Aluminium triisopropanolate

Carcinogenicity

Description of key information

Rats were exposed to isopropanol vapour for 24 months at 0, 500, 2500, or 5000 ppm (Burleigh-Flayer and Wagner, 1994). Effects included 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. The only neoplastic lesion which was elevated was an increase in Leydig cell tumors in male rats, also considered a common spontaneous lesion in male F344 rat.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.

In an 18 -month study in CD-1 mice (equivalent to OECD test guideline 451) which used concentration levels of 0, 500, 2500, or 5000 ppm (Burleigh-Flayer and Wagner, 1993). The study authors noted a few microscopic non-neoplastic lesions in isopropanol exposed animals; however, these findings were minimal in degree and considered to be not biologically significant. There were no increased frequencies of neoplastic lesions noted for male or female mice from any test substance exposure group. Clinical signs noted in some male and female mice during exposures to 5000 ppm included hypoactivity, lack of a startle reflex, ataxia, prostration, and arcosis. Hypoactivity, lack of startle reflex, and narcosis were also noted in some male and female animals during exposure to 2500 ppm. No clinical signs were noted for male or female animals during exposure to 500 ppm. A NOAEC of 5000 ppm for carcinogenicity was reported.

Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³ for 86 weeks. The respirable fraction of the particulates was 30 - 40% and the median diameter ca. 3.0μm). The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. The authors reported qualitatively that a minimal alveolar epithelialization was seen in control animals but that the numbers were slightly higher in rats dosed with aged Saffil. There were no lung tumors in the Saffil treated animals, and no significant group difference in the frequency of extrapulmonary tumors was observed.
The relevance of this study for the assessment of carcinogenic potential of aluminium tri-isopropylate is very low, as aluminium tri-isopropylate in contact with moisture or water hydrolizes immediately to form 2-propanol and aluminium hydroxide and inhalation exposure to aluminium is unlikely to occur, certainly not as dust exposure. Thus, the study findings are not considered relevant for aluminium tri-isopropylate per se but as alumina was used in this study not showing effects inducing tumors, the bioavailability of aluminium via lung tissue is considered being very low.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline available

GLP compliance:

not specified

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 °C
- Humidity (%): 50% ± 10%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Route of administration:

inhalation: dust

Type of inhalation exposure (if applicable):

whole body

Vehicle:

not specified

Details on exposure:

The rats were exposed in 1.4 m³ inhalation chambers that could house a total of 40 adult rats or, short-term, 50 young rats. Dust clouds were generated using dispensers (Timbrell, Hyett and Skidmore , Ann. Occup. Hyg., 1968, 11: 273) with modifications after 2 months of exposure (Beckett, Ann. Occup. Hyg., 1975, 18:187) that resulted in an improvement in concentration stability.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Respirable dust concentrations were measured with size-selective gravimetric dust samplers (Casella Type 113A; Dunmore, Hamilton and Smith, 1964). The collected samples were weighed at the end of each day’s exposure and, if necessary, modifications to air flow were made to correct variations.

Total atmospheric samples were taken from the exposure chambers for 1-hour periods during the exposure. These samples, together with the readings from the Casella dust samplers, were used to estimate the respirable fraction.

Duration of treatment / exposure:

86 weeks for the test fibres; 77 weeks for the positive control

Frequency of treatment:

6 hours a day (frequently extended by 2-3 hours) 5 days a week

Post exposure period:

No data.

Remarks:

Doses / Concentrations:
Saffil – 2.18 mg/m³; “Aged” Saffil – 2.45 mg/m³; UICC chrysotile asbestos – 4.57 mg/m³
Basis:
nominal conc.

No. of animals per sex per dose:

50 animals per group (25 of each sex)

Control animals:

yes, concurrent no treatment

Details on study design:

Interim killings were performed at 14 weeks (2 animals of each sex per group) and 27 weeks (2 animals of each sex per group) and at 53 weeks (one animal of each sex per group) of the experiment. The other animals were allowed to live until they died, appeared distressed, or until 85% mortality (averaged over all groups) was reached.

Positive control:

Yes. Exposed to a standard reference sample of UICC chrysotile A (Rhodesian) asbestos obtained from the Medical Research Council Pneumoconiosis Research Unit, Llandough Hospital, Penarth, Glamorgan.

Observations and examinations performed and frequency:

Frequency of the observations and examinations:
No information on frequency of health monitoring is provided.
Pathology examination was performed at 14, 27, 53 weeks of the experiment, after animals’ natural death, killing because of distressed condition or at the termination of the experiment when 85% mortality was reached.

Sacrifice and Pathology (methods):
The animals were killed by overexposure to halothane BP
The lungs were removed and inflated with formol saline; the nasal cavity was irrigated with formol salin also. Grossly abnormal tissues and samples of the major organs were fixed in formol sublimate and embedded in paraffin; 5 µm sections were cut and stained with haematoxylin and eosin. A median sections from each lung lobe were also stained and examined.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Other examinations:

The other lung sections were stained with van Gieson’s stain for collagen and by Gordon and Sweet’s method for reticulin.

Statistics:

Statistical analysis was not conducted; the results are presented qualitatively.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not specified

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:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

Non-neoplastic lesions
Histopathological examination at interim killing
At 14, 27 and 53 weeks lesions characteristic of a low grade pneumonitis were seen in both treated and control animals. The lesions were attributed to respiratory infection.
Generally there was a minimal reaction to both types of alumina fibres; Saffil fibres were seen in alveolar macrophages and in the superficial mediastinal lymph node of one animal killed at 27 weeks; in one animal Saffil fibres were seen in an area of alveolar epithelialization. Other lesions were described as typical of the Alderley Park rat colony and not due to treatment.
Focal necrosis and regeneration of olfactory epithelium was seen nasal cavity tissue of 2 animals exposed to Saffil fibres and in one animal exposed to asbestos.

Histopathological examination at animals’ death or terminal killing
Saffil fibres were seen in the lungs of most rats exposed to Saffil.
The observed effect was limited to pigmented alveolar macrophages.

A minimal alveolar epithelialization was observed in some control animals and in one female exposed to Saffil as manufactured. The number of animals with alveolar epithelialization was slightly higher in rats exposed to aged Saffil; this lesion was minimal in most animals, was more prevalent in females than in males, and was no longer evident after 106 weeks. In the authors’ opinion, this lesion might be at least partly attributable to intercurrent infection. There was no fibrosis in the lungs of the Saffil-treated animals.

In some animals, small numbers of Saffil fibres were seen in nasal passages with evidence of slight irritation of the nasal mucosa with minimal focal necrosis.
Degeneration of olfactory epithelium with replacement by respiratory epithelium seen in all groups was attributed to spontaneous age-related change.

Positive control
In animals exposed to asbestos, a minimal asbestosis was detected at week 14, which progressed to slight asbestosis by week 53 and became more marked as the experiment continued. All animals exposed to asbestos showed asbestosis of some degree.

Neoplasms
No pulmonary tumors (either benign or malignant) were found in the negative control (16 males and 18 females examined), in rats treated with Saffil fibres as manufactured (13 males and 19 females examined) or treated with aged Saffil (19 males and 19 females examined). In the positive control, 2 tumors (1 adenoma and one squamous cell carcinoma) were found among 19 examined male rats, and 7 tumors (4 adenomas, 1 adenocarcinoma and 2 squamous cell carcinomas) among 19 examined female rats. The tumors in the positive control were observed late in the experiment (the first benign tumor at 109 weeks and malignant tumors – at weeks 128 and 129).
Examination for extrapulmonary tumors did not include interim kills. There were no significant group differences in the frequency of extrapulmonary tumors (see table 1).

Relevance of carcinogenic effects / potential:

The relevance of this study for the assessment of carcinogenic potential of aluminium tri-isopropylate is very low, as aluminium tri-isopropylate in contact with moisture or water hydrolizes immediately to form 2-propanol and aluminium hydroxide and inhalation exposure to aluminium is unlikely to occur, certainly not as dust exposure. Thus, the study findings are not considered relevant for aluminium tri-isopropylate per se but as alumina was used in this study not showing effects inducing tumors, the bioavailability of aluminium via lung tissue is considered being very low.

Table 1:

	Number examined		Benign tumors		Malignant tumors
	male	female	Male	female	male	female
Negative control	19	19	9	21	2	8
Positive control	19	20	10	23	5	6
Saffil as manufactured	13	19	8	20	4	8
“Aged” Saffil	19	20	9	26	3	5

Conclusions:

Exposure to both types of alumina fibres produced minimal pulmonary reaction and no fibrosis. There were no lung tumors in the Saffil treated groups, and no significant group difference in the frequency of extrapulmonary tumors was observed. The authors concluded that “the pulmonary reaction to Saffil fibres observed in this study is…consistent with their classification as biologically inert materials.”

Executive summary:

Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³ for 86 weeks. The respirable fraction of the particulates was 30 - 40% and the median diameter ca. 3.0μm). The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. The authors reported qualitatively that a minimal alveolar epithelialization was seen in control animals but that the numbers were slightly higher in rats dosed with aged Saffil. There were no lung tumors in the Saffil treated animals, and no significant group difference in the frequency of extrapulmonary tumors was observed.

 

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study without detailed documentation

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

- opthalmology examinations, food and water consumption, and clinical chemistry not reported

GLP compliance:

yes

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Portage, MI
- Age at study initiation: 48 days
- Housing: 2 per cage in stainless steel wire mesh cages
- Diet (e.g. ad libitum): Pelleted, certified AGWAY PROLAB Animal Diet Mouse 3000, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.7-26.1
- Humidity (%): 40-70
- Air changes (per hr): 14
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: February 18, 1991 To: September 2, 1992

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Inhalation chamber
- Method of holding animals in test chamber: cage in chamber
- Temperature, humidity, pressure in air chamber: 22 ± 4°C
- Air flow rate: 1000 L/min
- Air change rate: 14 air changes/hour

TEST ATMOSPHERE
- Brief description of analytical method used: analyzed approximately twice each hour during the 6-hour exposure period by flame ionization gas chromotography

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyzed approximately twice each hour during the 6-hour exposure period by flame ionization gas chromotography.

Duration of treatment / exposure:

The exposures began on February 18, 1991 (Study Day 1). Animals assigned to the core group were exposed for at least 78 weeks. The animals assigned to the interim sacrifice group and the animals assigned to the recovery group were exposed for at least 54 weeks.

Frequency of treatment:

Animals assigned to the core group were exposed for 6 hours/day for 5 consecutive days/week for at least 78 weeks. The animals assigned to the interim sacrifice group and the animals assigned to the recovery group were exposed for 6 hours/day for 5 consecutive days/week for at least 54 weeks. Animals were not exposed during designated BRRC holidays. (Use of non-standard dosing regime was not justified in the study report).

Remarks:

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

No. of animals per sex per dose:

Core group: 55/sex/dose
Interim Sacrifice group: 10/sex/dose
Recovery group: 10/sex/dose

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: based on 9-day preliminary study
- Rationale for animal assignment (if not random): random

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day before and after each exposure


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly for the first 14 weeks and every other week thereafter


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


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 12 months and 18 months
- Anaesthetic used for blood collection: Yes : slightly anesthetized wtih methoxyflurane
- Animals fasted: No
- How many animals: all surviving animals

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

The data for quantitative continuous variables were intercompared for the 3 exposure groups and the control group by use of Levene's test for equality of variances, analysis of variance (ANOVA), and t-tests. The t-tests were used when the F value from the ANOVA was significant. When Levene's test indicated similar variances, and the ANOVA was significant, a pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by a separate variance t-test for pairwise comparisons.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

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
Mortality rates for males in the 0, 500, 2500, and 5000 ppm groups were 35, 40, 47, and 44%, respectively. The corresponding values for females were 24, 35, 22, and 33%, respectively. No differences in mean survival time were noted for any of the isopropanol exposure groups. Clinical signs noted in some male and female mice during exposures to 500 ppm included hypoactivity, lack of a startle reflex, ataxia, prostration, and narcosis. Hypoactivity, lack of startle reflex, and narcosis were also noted for some male ane female animals during exposure to 2500ppm. No clinical signs were noted for male or female animals during exposure to 500 ppm.

BODY WEIGHT AND WEIGHT GAIN
Concentration-related increases in body weight and weight gain were observed for male mice at most time ponts throughout the study, however, statistical significance was typically achieved only for the 2500 and 5000 ppm groups beginning at study week 6 and 3, respectively.


HAEMATOLOGY
No exposure-related changes in hematologic parameters were observed for male or female mice from any of the isopropanol exposed groups that were examined at week 56 or 57, or at the terminal sacrifice.


ORGAN WEIGHTS
A concentration -related increase in absolute and relative liver weight was noted for female mice at the terminal sacrifice, however, statistical significance was only achieved for animals from the 5000 ppm group.

GROSS PATHOLOGY
At terminal sacrifice, an increased frequency of seminal vesicle enlargement was noted at necropsy for male mice from the 5000 ppm group. In addition, the frequencey of this finding was increased for male mice from the 2500 and 5000 ppm groups which were found dead or sacrificed morbund. There were not exposure-related gross lesions noted for female animals at necropsy.

HISTOPATHOLOGY: NON-NEOPLASTIC
Upon microscopic evaluation, there were no nonneoplastice or neoplastic lesions observed that were believed to be related to the isopropanol exposures for male and female mice which were sacrificed at week 55.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Upon microscopic evaluation, there were no nonneoplastice or neoplastic lesions observed that were believed to be related to the isopropanol exposures for male and female mice which were sacrificed at week 55.

Relevance of carcinogenic effects / potential:

A few non-neoplastic lesions were noted microscopically for isopropanol exposed animals, however, these findings were minimal in degree and probably not biologically significant. There were no increased frequencies of neoplastic lesions noted for male or female mice from any test substance exposure group.

Dose descriptor:

NOEL

Effect level:

5 000 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Refer to Section on Results and discussions.

Conclusions:

The no-observed-effect level (NOEL) for toxic effects was 500 ppm and the NOEL for oncogenicity effects was determined to be 5000 ppm

Executive summary:

Information on the carcinogenicity of IPA was provided by this GLP carcinogenicity report; an 18 -month study in CD-1 mice (equivalent to OECD test guideline 451) which used concentration levels of 0, 500, 2500, or 5000 ppm (Burleigh-Flayer and Wagner, 1993). The study authors noted a few microscopic non-neoplastic lesions in IPA exposed animals; however, these findings were minimal in degree and deemed (by the study authors) to be not biologically significant. There were no increased frequencies of neoplastic lesions noted for male or female mice from any test substance exposure group. Clinical signs noted in some male and female mice during exposures to 5000 ppm included hypoactivity, lack of a startle reflex, ataxia, prostration, and narcosis. Hypoactivity, lack of startle reflex, and narcosis were also noted in some male and female animals during exposure to 2500 ppm. No clinical signs were noted for male or female animals during exposure to 500 ppm. A NOEC of 5000 ppm for carcinogenicity was reported.

Reference 3

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

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:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Remarks:

- Not monitoring food consumption

GLP compliance:

yes

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 (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on 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, or 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 stratified 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.

Relevance of carcinogenic effects / potential:

There were no increases in neoplastic lesions reported for females. Given the irrelevance of the neoplastic lesions in this rat study to humans, a carcinogenicity NOEC of 5000 ppm was identified by the study authors.  

Dose descriptor:

NOEL

Effect level:

5 000 ppm (nominal)

Sex:

male/female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

The study authors noted that the increased incidence of testicular tumors appeared to be reflective of lower incidence in the control group. The study authors stated that testicular adenomas are a common finding in aged male rats and that historical incidence of this finding has been reported to be high as 88% in NTP inhalation studies, which is much higher compared to an incidence of 64.9% reported for control animals in the study. Therefore, the testicular adenomas were considered possibly spurious by the study authors. 

Conclusions:

Isopropanol was shown to be non-carcinogenic in a 2-year inhalative exposure carcinogenicity study.

Executive summary:

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) have 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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

12 270 mg/m³

Study duration:

chronic

Species:

other: rat and mouse

Quality of whole database:

based on degradation product

System:

other: no effects observed

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the absence of effects in any of the available studies, aluminium triisopropylate is not classified for carcinogenicity according to CLP (Regulation EC No 1272/2008)

Additional information

No data on carcinogenicity of aluminium tri-isopropylate are available. However, as aluminium tri-isopropylate in contact with moisture or water hydrolyzes immediately to form 2-propanol and aluminium hydroxide indications about carcinogenicity could be thought from 2-propanol and aluminium hydroxide. 2-Propanol was investigated for carcinogenicity in two inhalative studies on mice and rats with negative results. As representative of aluminium 3+ compounds only aluminium oxide was investigated for carcinogenicity using inhalative exposure by Pigott et al. but this study, although absent of showing any tumour incidences following exposure, is considered to be of limited relevance as hydrolysis of aluminium tri-isopropylate would not result in airborne alumina fibres. However, the study showed, that inhalation exposure to aluminium 3+ species did not induce tumour in rats.

For explanation for using surrogate data in a weight of evidence approach see also the weight of evidence justification in section 13