Propan-2-ol

Endpoint summary

Description of key information

GLP-guideline study according to OECD guideline 451 in rats is available for IPA. The derived NOAEC is 5000 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented, according to accepted guidelines

Qualifier:

according to guideline

Guideline:

other: OECD 451

Deviations:

yes

Remarks:

Not monitoring food consumption

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague Dawley Inc. Indianapolis, IN
- Age at study initiation: 28-30 days old
- Weight at study initiation: 121.2-165 g (males) and 93.6 - 124.3 g (females) on the first day of exposure
- Fasting period before study: None
- Housing: 2 per cage in stainless steel, wire mesh cages
- Diet (e.g. ad libitum): Pelleted, certified AGWAY PROLAB animal diet rat 3000 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature : 17 - 26 °C
- Humidity (%): 40-70
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12-12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: Not reported

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation chamber (Wahmann Manufacting company, Timonium, MD)
- System of generating particulates/aerosols: liquid isopropanol was metered from a container by piston pump
- Temperature in air chamber: 22 +/- 4 degrees
- Air flow rate: 1000 l/min for first month and 900 l/min thereafter
- Air change rate: 14 air changes/hr for first month and 12.5 air changes/hr thereafter
- Method of particle size determination: not reported
- Treatment of exhaust air: not reported


TEST ATMOSPHERE
- Brief description of analytical method used: liquid isopropanol was metered from a container by piston pump into a heated glass evaporator and the temperature of the evaporators was maintained at the lowest level to sufficiently vaporize the test substance.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Each exposure chamber was analyzed for isopropanol twice each hour by flame ionization gas chromatography.

Duration of treatment / exposure:

at least 104 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Remarks:

Doses / Concentrations:
0, 500, 2500, 5000 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

65 sex/dose for the core group and 10 sex/dose for the interm sacrifice

Control animals:

yes, sham-exposed

Details on study design:

- Rationale for animal assignment (if not random): animals were assigned to 3 exposure groups and a control group using a sacrificed randomization procedure based on body weight
- Rationale for selecting satellite groups: 10 sex/group were sacrified in the middle of the study

Positive control:

None

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 14 weeks and then every other week after

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to experiment, and during weeks 71, 80, 104, and 107
- Dose groups that were examined: all rats


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 13 months, 19 months, and 25 months
- Anaesthetic used for blood collection: Yes (identity) methoxyflurane
- Animals fasted: No
- How many animals: 10 sex/dose level

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 57
- Animals fasted: No
- How many animals: 10 sex/dose group

URINALYSIS: Yes
- Time schedule for collection of urine: week 57, 59, 74, and 104
- Metabolism cages used for collection of urine: No
- Animals fasted: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

None

Statistics:

The data for the 3 treatment groups and the control group were compared with Levene's test for equality of variances, analysis of variance (ANOVA), and t-tests. The nonparmetric data were statistically evaluated with the Kruskal-Wallis test followed by the Mann-Whitney U-test. Mortality was analysed by life-table analyses. Incidence data were compared using Fishers exact test.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
- Mortality rates for males in the 0, 500, 2500, and 5000 ppm groups were 82, 83, 91, and 100%, respectively. For females, 54, 48, 55, and 69%. No significant differences were noted for male rats from 500 or 2500 groups or any female rats.
-In males and females exposed to 5000 ppm; hypoactivity, lack of a startle reflex, and narcosis were identified. In males and females exposed to 2500 ppm; hypoactivity, and a lack of a startle reflex were observed. No effects in 500 ppm group. During non-exposure periods in males 5000 ppm group emaciation and dehydration was observed. In males and females in 5000 ppm there was greater numbers of rats with urine stains and swollen periocular tissue (females only). Females in the 2500 ppm group also had increased incidence of urine stains.

BODY WEIGHT AND WEIGHT GAIN
-Decreased body weights were observed for male rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 6 body weights were increased significantly over the control group. Increased body weights were also noted for male rats from the 2500 ppm group.
-Decreased body weights were observed for female rats from the 5000 ppm group in the first and second weeks of exposure, and then increased and at the end of week 5 body weights were increased significantly over the control group. Increased body weights were also noted for female rats from the 500 ppm group. At week 72, all female body weights were significantly increased when compared to the control group.

URINALYSIS
-In males in the 5000 ppm group, in weeks 57, 59, 74, and 104 decrease in osmolality and increase in total protein and total volume were reported.
-In females rats in the 5000 ppm group, a decrease in osmolality and an increase in total volume was reported. At week 74, total glucose excreted in the urine was increased for females in the 5000 ppm group.


ORGAN WEIGHTS
- At the interim sacrifice, absolute and relative kidney weights were increased for male rats in the 5000 ppm group. Relative liver weights were increased for male rats in the 2500 ppm group. Concentration-related increases in absolute and relative testes weight was reported for male rats in 5000 ppm group. In females, increases in absolute and relative lung weight for rats in the 5000 ppm was reported.
-At the terminal sacrifice, increase in relative liver weight was noted for male rats in 2500 ppm group. In females, an increase in absolute and relative liver and kidney weights were noted for the 5000 ppm group.


GROSS PATHOLOGY
- At the interim sacrifice, an increase in granular kidneys in male rats from the 2500 and 5000 ppm groups were noted
- At the terminal sacrifice, an increase in granular kidneys in male rats from the 2500 ppm group was noted. Increased frequencies of gross lesions for male rats that died included increase incidence of thickened stomachs, granular kidneys, and color change of the kidneys for animals in 2500 and 5000 ppm groups.
- For females that died before the end of the study, an increased incidence of thickened stomachs was noted for animals from the 5000 ppm group and granular kidneys were noted for animals from the 2500 and 5000 ppm groups.


HISTOPATHOLOGY: NON-NEOPLASTIC
- At the interim sacrifice, male rats from the 5000 ppm group had an increased frequency of testicular seminiferous tubule atrophy.
-Increased frequencies of kidney lesions were observed in male rats in the 2500 and 5000 dose groups that died during the study. Increased in the frequency of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs, kidney, cornea, and testes was noted for male rats in the 2500 and 5000 ppm dose groups that died during the study. Additionally, basophilic cell foci in the liver, splenic hemosiderosis, rhinitis, and squamous metaplasisa of the respiratory epithelium in the nasal cavity were reported for male rats in the 5000 ppm group that died during the study.
-Increased severity of glomerulosclerosis was observered in female rats in the 5000 ppm group. Renal disease was also increased in female rats in the 5000 ppm group.
- For female rats that died during the study, increased frequencies of mineralization in the heart, aorta, vasculature, stomach, larynx, trachea, lungs and kidney. Increase in myocardial degeneration, atrial thrombosis, splenic hemosiderosis, ocular keratitis, inflammatory and metaplastic changes in the nasal cavity, squamous metaplasia of the respiratory epithelium and glandular ectasia in the gastric mucosa was also evident in females in the 5000 ppm group that died during the study.


HISTOPATHOLOGY: NEOPLASTIC (if applicable)
-Dose-related increase in interstitial cell adenomas of the testis in male rats at interim sacrifice, at the terminal sacrifice, and in male rats that died during the study.

Dose descriptor:

NOEC

Effect level:

500 ppm

Sex:

male/female

Basis for effect level:

other: for species specific toxic effects

Dose descriptor:

NOAEC

Effect level:

5 000 ppm

Basis for effect level:

other: The report allows the conclusion that there are no substance specific adverse exposure related effects. A NOAEL of 5000 ppm can be derived.

Dose descriptor:

NOEC

Effect level:

5 000 ppm

Sex:

male/female

Basis for effect level:

other: for oncogenicity effects

Critical effects observed:

not specified

Executive summary:

The inhalation toxicity of IPA has been assessed in a 104-week oncogenicity study in rats (Burleigh-Flayer and Benson, 1994). This GLP study was conducted according to OECD test guideline 451.  IPA was administered by whole-body inhalation to groups of male and female Fischer 344 rats (75 rats/sex) for6 hours/day 5 days/weekfor at least 104 weeks at nominal concentrations of 0 (control), 500, 2500, or 5000 ppm (measure concentrations of0, 504, 2509, or 5031 ppm, respectively).  Ten rats/sex/group were assigned to interim sacrifice at Week 73. Animals were monitored for clinical observations, body and organ weights, ophthalmology examinations, hematology, urinalysis and urine chemistry examinations, gross pathology and microscopic examinations.

Exposure of rats to IPA vapour for 104 weeks produced clinical signs of toxicity (including hypoactivity, lack of startle reflex, and/or narcosis), changes in body weight, and urinalysis and urine chemistry indicative of kidney changes (decrease in osmolality and increase in total volume and/or protein) in the 2500 and 5000 ppm groups. At terminal sacrifice, increased absolute and relative kidney weights were noted in males at 2500 ppm and females at 5000 ppm. Macroscopic changes such as granular kidney were noted in males and females of 2500 and 5000 ppm groups. A number of non-neoplastic histopathological changes were observed, with the most significant being in the kidney. The only neoplastic change observed was in male rats and was an increase in interstitial cell adenomas of the testis considered to represent marked hyperplasia and not autonomous growth. The increased incidence was considered related to the unusually low frequency of testicular tumors in the control group. No increases in the incidence of neoplastic lesions were noted for female rats. In summary, the report allows the conclusion that there no adverse exposure related effects. Therefore, from the present report, a NOAEL of 5000 ppm IPA can be derived.

Endpoint conclusion

Dose descriptor:

NOAEC

12 500 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

A GLP whole-body inhalation oncogenicity study in Fischer 344 rats with IPA concentrations of 0, 500, 2500, 5000 ppm for 6 hours/day 5 days/week for 104 weeks was conducted according to OECD Test Guideline 451 and in compliance with GLP. Exposure of rats to isopropanol vapor for 24 months produced clinical signs of toxicity, changes in body weight, and urinalysis and urine chemistry indicative of kidney changes in the 2500 and 5000 ppm groups. These changes were considered by the study authors to be indicative of chronic progressive nephropathy, a spontaneous lesion in aging rats which tends to be more prominent in male than female rats. Based on human and animal evidence relating to CPN, Hard et al. (2009) concluded that this is a rodent-specific lesion which should not be regarded as an indicator of human toxic hazard. The only neoplastic lesion which was elevated was an increase in Leydig cell tumors in male rats. This is also a common spontaneous lesion in male rat which is very common in the rat strain used for this evaluation, F-344. The authors observed that the statistical significance attached to the frequency of this observation was probably due to the unusually low incidence in the concurrent control group. No increase in neoplastic lesions were noted in female rats. It was concluded that the NOAEL was 5000 ppm, equivalent to 12500 mg/m³.

A shorter duration key study was a subchronic inhalation study in Fischer 344 rats and CD-1 mice with IPA administered at concentrations of 0, 500, 2500, 5000 ppm for 6 hours/day 5 days/week for 98 days (Burleigh-Flayer et al.,1991). This study was conducted according to OECD Test Guideline 413 and in compliance with GLP. During the 14th week, male and female rats (excluding those animals designated for neuroanatomic pathology evaluation) received 2 and 3 consecutive days of exposure, respectively. The 10 female rats of the 500, 1500, and 5000 ppm group designated for neuroanatomic pathology evaluation were exposed for 1 day during the 14th week; the male rats of the 500, 1500, and 5000 ppm group designated for neuroanatomic pathology evaluation were not exposed during the 14th week. Male and female mice received 4 and 5 consecutive days of exposure during the 14th week, respectively. NOAECs were not identified by the authors. Rats showed acute signs of toxicity (including ataxia, narcosis, lack of a startle reflex, and/or hypoactivity), decreases in absolute body weight and body weight gain, and changes in hematology parameters in animals exposed to 1500 and 5000 ppm of isopropanol, increased relative liver weight in male and female rats exposed to 5000 ppm, as well as increased motor activity for female rats in the 5000 ppm group. Mice showed clinical signs of acute toxicity (including ataxia, narcosis, lack of a startle reflex, and/or hypoactivity) in animals exposed to 1500 and 5000 ppm of isopropanol, increased body weight and body weight gain observed in female mice of the 5000 ppm group, various changes in hematologic and serum clinical chemistry parameters observed in female mice of the 5000 ppm group, and increased relative liver weight in female mice of the 5000 ppm group.

Supportive information on the repeated dose inhalation toxicity of IPA also is provided. A 78-week inhalation oncogenicity study based on OECD Test Guideline 453 and conducted in compliance with GLP in CD-1 mice identified a NOEL [equivalent to a no-observed effect concentration (NOEC)] for toxic effects of 500 ppm due to clinical signs of toxicity and increases in body weights and body weight gains noted at the higher doses, and a NOEL for oncogenicity effects of 5000 ppm (the highest dose tested) as an increased frequency in neoplastic lesions was not noted (Burleigh-Flayer and Wagner, 1993). 

A 9-day inhalation study in Fischer 344 rats and CD-1 mice conducted according to OECD test guideline 412 was conducted according to GLP (Burleigh-Flayer et al., 1990). Animals were administered IPA for 6 hours/day, 5 days/week at 1000, 5000, 10000, and 15000 ppm. Mortality was observed in rats and mice at the highest two doses. Histologic lesions observed in the kidneys of male rats at 1000 and 5000 ppm are considered to be species and sex specific.

Reference

Gordon C. Hard, Kent J. Johnson, Samuel M. Cohen; Critical Reviews in Toxicology; 2009, Vol. 39, No. 4, Pages 332-346; A comparison of rat chronic progressive nephropathy with human renal disease.

Justification for classification or non-classification

The substance does not meet the criteria for classification and labelling for repeated dose toxicity according to Annex VI of Regulation (EC) No. 1272/2008.