetic used for blood collection: Yes (methoxyfluorane)
- Animals fasted: food was removed from all cages at the start of the blood collection period, water was supplied ad libitum
- Parameters examined: Serumchemistry: glucose, urea nitrogen, creatinine, total protien, albumin, globulin, total bilirubin, direct bilirubin, indirect bilirubin, AST, ALT, CK, LDH, GGT, SDH, ALK, calcium, phosphorus, sodium, potassium, chloride; Hematology: total and differential leukocyte counts, platelet count, erythrocyte count, hematocrit, hemoglobin mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration

URINALYSIS: Yes
- Time schedule for collection of urine: during fourteenth week of exposure (see food and water consumption)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No (food and water were available ad libitum)
- Parameters examined: pH; protein, glucose, ketone, bilirubin, urobilinogen, blood, microscopic constituents
Urinanalysis was not performed on the recovery animals.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)

The rats were killed by exsanguination via the brachial blood vessels following anesthesia with methoxyfluorane. A complete necropsy was performed on each animal. Gross examinations were performed on all study animals and selected tissues were fixed in 10% neutral buffered formalin (except for eyes) for histologic evaluation. Histologic evaluations were performed on seleceted tissues from the conrtol and high concentration animals. Eyes were preserved in Bouin's solution. One eye from each rat was embedded in plastic, stained with Periodic Acid-Schiff (PAS), and histologically evaluated. The details of the necropsy procedure and the list of selected tissues saved are presented in the Anatomic Patology Report.

Other examinations:

Organ weights: liver, lungs, adrenals, kidneys, thymus, spleen, and brain, from all surviving animals and testes (males only) were weighed at sacrifice. Organ weights were reported as absolute weights and as a percentage of body and brain weight.

Statistics:

Results of quantitative continuous variables were intercompared among the PROPASOL Solvent P concentration groups and one control group by use of analysis of variance (ANOVA), Bartlett's homogeneity of variance, and Duncan's multiple range tests. The latter test was used to delineate which exposure groups differed from the control, when F from the ANOVA was significant. If Bartlett's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, if necessary by a t-test. Details of the statistical procedures for hematologic variables can be found in the Clinical Pathology Report. The fiducial limit of 0.05 (two-tailed) was used as the critical level of significance for all comparisons.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

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):

no effects observed

Ophthalmological findings:

effects observed, treatment-related

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

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:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
There were no exposure-related clinical signs during the study. A 100 ppm group SD male rat was found dead on study day 21, and a control group SD female rat was sacrificed on study day 73. The apparent cause of death for the male rat was renal failure due to a urinary tract obstruction. The female rat probably died due to trauma following a caging accident.

BODY WEIGHT AND WEIGHT GAIN:
There were statistically significant decreased body weights and body weight gains for female F-344 rats of the 300 ppm group. The weight gains were lower for most of the exposure period and for 4 weeks following the end of the exposure regimen. At the end of the last full week of exposure (week 13) the body weight gain for the 300 ppm group females was 84% of that of controls. Female F-344 rats of the 100 ppm group had a statistically significantly lower body weight gain at the end of the second exposure week, after which no further effects occurred during the exposure regimen. There were no significant exposure-related effects on the body weight or body weight gain for female F-344 rats of the 30 ppm group, any of the groups of male F-344 rats, or either sex of the SD rats.

FOOD AND WATER CONSUMPTION;
There were no exposure-related effects on food or water consumption for any of the groups of PROPASOL Solvent P exposed rats; the statistically significant decrease for the food consumption value for the 30 ppm female F-344 rats was considered to be a random occurrence.

OPHTHALMOSCOPIC EXAMINATION:
There were no exposure-related changes in this study.

HAEMATOLOGY:
At the conclusion of the exposure regimen, female F-344 rats had a slight decrease in total leukocyte count (300 and 30 ppm groups) associated with a decrease in lymphocytes (300 ppm group). These effects were absent at the end of the recovery period. Other statistically significant differences were neither consistent nor concentration related and were considered to be spurious.

CLINICAL CHEMISTRY:
Statistically significant differences in serum chemistry values between PROPASOL Solvent P exposed and control rats were neither consistent nor concentration related and were considered to be spurious.

URINALYSIS:
There were no alterations in urinanalysis values between PROPASOL Solvent P exposed and control groups for either sex or strain of rats during the study.

ORGAN WEIGHTS:
There were no exposure-related organ weight changes in the PROPASOL Solvent P exposed rats. The few mean values for which statistical significance was achieved are considered to be random occurrences unrelated to the exposure.

GROSS PATHOLOGY:
There were no exposure-related changes observed at the necrospy for any of the PROPASOL Solvent P exposed groups of rats. The male SD rat of the 100 ppm group found dead had a blockage in the lower urinary tract. The control group SD rat sacrificed moribund had head trauma.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no microscopic lesions seen at either the 14-week or the 27-week sacrifice which were attributable to PROPASOL Solvent P exposure. The microscopic eye lesions found in this study were primarily related to the spontaneous condition of corneal dystrophy which occurs in both of these strains of rats. Additional tissue lesions observed in this study were considered to be within the normal spectrum of diseases expected for rats of these strains, ages, and gender.

Dose descriptor:

NOAEC

Effect level:

300 ppm

Sex:

male/female

Basis for effect level:

other: decreased body weight gain reversible in the course of the study

Critical effects observed:

not specified

Conclusions:

The only dose-related effect observed in this study was decreased body weight gain in female rats. This effect was reversible in the course of this study and is not considered to be adverse. Based on this study an NOAEC of 300 ppm can be established.

Executive summary:

Four groups of Fischer 344 (F-344) and Sprague-Dawley (SD) rats, each containing 20 males and 20 females, received whole-body exposures of either filtered air or vapor of PROPASOL Solvent P for 6 hours/day, 5 days/week for 14 weeks; target concentrations were 0 (control), 30, 100 or 300 ppm. Half the animals (10/sex/strain/group) were kept for an additional 3 -month recovery period. Monitors for toxic effects included clinical observations, ophthalmic examinations, body and organ weights, clinical pathology (hematology, serum chemistry, and urinanalysis), and macroscopic and microscopic evaluations. Mean (+/- SD) analytical concentrations of 30 (+/- 0.8), 101 (+/- 3), and 304 (+/- 8) ppm PROPASOL Solvent P were measured. There were no exposure-related clinical signs during the study. For all groups of animals, eyes appeared normal during ophthalmic examinations. Body weight gains were consistently lower for the female F-344 rats of the 300 ppm group, except during the recovery period. Female F-344 rats of the 100 ppm group had decreased body weight gains for the first two weeks of the exposure regimen. There were no additional PROPASOL Solbent P exposure-related differences in body weights, and food and water consumptions were normal for rats of all study groups. Urinanalysis results for PROPASOL Solvent P exposed rats were normal. Female F-344 rats had a slight decrease in total leukocyte count (300 and 30 ppm groups) associated with a decrease in lymphocytes (300 ppm group). These hematologic effects were absent at the end of the recovery period and no clear-dose response was observed. Additional statistically significant differences in hematology or serum chemistry values between exposed and control rats were considered to be spurious in nature. No exposure-related gross lesions were identified at necropsy, and organ weight values for PROPASOL Solvent P exposed rats were normal. There were no microscopic tissue lesions attributable to PROPASOL Solvent P exposure. Corneal dystrophy was observed in rats of all groups, including the control group. Based on this study an NOAEC of 300 ppm can be established.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1 474 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

good

Additional information

Inhalation is the most likely route of exposure to propylene glycol n-propyl ether (PnP) for humans. Therefore, all repeated dose studies with PnP were conducted with whole body inhalation exposure. In several 2 -week vapor inhalation studies ocular lesion were observed in rats. These effects were less pronounced in other species (rabbits and guinea pigs). In a 90 -day vapor inhalation study groups of Fischer 344 (F-344) and Sprague-Dawley (SD) rats, were exposed to target concentrations of 0 (control), 30, 100 or 300 ppm. Half the animals were kept for an additional 3 -month recovery period. There were no exposure-related clinical signs during the study. For all groups of animals, eyes appeared normal during ophthalmic examinations. Body weight gains were consistently lower for the female F-344 rats of the 300 ppm group, except during the recovery period. Female F-344 rats of the 100 ppm group had decreased body weight gains for the first two weeks of the exposure regimen. There were no additional exposure-related differences in body weights. Female F-344 rats had a slight decrease in total leukocyte count (300 and 30 ppm groups) associated with a decrease in lymphocytes (300 ppm group). These hematologic effects were absent at the end of the recovery period and no clear-dose response was observed. Additional statistically significant differences in hematology or serum chemistry values between exposed and control rats were considered to be spurious in nature. No exposure-related gross lesions were identified at necropsy, and organ weight values for exposed rats were normal. There were no microscopic tissue lesions attributable to PnP exposure. Corneal dystrophy was observed in rats of all groups, including the control group. Therefore, those effects were considered not to be related to the test material. Based on this study an NOAEC of 300 ppm can be established. This is equivalent to 1474 mg/m3 (based on molecular weight and temperature of 20 deg C, 1 atm)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
90-day inhalation study, well performed, according to GLP.

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

No classification for repeated dose toxicity is required for propylene glycol n-propyl ether as the NOAECs are above the limits for classification according to EU criteria.