Registration Dossier

Administrative data

Description of key information

For repeated dose toxicity of PnB studies via all routes of exposure are available.
Oral: 14-day oral gavage and 13-week d.w. studies in rats.
Dermal: 13-week dermal study in rats.
Inhalation: two 2-week and one 31-day whole body inhalation studies in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09/1990-04/1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston, N.Y.
- Age at study initiation: at least 5 weeks
- Weight at study initiation: 105 to 110 g (males) and 87 to 89 g (females)
- Fasting period before study:
- Housing: Individually in stainless steel cages with wire-mesh bottoms.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum (with test material)
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Approximately 72°F
- Humidity (%): no data
- Air changes (per hr): 13
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

A premixed solution (test material - water concentrate) to a determined amount of tap water. Test solutions and premixes were prepared weekly to maintain the the targeted concentrations as determined in the one week probe study.

Initial concentrations of test material were in the water were calculated from pretest body weights and water consumption data targeted on the desired dose levels on a mg/kg bw/day basis. Thereafter, the most recent body weight and water consumption data was used to adjust the concentration of the test material in the water to maintain those targeted dose levels. Water concentrations were adjusted weekly to maintain the targeted exposure levels.

Concentrations of PnB in drinking water were targeted to correspond to nominal doses of 0, 100, 350, or 1000 mg/kg-day.  These concentrations were based on anticipated drinking water consumption volumes by the test animals.  When the measured concentration of PnB in the treatment water was multiplied by the amount of water actually consumed, the actual dose of PnB was higher than the target doses (by a factor of 10-15%).  However, wastage may have occurred that would reduce the dose and offset the 10-15% increased dose factor.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of premix, test material/water mixtures, and municipial tap water taken on Study Day 1, Study Day 29, Study Day 57, and Study Day 85 were analyzed to confirm targeted concentrations of PnB in the water.

The samples were diluted with methanol (2/5) and analyzed by high pressure liquid chromatography using refractive index detection (HPLC).
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Daily
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Basis:
nominal in water
Dose / conc.:
350 mg/kg bw/day (nominal)
Remarks:
Basis:
nominal in water
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Basis:
nominal in water
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: the high dose of 1000 mg/kg bw/day was considered adequate for a limit test as definedby OECD. The lower dose levels were selected to establish a dose-response for potential effects and to determine the no-observed-effect-level (NOEL) and the no-observed-adverse-effect-level (NOAEL).
- Rationale for animal assignment: animal were weighed and randomly allocated to study groups using a computerized, weight-stratification and random number-based procedure. 
- Post-exposure recovery period: 4 weeks
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations: including evaluation of the skin, fur, and mucous membranes, respiration, nervous system, and behaviour patterns. bservations on weekends and holidays were limited to a check of all cages for dead animalss and the availability of feed and water.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Rats were observed for clinical signs of toxicity on a daily basis (week days). Particular attention was directed to observations for possible tremeors, convulsions, lethargy and other signs related to central nervous system function, salivation and diarrhea.

BODY WEIGHT: Yes
- body weights were monitored weekly.

FOOD CONSUMPTION:
- food consumption was monitored weekly.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- body weights, water, and food consumption were monitored weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
Ophthalmological examinations were conducted prior to treatment and at sacrifice.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: hematology and electrolytes were evaluated at sacrifice.
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes (overnight before sacrifice)
- Parameters examined: packed cell volume, hemoglobin concentration, red and white blood cell counts, platelet counts, and WBC differential counts.
Complete blood smear examinations were conducted which included differential leukocyte counts (the number of leukocytes counted to be specified if other than 100 cells were counted) and an assessment of erythrocyte, leukocyte, and platelet morphology.

CLINICAL CHEMISTRY: Yes
Clinical chemistries were evaluated at sacrifice.
- Time schedule for collection of blood:
- Animals fasted: Yes (over night before sacrifice)
- Parameters examined: alanine aminotransferase, alkaline phosphatase, aspartate aminitransferase, blood urea nitrogen, cholesterol, triglycerides, creatinine, creatine phosphokinase, total bilirubin, glucose, total protein, calcium, phosphorus, chloride, sodium, potassium, and albumin using a Spectrum Analyzer. The globulin concentrations were celaculated from the total protein and albumin values.

URINALYSIS: Yes
- Time schedule for collection of urine: urinalyses were conducted one week prior to sacrifice
- Metabolism cages used for collection of urine: No data
- Animals fasted: No
- Parameters examined: specific gravity, pH, bilirubin, glucose, protein, ketones, blood, and urobilinogen. In addition, the microsediment from a pooled sample from each group was examined microscopically.

NEUROBEHAVIOURAL EXAMINATION: Yes
Functional observational battery evaluations were conducted prior to treatment and at monthly intervals during treatment.

Sacrifice and pathology:
At sacrifice, all surviving animals were subjected to complete necropsy. A complete histologic evaluation was made on all control and high dose animals. Selected organs evaluated histologically in lower dose subjects included liver, kidneys, adrenal glands, lungs, testes, and, potentially, other target organs identified in high dose animals.
Other examinations:
none
Statistics:
Hematology (excluding differential counts), electrolyte, clinical chemistry data, body weights, and absolute (grams) and relative (g to 100g terminal body weight) organ weights were evaluated by Bartlett's test for equality of varaiances. Based on the outcome of Bartlett's test, exploratory data analysis was performed by a parametric or non-parametric analysis of variance (ANOVA), followed, if appropriate, by Dunnett's test or Wilcoxon rank-sum test with Bonferroni's correction for multiple comparisons. Statistical outliers were identified by a sequential test described by Grubbs. Feed and water consumption data, which were used in the computation of desired test material concentrations and shown in this final report, were not analyzed for differences of statistical significance.
Differences found to be statistically significant were not necessarily accepted as toxicologically significant, i.e., final interpretation of the numerical data did consider the statistical outcomes together with other factors, such as dose-response relationships, biologic plausibility, and pathological observations.
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:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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
All rats survived treatment with the test compound.

BODY WEIGHT AND WEIGHT GAIN
Slight decrease (less than 5% but statistically significant) in high dose males on days 21 through day 42. Correlated to reduced water and food intake.

FOOD CONSUMPTION
Slight decrease in high dose males and females (not statistically evaluated).

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Slight decrease in high dose males and females (not statistically evaluated).

OPHTHALMOSCOPIC EXAMINATION
No lesions noted.

HAEMATOLOGY
Statistically decreased red blood cell count and hemoglobin in high-dose (1000 mg/kg-day) males at 13-week sacrifice. Statistically decreased platelet count in high dose females after 13 weeks. Statistically decreased platelet count in high dose recovery males. No corresponding hypertrophy or lesions in bone marrow or spleen for any group.

CLINICAL CHEMISTRY
In high dose males (1000 mg/kg-day), several parameters were statistically different from controls: Sodium (decrease), potassium (increase), chloride (decrease), creatine phosphokinase (increase), urea (increase), and cholesterol (increase). In the mid-dose group (350 mg/kg-day), slight statistically significant changes in sodium (decrease) and potassium (increase) were noted. High dose females showed slightly increased urea and creatine phosphokinase.

URINALYSIS
No abnormalities noted.

NEUROBEHAVIOUR
No behavioral effects noted.

ORGAN WEIGHTS
Absolute and relative liver weights were increased in high dose males with no accompanying histopathology. In females at the high dose level, absolute and relative kidney weights were increased with no accompanying histopathology. High-dose males showed increased absolute and relative liver weights. Females showed increased absolute and relative kidney weights. No corresponding histopathology was found in these organs.

GROSS PATHOLOGY

HISTOPATHOLOGY: NON-NEOPLASTIC
No lesions noted.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No lesions noted.
Dose descriptor:
NOAEL
Effect level:
350 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: PnB at doses of 1000 mg/kg-d for 13 weeks caused increased absolute and relative liver weights in males and increased absolute and relative kidney weights in females
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: increased absolute and relative liver weights in males and increased absolute and relative kidney weights in females.
Critical effects observed:
not specified
Conclusions:
PnB at doses of 1000 mg/kg-d for 13 weeks caused increased absolute and relative liver weights in males and increased
absolute and relative kidney weights in females. The authors of the study concluded that the slight decreases in red blood cell count and hemoglobin in high-dose males may be related to decreased water and food consumption. This may also explain the slight decrease in male body weights
mid-way through exposures. Clinical chemistry changes, which may be similarly related to food and water consumption, were considered by the authors to be slight and not toxicologically significant. No effects from PnB were found at the lower dose levels of 100 or 350 mg/kg-day. The NOAEL for PnB is 350 mg/kg-day and the LOAEL is 1000 mg/kg-day.
Executive summary:

Four groups of Fischer 344 rats (10/sex/dose level) received propylene glycol n-butyl ether (PnB) in their drinking water at concentrations equivalent to target doses of 0, 100, 350,
or 1000 mg/kg-day for 13 weeks.  Two additional groups of 10/sex/dose receiving 0 or 1000 mg/kg-d for 13 weeks, were administered untreated water for four weeks following the 13-week exposure period in order to evaluate recovery.  Rats were observed for clinical signs of toxicity on a daily
basis (week days).  Body weights, water, and food consumption were monitored weekly.  Functional observational
battery evaluations were conducted prior to treatment and at monthly intervals during treatment.  Ophthalmological
examinations were conducted prior to treatment and at sacrifice.  Hematology, electrolytes, and clinical
chemistries were evaluated at sacrifice and urinalyses were conducted one week prior to sacrifice.  At sacrifice, all
control and high dose animals were subjected to complete necropsy and histopathological evaluations.  Selected organs evaluated histologically in lower dose subjects included
liver, kidneys, adrenal glands, lungs, testes, and, potentially, other target organs identified in high dose animals. 

Concentrations of PnB in drinking water were targeted to correspond to nominal doses of 0, 100, 350, or 1000
mg/kg-day.  These concentrations were based on anticipated drinking water consumption volumes by the test animals.  When the measured concentration of PnB in the treatment
water was multiplied by the amount of water actually consumed, the actual dose of PnB was higher than the target
doses (by a factor of 10-15%).  However, wastage may have occurred that would reduce the dose and offset the 10-15% increased dose factor.

Absolute and relative liver weights were increased in high dose males with no accompanying histopathology. In females at the high dose level, absolute and relative kidney weights were increased with no accompanying histopathology.  Slight alterations in clinical chemistries, electrolytes, and
hematology also were noted in both sexes at the high dose level. No changes in any other monitored parameters were noted at any dose level. 

The NOAEL for PnB is 350 mg/kg-day and the LOAEL is 1000 mg/kg-day (for organ weight changes). 
 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
350 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02/1988-03/1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study equivalent to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston NY
- Age at study initiation: ca. 8 weeks
- Weight at study initiation: ca. 160 g (males) and ca. 120 g (females)
- Fasting period before study: none
- Housing: Animals were placed in rooms designated to maintain adequate environmental conditions concerning temperature, relative humidity and photocycle for the specific species under test.
- Diet (e.g. ad libitum): ad libitum (except during exposure)
- Water (e.g. ad libitum): ad libitum (except during exposure)
- Acclimation period: at least 2 weeks
Route of administration:
inhalation
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: 157 liter stainless steel and glass exposure chambers
- Source and rate of air: dynamic air flow conditions
- Method of conditioning air: Vapors were generated using a glass J-tube method. Liquid test material was metered into the J-tube. Compressed air, heated with a flameless torch to the minimum extent necessary, passed through the J-tube to volatalize the test material. An additional glass J-tube was inserted to add water vapor to the generating system in an effort to increase the relative humidity in the exposure chambers.
- Temperature, humidity: 22-24°C; 40-60%
- Air flow rate: 30 liter/minute

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytica concentration of PnB in the chamber was determined at least four times/exposure by gas chromatography using a flame ionization detector. The gas chromatographic conditions were: helium flow = 30 ml/min, hydrogen flow = 30 ml/min, air flow = 300 ml/min, oven = 110°C and detector = 190°C. A 6 foot x 1/8 inch nickel column packed with 10% OV-101 on 100/120 mesh Chromosorb WHP was used for seperation of the test material from air.
Duration of treatment / exposure:
2 weeks (9 exposure)
Frequency of treatment:
6 h daily, 5 days/week
Dose / conc.:
50 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
200 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
700 ppm (nominal)
Remarks:
Doses / Concentrations:
700 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Dose selection rationale: the highest exposure concentration was the maximum concentration that could be practically attained.
- Rationale for animal assignment: random
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE and CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for overt signs of toxicity or changes in demeanor. These observations included an evaluation of the fur, eyes, mucous membranes and respiration. Behaviour pattern and nervous system activity was assessed by specific observations for lethargy, tremors, convulsions, salivation, lacrimation, diarrhea and other signs of altered central nervous system function. An additional dailt observation and routine monitoring on weekends was limited to animal husbandry procedures required to ensure the availability of food and water.

BODY WEIGHT: Yes
- Time schedule for examinations: all animals were weighed on test days 1, 3, 5, 8, and 11.

FOOD CONSUMPTION:
No data

FOOD EFFICIENCY:
No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: each animal received a pen-light ophthalmological examination prior to the initial exposure and after the final exposure to PnB.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to necropsy
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: hematocrit (HCT), hemoglobin (HGB), erythrocyte count (RBC), total leukocyte counts and red blood cell morphology were prepared and evaluated by light microscopy for each animal.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the terminal sacrifice
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: urea nitrogen (UN), alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), alkaline phosphatase activity (AP), glucose (GLUC), total protein (TP), albumin (ALB), globulin (GLOB, calculated), total bilirubin (TBILI), cholesterol (CHOL), triglycerides (TRIG), phosphorus (PHOS), calcium (CALC), sodium (Na), potassium (K) and chloride (CL).

URINALYSIS: Yes
- Time schedule for collection of urine: during the second week of exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: bilirubin, glucose, ketones, blood, pH, protein, urobilinogen, pecific gravity and microscopic examinations were made on sediments from samples pooled by exposure group.

NEUROBEHAVIOURAL EXAMINATION: Yes
Behaviour pattern and nervous system activity was assessed by specific observations for lethargy, tremors, convulsions, salivation, lacrimation, diarrhea and other signs of altered central nervous system function.

Sacrifice and pathology:
All animals were fasted over night and were necropsied the day following the last exposure to the test material. Each animal was weighed, anesthetized with methoxyflurane, sampled for hematology and clinical chemistry and humanely euthanized. All animals were examined for gross pathological alterations by a veterinary pathologist and weights of the brain, heart, liver, kidneys, adrenals and testes were recorded from all animals. The necropsy included in situ examination of the eyes using a moistened glass slide pressed against the corneal surface. A complete set of tissues was collected from each animal and preserved in neutral, phosphate-buffered 10% formaline. Following examination, the lungs were distended with buffered formalin to their approximate normal inspiratory volume. The nasal cavity was flushed with formalin via the pharyngeal duct to insure rapid fixation. A complete histopathological examination of tissues (except for auditory sebaceous galnds) was made from all animals in the control and highest exposure group. Tissues examined histopathologically were processed by conventional techniques, sectioned at approximately 6 µ, stained with hematoxylin and eosin and evaluated by light microscopy. No tissues were examinated histologically from rats exposed to 50 or 200 ppm PnB.
Statistics:
Descriptive statistics (means and standard deviations) were used to report chamber concentrations, chamber temperature, and relative humidity, and white blood cell differential counts. All remaining parameters examined statistically were first tested for equality of variance using Bartlett's test. If the results from Bartlett's test rejected the equality of variances, the parameter was flagged for careful evaluation of results. All parameters were then subjected to approriate parametric analysis as described below. In-life body weights, hematologic (excluding differential WBC) and clinical chemistry parameters, terminal body weights, organ weights (absolute and relative except testes) and urine specific gravities were evaluated using a two-way analysis of variances (ANOVA) with the factors of sex and dose. Results for absolute and relavtive testes weights were analysed using a one-way ANOVA. If significant dose effects were determined in the one-way ANOVA, then separate doses were compared to controls using Dunnett's test. For those parameters examined by a two-way ANOVA, examination was first for a significant sex-dose interaction. If this existed, a one-way ANOVA was done separately for each sex. If no sex-dose interaction was identified, and a dose effect was identified, or if in the subsequent ANOVA's separated by sex a dose effect was identified, then separate ANOVA's were used for each exposure group with control. To control for multiple comparisons with control, a Bonferroni correction was used.
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats survived until the scheduled necropsy with no clinical signs attributed to exposure to the test material.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of male and female rats were not adversely affected by exposure to PnB.

FOOD CONSUMPTION
no data

FOOD EFFICIENCY
no data

WATER CONSUMPTION
no data

OPHTHALMOSCOPIC EXAMINATION
A minor ocular change (hazy corea) was observed in the left eye of one male rat at 700 ppm just prior to necropsy. No other ophthalmologic changes were detected in any other animal.

HAEMATOLOGY
There were no adverse effects on hematologic parameters in male and female rats following exposure to PnB. In addition, the mean differntial leukocyte counts for male and female rats were similar to controls at all concentrations.

CLINICAL CHEMISTRY
A statistically significant decrease in total protein (TP) was observed in serum of both sexes (3.3% for males and 1.8% for females) at the lowest concentration. A statistically significant increase was also observed in blood glucose in both sexes (6.5% for males and 10.7% for females) at the highest concentration.

URINALYSIS
A statistically significant, but minimal increase in urine specific gravity was noted in both sexes at the highest concentration. All other urinary parameters were comparable to controls.

ORGAN WEIGHTS
Statistically significant increased relative but not absolute liver weights were noted in both sexes (6.7% for males and 6.5% for females) exposed to 700 ppm PnB. No effects were observed in any other organ weight.

PATHOLOGY
Microscopic examination of full sets of tissues from control and high exposure animals revealed no treatment-related effects. The few changes were generally of a minimal degree and occurred in similar incidences in both the controls and the exposed groups. These changes were considered typical of spontaneous lesions frequently noted in rats of this strain and age. Consequently, tissues were not examined from male and female rats exposed to 50 and 200 ppm PnB.

The hazy cornea of one eye observed in male rats exposed to 700 ppm PnB during the ophthalmic exam was confirmed at necropsy. Histologically, there was evidence of inflammation and mineralization of the cornea.
Dose descriptor:
NOAEL
Effect level:
> 700 ppm
Sex:
male/female
Basis for effect level:
other: highest attainable concentration.
Dose descriptor:
LOAEL
Effect level:
> 700 ppm
Sex:
male/female
Basis for effect level:
other: highest attainable concentration.
Critical effects observed:
not specified
Conclusions:
The observed adverse effect level (NOAEL) after 9-days of exposure to PnB is 700 ppm which was the highest attainable concentration.
Executive summary:

Whole-body exposures of male and female Fischer 344 (5 per sex and group) rats to targeted concentrations of 0, 50, 200 or 700 ppm (0, 0.27, 1.08 or 3.78 mg/l) PnB vapors resulted in no adverse effects following 9 exposures, each of six hours duration. The highest exposure concentration was the maximum that could be practically attained. Each animal was evaluated for changes in body weight, clinical chemistry, haematology, urinalysis, clinical observations, selected organ weights, and gross and histopathological evaluations.

The only effect noted was a slightly increased realtive liver weight in both sexes exposed to 700 ppm PnB. However, this was unaccompanied by any histologic lesions or change in clinical chemistry parameters reflective of hepatic dysfunction. Therefore, this minimal effect on liver weight was considered to be of no toxicicologic significance.

In summary, there were no adverse effects ascribed to the inhalation of up to 700 ppm PnB, six hours/day for nine exposures over two weeks. Based on the low biological activity and moderate vapor pressure, PnB is expected to have a low potential for adverse effects following short-term exposure.

 

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study equivalent to OECD guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Species:
rat
Strain:
other: Fischer 344, Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague-Dawley Inc., Indianapolis
- Age at study initiation: ca. 7 weeks
- Weight at study initiation: males ca. 150 g and females ca. 120 g (Fischer 344); males ca. 310 g and females ca. 190 g (Srague-Dawley)
- Fasting period before study: none
- Housing: 1 or 2 animals per cage separated by sex and test group in stainless steel, wire mesh cages
- Diet (e.g. ad libitum): ad libitum (during non-exposure periods)
- Water (e.g. ad libitum): ad libitum (during non-exposure periods)
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22°C (non-exposure) & 21-26°C (exposure chambers)
- Humidity (%): 42-62% (non-exposure) & 39-48% (exposure chambers)
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation
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 inhalation chambers with glass windows for animal observation (volume 4320 liter)
- Method of conditioning air: liquid Propasol Solvent B was metered from a piston pump and from a syringe pump equipped with a 50 ml syringe into a glass evaporator. The temperature in the evaporator was maintained at a level sufficient to vaporize the test material. The evaporator temperature was obtained once a week from each evaporator column. The evaporator temperature ranged from 50 to 89°C. The resultant vapor was carried into the chamber by a countercurrent airstream that entered the bottom of the evaporator.
- Temperature, humidity: 21-26°C, 39-48%
- Air flow rate: 1000 l/min
- Air change rate: 14 per hour
- Treatment of exhaust air:

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations of Propasol Solvent B vapor were analyzed approximately every 32 minutes by gas chromatography. A Perkin-Elmer Model 8500 gas chromatograph equipped with a flame ionization detector was used to monitor the vapor concentrations in the chambers (for gc operating parameters see attachment below).
Duration of treatment / exposure:
11 days
Frequency of treatment:
6 hours/day, 9 exposures/11 days
Dose / conc.:
10 ppm
Remarks:
Basis:
nominal conc.
Dose / conc.:
100 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
300 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
600 ppm (nominal)
Remarks:
Basis:
nominal conc.
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: 600 ppm was the highest attainable concentration
- Rationale for animal assignment (if not random): computer-based randomization program
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
All animals were observed prior to, during, and following each exposure for signs of toxic effects and ocular abnormalities. Animals were observed once a day on nonexposure days for signs of toxic effects. Animals held for the 4-week recovery period were observed at least once a day for signs of toxic effects and ocular abnormalities.

BODY WEIGHT: Yes
- Time schedule for examinations: on the morning prior to initiation of the first exposure (day 0); on the morning preceding the second, fifth, sixth, and seventh exposures; immediately prior to sacrifice;
during the 4-week recovery period: animals were weighed once a week and immediately prior to sacrifice

FOOD and WATER CONSUMPTION:
Food and water consumption were measured for 13-15 hours following the eight exposure. Food and water consumption data were not obtained for rats held for recovery.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to first exposure and 1 to 2 days prior to sacrifice
- Dose groups that were examined: animals of all dose groups except for the recovery animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day of sacrifice
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: food was removed at start of the blood collection period; water was supplied ad libitum
- How many animals: 10/sex/group
- Parameters examined: leukocyte count, erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and platelet count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day of sacrifice
- Animals fasted: food was removed at start of the blood collection period; water was supplied ad libitum
- How many animals: 10/sex/group
- Parameters examined: glucose, urea nitrogen, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total protein, albumin, globulin, total bilirubin, direct bilirubin, indirect bilirubin, creatine kinase (CK), lactate dehydrogenase (LD), gamma-glutamyl transferase (GGT), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALK), calcium, phosphorus, sodium, potassium, chloride

URINALYSIS: Yes
- Time schedule for collection of urine: for 13-15 hours following the eight exposure
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters examined: pH, protein, glucose, ketone, bilirubin, blood, and urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
A complete necropsy was performed on each animal. Histologic evaluations were performed on selected tissues from all animals in the control group and in the 600 ppm exposure group. Additionally, one eye per rat of the control, 300 ppm, and 600 ppm exposure groups was randomly selected and embedded in plastic, stained with Periodic Acid-Schiff (PAS), and histologically evaluated. Similar procedures were followed for evaluation of eyes for the control and 600 ppm group rats maintained for the 4-week recovery.
Other examinations:
Organ weights: brain, liver, kidneys, lungs, and heart from all animals and testes from all males were weighed at sacrifice. Organ weights were recorded as absolute weights and as a percentage of body and brain weights.
Statistics:
Results of quantitative continuous variables were intercompared among the 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 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. A t-test was used to compare the control and 600 ppm exposure groups during the recovery period. 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:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
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:
effects observed, treatment-related
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
All animals survived to sacrifice. There were no exposure-related clinical signs observed during the study for either sex of either strain.

BODY WEIGHT AND WEIGHT GAIN
There were no exposure-related effects on absolute body weight or body weight gain during the study.

FOOD and WATER CONSUMPTION
There were some values that were statistically significantly different from controls (food consumption was decreased for 10 ppm female F-344 rats and increased for the 10 and 100 ppm female SD rats; water consumption was increased for the 100 ppm and 600 ppm female SD rats). However, these changes were considered to be spurious and not exposure related.

OPHTHALMOSCOPIC EXAMINATION
There were no exposure-related eye lesions observed during the study.

HAEMATOLOGY
There were no toxicologically significant alterations in hematology parameters for either sex of either rat strain during this study.

CLINICAL CHEMISTRY
There were no toxicologically significant alterations in serum chemistry parameters for either sex of either rat strain during this study.

URINALYSIS
There were no toxicologically significant alterations in urinanalysis parameters for either sex of either rat strain during this study.

ORGAN WEIGHTS
Absolute and relative (both to body and brain weight) liver weights were statistically significantly increased in the 600 ppm male F-344 rats sacrificed at the end of the exposure regimen. The liver/body weight value for the 600 ppm female F-344 rats was also significantly increased. No effects on liver weight occurred in F-344 rats sacrificed at the end of the recovery period.
No exposure-related effects occurred on organ weights of the SD-rats. The decreased absolute and testes/brain weight values for the 600 ppm male SD rats sacrificed at the end of the 4-week recovery period were considered to be spurious changes and not to be exposure related.

GROSS PATHOLOGY
There were no biologically significant macroscopic lesions observed in either strain of rat at necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
The eye was the only site of histologic lesions in this study. Results from SD rats exposed to 300 or 600 ppm Propasol Solvent B were equivical since the incidence of a given lesion often involved either one animal or one more animal was affected than in the control group. This was generally the case for the findings of conjunctivitis and corneal fibroblastic proliferation in SD rats. One female SD rat had a minimal suppurative keratitis (day 11 sacrifice) and one also had a mild corneal fibrosis (day 39 sacrifice). Neither of these changes was observed in the controls, but again they occurred in just a single rat of the 600 ppm group. However, in F-344 rats there appeared to be some mild exposure-related effects. Some effects took the form of a slight exacerbation of changes that were observed to a limited extent in the eyes of control rats. For example, fibroblastic proliferation occurred with an increased incidence and severity in rats exposed to 300 or 600 ppm of Propsaol Solvent B than in control rats. Other effects were manifested as generally mild changes that are usually not found in control rats. For instance, suppurative keratitis occurred in 4 of 20 retas (combined sexes) of the 600 ppm group sacrificed at the end of the exposure regimen. This lesion was not observed in either the control or 300 ppm groups sacrificed at that same period. Suppurative keratitis was not observed in any of the control or 600 ppm groups sacrificed at the end of the 4-week recovery period. Corneal degeneration was also observed in some F-344 rats of the 600 ppm group sacrificed at the end of the exposure regimen and at the end of the 4-week recovery period (8 of 40; primarily females). This lesion was observed in only one control rat.
Dose descriptor:
NOAEL
Effect level:
600 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absolute and/or relative (to body and/or brain) liver weights were increased for the 600 ppm F-344 rats only at the end of the exposure regimen.
Critical effects observed:
not specified
Conclusions:
There were no exposure-related adverse effects. The no observed adverse effect level (NOAEL) is 600 ppm.
Executive summary:

Five groups of male and female Fischer 344 (F-344) and Sprague-Dawley (SD) rats recieved whole-body exposures for 6 hours/day, for 9 days over an 11 -day period, to either filtered air or to vapor of Propasol Solvent B. A portion of the rats from both strains was maintained for a 4 -week recovery period. Analytically-measured mean concentrations of 0, 10.6, 99.5, 289, and 600 ppm were obtained for the respective target concentrations of 0 (control), 10, 100, 300, and 600 (the highest attainable concentration) ppm Propasol Solvent B. Monitors for toxic effects included clinical observations, ophthalmic examinations, food and water consumption, body and organ weights, hematology, erythrocyte osmotic fragility, serum chemistry, urinanalysis, and macroscopic and microscopic evaluations.

There were no exposure-related effects on any of the monitors for toxic effects except liver weights and histologic evaluation of the eyes (0, 300, and 600 ppm group eyes were evaluated). Absolute and/or relative (to body and/or brain) liver weights were increased for the 600 ppm F-344 rats only at the end of the exposure regimen. No histopathologic lesions occurred in the liver. A low incidence of mild eye lesions (corneal degeneration, suppurative keratitis, corneal fibroblastic proliferation) occurred primarily in F-344 rats exposed to 300 or 600 ppm Propasol Solvent B.

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1965
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: non-GLP study similar to OECD guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
not specified
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: n.a.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
31 days
Frequency of treatment:
7 hours/day, 5 days/week
Dose / conc.:
600 ppm (analytical)
No. of animals per sex per dose:
6
Control animals:
yes
Details on study design:
Post-exposure period: no data
Observations and examinations performed and frequency:
no data
Sacrifice and pathology:
The livers and kidneys from all animals were weighed, and these two organs as well as the lungs and abnormally-appearing tissues were sampled for histological examination.
Other examinations:
none
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
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
The only death during this study was a moribund female rat which was killed after 16 days of exposure to the butoxypropanol vapors. Autopsy revealed an acute pneumonia which could not be considered to be of toxic origin.

BODY WEIGHT AND WEIGHT GAIN
The mean body weight gains in the exposed rats did not differ significantly from those of the controls.

FOOD CONSUMPTION
no data

FOOD EFFICIENCY
no data

WATER CONSUMPTION
no data

OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
Erythrocyte fragility values in the exposed rats did not differ significantly from those of the controls.

CLINICAL CHEMISTRY
Hematocrit values in the exposed rats did not differ significantly from those of the controls.

URINALYSIS
no data

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
The mean liver weights of the exposed females were significantly higher (0.01 > P > 0.001), than those of the controls.

PATHOLOGY
The occurrence of gross and microscopic lesions in the exposed rats did not differ significantly from those of the controls.

Dose descriptor:
NOAEL
Effect level:
600 ppm
Sex:
male/female
Basis for effect level:
other: no biologically significant observable adverse effects in rats.
Critical effects observed:
not specified
Conclusions:
The inhalation of 600 ppm butoxypropanol vapor 7 hours per day, 5 days per week for 31 days produced no biologically significant observable adverse effects in rats.
Executive summary:

Groups of six male and six female rats were exposed to a metered concentration of 600 ppm butoxypropanol vapor 7 hours per day, 5 days per week, for a total of 31 exposure days. Control animals of similar weight were exposed to air alone on the same schedule. All animals were weighed twice weekly and immediately before autopsy. At this time, blood was taken from two or three males and females from the exposure and control groups for the determination of hematocrit values and osmotic erythrocyte fragility values. The livers and kidneys from all animals were weighed, and these two organs as well as the lungs and abnormally-appearing tissues were sampled for histological examination.

The only death during this study was a moribund female rat which was killed after 16 days of exposure to the butoxypropanol vapors. Autopsy revealed an acute pneumonia which could not be considered to be of toxic origin. The mean body weight gains, hematocrit values, erythrocyte fragility values and the occurrence of gross and microscopic lesions in the exposed rats did not differ significantly from those of the controls. However, the mean liver weights of the exposed females were significantly higher (0.01 > P > 0.001), than those of the controls.

The inhalation of a metered concentration of 600 ppm butoxypropanol vapor 7 hours per day, 5 days per week for 31 days produced no observable adverse effects in 6 male rats.

The only apparent adverse response of the female rats to the above conditions was a significant rise in their liver weights. The biological significance of this alteration of liver weights cannot be interpreted in terms of organ injury or damage, but it does represent a deviation from the controls.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3 244 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02/1988-03/1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study equivalent to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc., Kingston NY
- Age at study initiation: ca. 8 weeks
- Weight at study initiation: ca. 160 g (males) and ca. 120 g (females)
- Fasting period before study: none
- Housing: Animals were placed in rooms designated to maintain adequate environmental conditions concerning temperature, relative humidity and photocycle for the specific species under test.
- Diet (e.g. ad libitum): ad libitum (except during exposure)
- Water (e.g. ad libitum): ad libitum (except during exposure)
- Acclimation period: at least 2 weeks
Route of administration:
inhalation
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: 157 liter stainless steel and glass exposure chambers
- Source and rate of air: dynamic air flow conditions
- Method of conditioning air: Vapors were generated using a glass J-tube method. Liquid test material was metered into the J-tube. Compressed air, heated with a flameless torch to the minimum extent necessary, passed through the J-tube to volatalize the test material. An additional glass J-tube was inserted to add water vapor to the generating system in an effort to increase the relative humidity in the exposure chambers.
- Temperature, humidity: 22-24°C; 40-60%
- Air flow rate: 30 liter/minute

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytica concentration of PnB in the chamber was determined at least four times/exposure by gas chromatography using a flame ionization detector. The gas chromatographic conditions were: helium flow = 30 ml/min, hydrogen flow = 30 ml/min, air flow = 300 ml/min, oven = 110°C and detector = 190°C. A 6 foot x 1/8 inch nickel column packed with 10% OV-101 on 100/120 mesh Chromosorb WHP was used for seperation of the test material from air.
Duration of treatment / exposure:
2 weeks (9 exposure)
Frequency of treatment:
6 h daily, 5 days/week
Dose / conc.:
50 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
200 ppm (nominal)
Remarks:
Basis:
nominal conc.
Dose / conc.:
700 ppm (nominal)
Remarks:
Doses / Concentrations:
700 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Dose selection rationale: the highest exposure concentration was the maximum concentration that could be practically attained.
- Rationale for animal assignment: random
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE and CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for overt signs of toxicity or changes in demeanor. These observations included an evaluation of the fur, eyes, mucous membranes and respiration. Behaviour pattern and nervous system activity was assessed by specific observations for lethargy, tremors, convulsions, salivation, lacrimation, diarrhea and other signs of altered central nervous system function. An additional dailt observation and routine monitoring on weekends was limited to animal husbandry procedures required to ensure the availability of food and water.

BODY WEIGHT: Yes
- Time schedule for examinations: all animals were weighed on test days 1, 3, 5, 8, and 11.

FOOD CONSUMPTION:
No data

FOOD EFFICIENCY:
No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: each animal received a pen-light ophthalmological examination prior to the initial exposure and after the final exposure to PnB.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to necropsy
- Anaesthetic used for blood collection: Yes (methoxyflurane)
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: hematocrit (HCT), hemoglobin (HGB), erythrocyte count (RBC), total leukocyte counts and red blood cell morphology were prepared and evaluated by light microscopy for each animal.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the terminal sacrifice
- Animals fasted: No data
- How many animals: all animals
- Parameters examined: urea nitrogen (UN), alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), alkaline phosphatase activity (AP), glucose (GLUC), total protein (TP), albumin (ALB), globulin (GLOB, calculated), total bilirubin (TBILI), cholesterol (CHOL), triglycerides (TRIG), phosphorus (PHOS), calcium (CALC), sodium (Na), potassium (K) and chloride (CL).

URINALYSIS: Yes
- Time schedule for collection of urine: during the second week of exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: bilirubin, glucose, ketones, blood, pH, protein, urobilinogen, pecific gravity and microscopic examinations were made on sediments from samples pooled by exposure group.

NEUROBEHAVIOURAL EXAMINATION: Yes
Behaviour pattern and nervous system activity was assessed by specific observations for lethargy, tremors, convulsions, salivation, lacrimation, diarrhea and other signs of altered central nervous system function.

Sacrifice and pathology:
All animals were fasted over night and were necropsied the day following the last exposure to the test material. Each animal was weighed, anesthetized with methoxyflurane, sampled for hematology and clinical chemistry and humanely euthanized. All animals were examined for gross pathological alterations by a veterinary pathologist and weights of the brain, heart, liver, kidneys, adrenals and testes were recorded from all animals. The necropsy included in situ examination of the eyes using a moistened glass slide pressed against the corneal surface. A complete set of tissues was collected from each animal and preserved in neutral, phosphate-buffered 10% formaline. Following examination, the lungs were distended with buffered formalin to their approximate normal inspiratory volume. The nasal cavity was flushed with formalin via the pharyngeal duct to insure rapid fixation. A complete histopathological examination of tissues (except for auditory sebaceous galnds) was made from all animals in the control and highest exposure group. Tissues examined histopathologically were processed by conventional techniques, sectioned at approximately 6 µ, stained with hematoxylin and eosin and evaluated by light microscopy. No tissues were examinated histologically from rats exposed to 50 or 200 ppm PnB.
Statistics:
Descriptive statistics (means and standard deviations) were used to report chamber concentrations, chamber temperature, and relative humidity, and white blood cell differential counts. All remaining parameters examined statistically were first tested for equality of variance using Bartlett's test. If the results from Bartlett's test rejected the equality of variances, the parameter was flagged for careful evaluation of results. All parameters were then subjected to approriate parametric analysis as described below. In-life body weights, hematologic (excluding differential WBC) and clinical chemistry parameters, terminal body weights, organ weights (absolute and relative except testes) and urine specific gravities were evaluated using a two-way analysis of variances (ANOVA) with the factors of sex and dose. Results for absolute and relavtive testes weights were analysed using a one-way ANOVA. If significant dose effects were determined in the one-way ANOVA, then separate doses were compared to controls using Dunnett's test. For those parameters examined by a two-way ANOVA, examination was first for a significant sex-dose interaction. If this existed, a one-way ANOVA was done separately for each sex. If no sex-dose interaction was identified, and a dose effect was identified, or if in the subsequent ANOVA's separated by sex a dose effect was identified, then separate ANOVA's were used for each exposure group with control. To control for multiple comparisons with control, a Bonferroni correction was used.
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):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
effects observed, treatment-related
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
All rats survived until the scheduled necropsy with no clinical signs attributed to exposure to the test material.

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of male and female rats were not adversely affected by exposure to PnB.

FOOD CONSUMPTION
no data

FOOD EFFICIENCY
no data

WATER CONSUMPTION
no data

OPHTHALMOSCOPIC EXAMINATION
A minor ocular change (hazy corea) was observed in the left eye of one male rat at 700 ppm just prior to necropsy. No other ophthalmologic changes were detected in any other animal.

HAEMATOLOGY
There were no adverse effects on hematologic parameters in male and female rats following exposure to PnB. In addition, the mean differntial leukocyte counts for male and female rats were similar to controls at all concentrations.

CLINICAL CHEMISTRY
A statistically significant decrease in total protein (TP) was observed in serum of both sexes (3.3% for males and 1.8% for females) at the lowest concentration. A statistically significant increase was also observed in blood glucose in both sexes (6.5% for males and 10.7% for females) at the highest concentration.

URINALYSIS
A statistically significant, but minimal increase in urine specific gravity was noted in both sexes at the highest concentration. All other urinary parameters were comparable to controls.

ORGAN WEIGHTS
Statistically significant increased relative but not absolute liver weights were noted in both sexes (6.7% for males and 6.5% for females) exposed to 700 ppm PnB. No effects were observed in any other organ weight.

PATHOLOGY
Microscopic examination of full sets of tissues from control and high exposure animals revealed no treatment-related effects. The few changes were generally of a minimal degree and occurred in similar incidences in both the controls and the exposed groups. These changes were considered typical of spontaneous lesions frequently noted in rats of this strain and age. Consequently, tissues were not examined from male and female rats exposed to 50 and 200 ppm PnB.

The hazy cornea of one eye observed in male rats exposed to 700 ppm PnB during the ophthalmic exam was confirmed at necropsy. Histologically, there was evidence of inflammation and mineralization of the cornea.
Dose descriptor:
NOAEL
Effect level:
> 700 ppm
Sex:
male/female
Basis for effect level:
other: highest attainable concentration.
Dose descriptor:
LOAEL
Effect level:
> 700 ppm
Sex:
male/female
Basis for effect level:
other: highest attainable concentration.
Critical effects observed:
not specified
Conclusions:
The observed adverse effect level (NOAEL) after 9-days of exposure to PnB is 700 ppm which was the highest attainable concentration.
Executive summary:

Whole-body exposures of male and female Fischer 344 (5 per sex and group) rats to targeted concentrations of 0, 50, 200 or 700 ppm (0, 0.27, 1.08 or 3.78 mg/l) PnB vapors resulted in no adverse effects following 9 exposures, each of six hours duration. The highest exposure concentration was the maximum that could be practically attained. Each animal was evaluated for changes in body weight, clinical chemistry, haematology, urinalysis, clinical observations, selected organ weights, and gross and histopathological evaluations.

The only effect noted was a slightly increased realtive liver weight in both sexes exposed to 700 ppm PnB. However, this was unaccompanied by any histologic lesions or change in clinical chemistry parameters reflective of hepatic dysfunction. Therefore, this minimal effect on liver weight was considered to be of no toxicicologic significance.

In summary, there were no adverse effects ascribed to the inhalation of up to 700 ppm PnB, six hours/day for nine exposures over two weeks. Based on the low biological activity and moderate vapor pressure, PnB is expected to have a low potential for adverse effects following short-term exposure.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
3 244 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
06/1987-04/1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann - Institute for the Breeding of Laboratory Animals GmbH & Co. KG, Borchen West-Germany
- Age at study initiation: ca. 10 weeks
- Weight at study initiation: Males: 249 ± 2.9 grams; Females: 173 ± 1.5 grams.
- Fasting period before study: none
- Housing: individually in suspended stainless steel cages fitted with wire-screen floor, sides and front
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 40-85%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
open
Vehicle:
propylene glycol
Details on exposure:
TEST SITE
- Area of exposure: dorsal trunk of each rat
- coverage: area for dermal application was ca. 25-40 cm2)
- Type of wrap if used: no wrap (rats wore collars to prevent grooming and ingestion of test material)
- Time intervals for shavings or clipplings: weekly (every Friday)

REMOVAL OF TEST SUBSTANCE
- Contact time was 24 hr/day (skin was cleaned shortly before daily treatment).

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 1 ml
- Concentration (if solution): 6.3%, 16.7% and 40.0% (v/v) PnB in propylene glycol
- Constant volume or concentration used: yes (constant volume)

VEHICLE
- Justification for use and choice of vehicle (if other than water): good solubilty of PnB in propylene glycol

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (collars)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The content of PnB was determined in the solutions prepared on 1-6-87, 12-6-87, 10-7-87 and 24-7-87. The left overs of the test solutions prepared on 10-7-87 were reanalyzed after storage for 2 weeks under the epxerimental conditions, in order to determine the stability of PnB in the test solutions. The analyses were carried out at TNO, Institute CIVO-Analysis.

Samples were diluted with acetone and a known amount of the solution was injected in a gas chromatographic column. Detection was performed by means of a flame ionization detector. Quantitation was performed by means of a calibration curve of Propylene Glycol n-Butyl Ether.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
Once daily, 5 days/week
Dose / conc.:
0.1 other: ml/kg bw
Remarks:
Basis: nominal per unit body weight
Dose / conc.:
0.3 other: ml/kg bw
Remarks:
Basis: nominal per unit body weight
Dose / conc.:
1 other: ml/kg bw
Remarks:
Basis: nominal per unit body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: since PnB is considered a substance of low toxicity, a top dose level of 1 ml PnB/kg body weight was chosen.
- Rationale for animal assignment (if not random): Computerized, random number-based procedure.
- Post-exposure recovery period in satellite groups: no
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed daily and all signs of ill health and reaction to treatment were recorded.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Rats were observed for clinical signs of toxicity on a daily basis (week days).

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Rats were observed for skin reactions on a daily basis (week days).

BODY WEIGHT: Yes
- Time schedule for examinations: The individual body weights of all rats were recorded initially, and once every week thereafter. In addition, females were weighed on day 92 in order to calculate the correct organ to body weight ratios at the day of autopsy.

FOOD CONSUMPTION:
- Food intake was measured per animal weekly, and the efficiency of food utilization was calculated and expressed as gram weight gain per gram food consumed.

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at the beginning (day 0) and at the end of the (day 87)
- Dose groups that were examined: all rats of the control group and the high-dose group

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 85 (males) and day 86 (females)
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all surviving animals in the study
- Parameters examined: haemoglobin, packed cell volume, red blood cells, white blood cells, differential white blood cell count, thrombocytes, prothrombin time, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 88 (for glucose determination) and at autopsy (day 91 for males, day 92 for females)
- Animals fasted: Yes for glucose determination (24 h depriviation of water and 16 h depriviation of food)
- How many animals: all surviving animals in the study
- Parameters examined: alkaline phosphatase activity (ALP), glutamic-oxalacetic-transaminase (GOT)/aspartate amino transferase (ASAT) activity, glutamic-pyruvic transaminase (GPT)/alanine aminotransferase (ALAT) activity, gamma glutamyl transpeptidase activity, total protein, albumin, albumin/globulin ratio, urea, creatinine, bilirubin total, cholesterol, triglycerides, sodium (Na), potassium (K), calcium (Ca), chloride (Cl), inorganic phosphate

URINALYSIS: Yes
- Time schedule for collection of urine: day 88
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes (deprived of water for 24 hours and of food for 16 hours, urine collected during last 16 hours of depriviation period)
- Parameters examined: in individual samples (volume, density) and in pooled samples - one sample per sex per group (appearance, pH, protein, glucose, occult blood, ketones, bilirubin, uribilinogen, erythrocytes, leucocytes, epithelial cells, amorph material, crystals, casts, bacteria, sperm cells and worm eggs)

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
At sacrifice, all animals were subjected to complete necropsy. An extensive list of tissues was preserved from all animals and histopathological evaluations of these tissues were conducted on control and high dose animals.
Other examinations:
none
Statistics:
Data on body weights were evaluated by one-way analysis of co-variance followed by Dunnett's multiple comparison test. Data on food intake, food efficiency, red blood cell variables, total white blood cells, clinical chemistry values, volume and density of the urine, and organ weights were evaluated by one-way analysis of variances (ANOVA) followed by Dunnett's multiple comparison test. Differential white blood cell counts were analysed by the Mann-Whitney U-test. The results of ophthalmoscopic and microscopic examinations were analysed by Fisher's exact probability test.
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
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:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
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 deaths and no changes in clinical observations

BODY WEIGHT AND WEIGHT GAIN
no changes observed

FOOD CONSUMPTION
no changes observed

WATER CONSUMPTION
no data

OPHTHALMOSCOPIC EXAMINATION
no changes observed

HAEMATOLOGY
no changes observed

CLINICAL CHEMISTRY
no changes observed

URINALYSIS
no changes observed

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
In females at the high dose level, relative but not absolute heart weights were slightly but statistically significant increased. Because no clinical chemistry or histopathology indicated damage to the heart, the authors considered increased relative weights to be a spurious finding without toxicological significance.

GROSS PATHOLOGY
no changes observed

HISTOPATHOLOGY: NON-NEOPLASTIC
no changes observed

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
no changes observed

OTHER FINDINGS
Skin at the site of application showed irritation in all treatment groups including PG-controls. Skin lesions were characterized by focal necrosis of the epidermis, crust formation, mild inflammatory changes and acanthosis. While the severity of these lesions was higher in PnB-treatment groups than in the PG-control, the differences were not statistically significant and did not show a dose-response effect. Untreated skin was unaffected (one mid-dose male and one high-dose male showed “very slight” acanthosis). The authors considered skin lesions to be a direct, local effect from the solvents and the clipping procedure.
Dose descriptor:
NOAEL
Effect level:
880 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no biologically significant observable adverse effects in rats.
Critical effects observed:
not specified
Conclusions:
The systemic toxicity NOAEL for PnB is 1.0 ml/kg-day, or 880 mg/kg-day, and the LOAEL was not established in this study.
Executive summary:

Propylene glycol n-butyl ether (PnB) was applied daily (5 days/week) for 13 weeks to the skin of four groups of Wistar
rats (10/sex/dose level) at various dilutions in propylene glycol (PG) equivalent to doses of 0 (PG-only; 1.5 ml/kg-day), 0.1, 0.3, or 1.0 ml PnB/kg-day. These doses equate to 0, 88, 264, or 880 mg PnB/kg-day. Treatment
solutions were applied to the clipped dorsal trunk of each rat. Dilutions of PnB in PG resulted in applied volumes of 1.5 to 2.5 ml test solution per kg body weight. Rats wore collars to prevent grooming and ingestion of test material. Solutions were applied unoccluded since the low vapor pressure of PnB and PG precluded evaporative loss. Contact time was 24 hr/day (skin was cleaned shortly before daily treatment). 

Rats were observed for clinical signs of toxicity and skin reactions on a daily basis (week days). Body weights and
food consumption were monitored weekly. Ophthalmological examinations were conducted in control and high dose
subjects prior to treatment and on day 87 of the study. Hematology, clinical chemistries, and urinalyses were
conducted at the end of the treatment period. At sacrifice, all animals were subjected to complete necropsy. An extensive list of tissues was preserved from all animals and histopathological evaluations of these tissues were conducted on control and high dose animals. 

Skin at the site of application showed irritation in all treatment groups including PG-controls.  Skin lesions were
characterized by focal necrosis of the epidermis, crust formation, mild inflammatory changes and acanthosis.  While
the severity of these lesions was higher in PnB-treatment groups than in the PG-control, the differences were not
statistically significant and did not show a dose-response effect.  Untreated skin was unaffected (one mid-dose male
and one high-dose male showed "very slight" acanthosis).  The authors considered skin lesions to be a direct, local
effect from the solvents and the clipping procedure.

No changes were observed in clinical observations, food consumption, body weights, ophthalmology, hematology,
clinical chemistries, urinalyses, or gross lesions/histopathology (other than skin).  In females at the
high dose level, relative but not absolute heart weights were slightly but statistically increased.  Because no clinical chemistry or histopathology indicated damage to the heart, the authors considered increased relative weights to be a spurious finding without toxicological significance. 
This study established a systemic toxicity NOAEL for PnB of 1.0 ml/kg-day (880 mg/kg-day).  A LOAEL for systemic
toxicity was not established.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
880 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
good

Additional information

Oral

Key study - 13 week drinking water study in rats (F344)

Four groups of Fischer 344 rats (10/sex/dose level) received propylene glycol n-butyl ether (PnB) in their drinking water  at concentrations equivalent to target doses of 0, 100, 350, or 1000 mg/kg-day for 13 weeks.  Two additional groups of 10/sex/dose receiving 0 or 1000 mg/kg-d for 13 weeks, were administered untreated water for four weeks following the 13-week exposure period in order to evaluate recovery.  Rats were observed for clinical signs of toxicity on a daily basis (week days).  Body weights, water, and food consumption were monitored weekly.  Functional observational battery evaluations were conducted prior to treatment and at monthly intervals during treatment.  Ophthalmological examinations were conducted prior to treatment and at sacrifice.  Hematology, electrolytes, and clinical chemistries were evaluated at sacrifice and urinalyses were conducted one week prior to sacrifice.  At sacrifice, all control and high dose animals were subjected to complete necropsy and histopathological evaluations.  Selected organs evaluated histologically in lower dose subjects included liver, kidneys, adrenal glands, lungs, testes, and, potentially, other target organs identified in high dose animals. 

Concentrations of PnB in drinking water were targeted to correspond to nominal doses of 0, 100, 350, or 1000 mg/kg-day.  These concentrations were based on anticipated drinking water consumption volumes by the test animals.  When the measured concentration of PnB in the treatment water was multiplied by the amount of water actually consumed, the actual dose of PnB was higher than the target doses (by a factor of 10-15%).  However, wastage may have occurred that would reduce the dose and offset the 10-15% increased dose factor.

Absolute and relative liver weights were increased in high dose males with no accompanying histopathology. In females at the high dose level, absolute and relative kidney weights were increased with no accompanying histopathology.  Slight alterations in clinical chemistries, electrolytes, and hematology also were noted in both sexes at the high dose level. No changes in any other monitored parameters were noted at any dose level. 

The NOAEL for PnB is 350 mg/kg-day and the LOAEL is 1000 mg/kg-day (for organ weight changes). 

Supporting study - 14d  

A pilot study was conducted prior to this main study in order to select dose levels.  Two rats/sex/dose level were administered 0, 200, 500, or 1000 mg PnB/kg-day orally (gavage) for eight consecutive days.  One male from the 500 mg/kg-day group died on day 6 and one female from the 1000 mg/kg-day group died on day 2.  Signs of toxicity included lethargy, bloody eye encrustation, and gasping or rattled respiration.  Surviving subjects recovered from these signs by day 4.  Hematology and clinical chemistry parameters were unaffected.  In the non-surviving male, necropsy revealed hemorrhages of the lungs and intestines while the female showed gas accumulation, yellow-reddish contents, and hemorrhage.

Four groups of Sprague-Dawley rats (6/sex/dose level) received propylene glycol n-butyl ether (PnB) by gavage at doses of 0, 100, 200, or 400 mg/kg-day for 14 consecutive days. PnB was diluted in pharmacological grade propylene glycol to achieve the desired dosing volume. The negative controls (0 dose group 1) received propylene glycol only.

Rats were observed for mortality and clinical signs of toxicity once per day.  Once weekly, animals were given a more detailed clinical examination.  Body weights and food consumption were monitored weekly.  Hematological evaluations were conducted on day 7 (blood collected from orbital sinus) and day 14 (from aorta).  On day 14, additional blood was collected at sacrifice for clinical chemistries.  At sacrifice, all rats were subjected to complete necropsy and the following organs/tissues were collected, weighed, and preserved: liver, spleen, kidneys, adrenals, heart, testes, ovaries, and abnormal tissues.  These tissues were processed into slides for the control and high dose animals and examined microscopically.     Blood parameters measuring erythrocyte fragility were monitored due to the ability of ethylene glycol n-butyl ether to cause red cell hemolysis in rats at relatively low doses (e.g. 30 mg/kg).  Thus, osmotic fragility, hematocrit, mean corpuscular hemoglobin, and other erythrocyte parameters were recorded.

No mortality or clinically observable signs of toxicity were observed in any of the subjects.  Body weights, organ weights/ratios, food consumption, and clinical chemistries were unaffected by PnB treatment.  No effects on hematology, particularly for erythrocytes (including osmotic fragility), were detected.  Gross or microscopic pathology revealed no test substance related changes.

Summary of oral toxicity data:

Based on the 13 week drinking water study in rats, the oral NOAEL is determined to be 350 mg/kg bw/day based on organ weight changes observed at higher doses (increases in liver and kidney weights). In addition it is noted that unlike ehtylene glycol butyl ether, propylene glycol butyl ether does not cause hemolysis of red blood cells.

Inhalation

31-day inhalation study in rats:

A single dose group of six male and six female rats was exposed to a metered concentration of 600 ppm propylene glycol n-butyl ether vapor 7 hours per day, 5 days per week, for a total of 31 exposure days. Control animals of similar weight were exposed to air alone on the same schedule. All animals were weighed twice weekly and immediately before autopsy. At this time, blood was taken from two or three males and females from the exposure and control groups for the determination of hematocrit values and osmotic erythrocyte fragility values. The livers and kidneys from all animals were weighed, and these two organs as well as the lungs and abnormally-appearing tissues were sampled for histological examination.

The only death during this study was a moribund female rat which was killed after 16 days of exposure to the propylene glycol n-butyl ether vapors. Autopsy revealed an acute pneumonia which could not be considered to be of toxic origin. The mean body weight gains, hematocrit values, erythrocyte fragility values and the occurrence of gross and microscopic lesions in the exposed rats did not differ significantly from those of the controls. However, the mean liver weights of the exposed females were significantly higher (0.01 > P > 0.001), than those of the controls.

The inhalation of a metered concentration of 600 ppm propylene glycol n-butyl ether vapor 7 hours per day, 5 days per week for 31 days produced no observable adverse effects in 6 male rats.

The only apparent adverse response of the female rats to the above conditions was a significant rise in their liver weights. The biological significance of this alteration of liver weights cannot be interpreted in terms of organ injury or damage, but it does represent a deviation from the controls.

2-week inhalation study in rats (Fisher 344):

Whole-body exposures of male and female Fischer 344 (5 per sex and group) rats to targeted concentrations of 0, 50, 200 or 700 ppm (0, 0.27, 1.08 or 3.78 mg/l) propylene glycol n-butyl ether vapors resulted in no adverse effects following 9 exposures, each of six hours duration. The highest exposure concentration was the maximum that could be practically attained. Each animal was evaluated for changes in body weight, clinical chemistry, haematology, urinalysis, clinical observations, selected organ weights, and gross and histopathological evaluations.

The only effect noted was a slightly increased realtive liver weight in both sexes exposed to 700 ppm PnB. However, this was unaccompanied by any histologic lesions or change in clinical chemistry parameters reflective of hepatic dysfunction. Therefore, this minimal effect on liver weight was considered to be of no toxicicologic significance.

In summary, there were no adverse effects ascribed to the inhalation of up to 700 ppm propylene glycol n-butyl ether, six hours/day for nine exposures over two weeks. Based on the low biological activity and moderate vapor pressure, propylene glycol n-butyl ether is expected to have a low potential for adverse effects following short-term exposure.

2-week inhalation study in rats (F344 and Sprague dawley):

Five groups of male and female Fischer 344 (F-344) and Sprague-Dawley (SD) rats recieved whole-body exposures for 6 hours/day, for 9 days over an 11 -day period, to either filtered air or to vapor of propylene glycol n-butyl ether. A portion of the rats from both strains was maintained for a 4 -week recovery period. Analytically-measured mean concentrations of 0, 10.6, 99.5, 289, and 600 ppm were obtained for the respective target concentrations of 0 (control), 10, 100, 300, and 600 (the highest attainable concentration) ppm propylene glycol n-butyl ether. Monitors for toxic effects included clinical observations, ophthalmic examinations, food and water consumption, body and organ weights, hematology, erythrocyte osmotic fragility, serum chemistry, urinanalysis, and macroscopic and microscopic evaluations.

There were no exposure-related effects on any of the monitors for toxic effects except liver weights and histologic evaluation of the eyes (0, 300, and 600 ppm group eyes were evaluated). Absolute and/or relative (to body and/or brain) liver weights were increased for the 600 ppm F-344 rats only at the end of the exposure regimen. No histopathologic lesions occurred in the liver. A low incidence of mild eye lesions (corneal degeneration, suppurative keratitis, corneal fibroblastic proliferation) occurred primarily in F-344 rats exposed to 300 or 600 ppm propylene glycol n-butyl ether.

Summary of inhalation data:

The toxicological findings via inhalation are consistent with those following oral exposure, with the target organs appearing to be the liver and to a lesser extent the kidneys. Increases in the weight of these organs with minimal histopathological correlates were observed across the 3 studies. The effects on the liver do not appear to increase in severity as the dosing duration is increased from 9 days to 31 days, providing support for the conclusion that the effects are likely to be adaptive ratehr than adverse. It is also noteworthy that there is minimal inter strain difference in the repeated dose inhalation toxicity of propylene glycol n-butyl ether. Based on these data, a NOAEC for inhalation appears to be approximately 600ppm for systemic toxicity.

Dermal

13 week study in rats (Wistar)

Propylene glycol n-butyl ether (PnB) was applied daily (5 days/week) for 13 weeks to the skin of four groups of Wistar rats (10/sex/dose level) at various dilutions in propylene glycol (PG) equivalent to doses of 0 (PG-only; 1.5 ml/kg-day), 0.1, 0.3, or 1.0 ml PnB/kg-day. These doses equate to 0, 88, 264, or 880 mg PnB/kg-day. Treatment solutions were applied to the clipped dorsal trunk of each rat. Dilutions of PnB in PG resulted in applied volumes of 1.5 to 2.5 ml test solution per kg body weight. Rats wore collars to prevent grooming and ingestion of test material. Solutions were applied unoccluded since the low vapor pressure of PnB and PG precluded evaporative loss. Contact time was 24 hr/day (skin was cleaned shortly before daily treatment).   Rats were observed for clinical signs of toxicity and skin reactions on a daily basis (week days). Body weights and food consumption were monitored weekly. Ophthalmological examinations were conducted in control and high dose subjects prior to treatment and on day 87 of the study. Hematology, clinical chemistries, and urinalyses were conducted at the end of the treatment period. At sacrifice, all animals were subjected to complete necropsy. An extensive list of tissues was preserved from all animals and histopathological evaluations of these tissues were conducted on control and high dose animals. 

Skin at the site of application showed irritation in all treatment groups including PG-controls.  Skin lesions were characterized by focal necrosis of the epidermis, crust formation, mild inflammatory changes and acanthosis.  While the severity of these lesions was higher in PnB-treatment groups than in the PG-control, the differences were not statistically significant and did not show a dose-response effect.  Untreated skin was unaffected (one mid-dose male and one high-dose male showed "very slight" acanthosis).  The authors considered skin lesions to be a direct, local effect from the solvents and the clipping procedure.

No changes were observed in clinical observations, food consumption, body weights, ophthalmology, hematology, clinical chemistries, urinalyses, or gross lesions/histopathology (other than skin).  In females at the high dose level, relative but not absolute heart weights were slightly but statistically increased.  Because no clinical chemistry or histopathology indicated damage to the heart, the authors considered increased relative weights to be a spurious finding without toxicological significance.  This study established a systemic toxicity NOAEL for PnB of 1.0 ml/kg-day (880 mg/kg-day).  A LOAEL for systemic toxicity was not established.

91-day study in rabbits (NZW)

There is minimal data available on this study as it was available only in an abstract. Groups of 5 male and female rabbits were exposed either to water or to 2 ml/kg bw propylene glycol n-butyl ether (unnoccluded) for 7 hours per day, 5 days per week for a total study period of 91 days. The study evaluated in-life clinical signs, in-life body weight changes, terminal organ weights, hematology, and gross and microscopic pathology.

With the exception of moderate irritation at the application ste, there were no adverse observations recorded. The NOEL for systemic toxicity from this study is therefore 2ml/kg bw/day or approximately 1760 mg/kg bw/day (adjusting for density).

Summary of dermal data:

Exposure to propylene glycol n-butyl ether via the dermal route resulted in minmal systemic toxicological findings in both rats and rabbits. The only conisstent treatment effect observed was irritation at the site of test material application.

Based on these data the Dermal NOAEL is considered to be 880 mg/kg bw/day.

Justification for classification or non-classification

The no observed adverse effect levels for propylene glycol n-butyl ether exceed the values triggering classification via all routes of exposure. Therefore no classification for prolonged exposure is required.