Isobutylamine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Isopropylamine

EC Number:

200-860-9

EC Name:

Isopropylamine

Cas Number:

75-31-0

Molecular formula:

C3H9N

IUPAC Name:

propan-2-amine

Test material form:

liquid: volatile

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 54 days
- Weight at study initiation: males 241 g to 300 g
females 163 g to 207 g
- Fasting period before study: no
- Housing: Individual in suspended stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 to 74 ° F
- Humidity (%): 35 to 60 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Ten-cibic meter stainless steel chambers
- Method of holding animals in test chamber: Animals were placed in the middle four rows of the cage racks. rotated weekly through the cage positions
- System of generating particulates/aerosols: substance was metered from a pressurized tank through a capillary tube into a Laskin-style nebulizer located at the top of the cage.


TEST ATMOSPHERE
- Brief description of analytical method used: Test atmosphere was drawn through a NIRAN 1A Generla purpose Gas Analyser
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 h/day amd 5 d/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/m³ air (analytical)

Doses / concentrations 2

Dose / conc.:

101 mg/m³ air (analytical)

Doses / concentrations 3

Dose / conc.:

499 mg/m³ air (analytical)

No. of animals per sex per dose:

15 animals

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
yes for mortality and moribundity; twice daily
During exposure between the second and fifth hour of exposure.
Immediatelky after exposure


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once a week for males and females

BODY WEIGHT: Yes
- Time schedule for examinations: Once a week for males and females



OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before exposure began and during last exposure week.
- Dose groups that were examined: Control and high level dose group.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy
- Anaesthetic used for blood collection: Yes (identity not specified)
- Animals fasted: Yes
- How many animals: 15/level/sex


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of scheduled necropsy
- Animals fasted: Yes
- How many animals: 15/level/sex

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

one low level female and a high level male.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weight of high exposure level males was reduced about 6% to 9% and slight body weight reductions were also seen in high level female at about 4% to 6%.

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:

effects observed, non-treatment-related

Description (incidence and severity):

The WBC count was significantly decreased in high expsoure level males. Erythrocytes parameters (RB, HCT, HGB) were increased in all amles exposure groups. The retyculocyte count was decreased in high level males. The MCHC values were decreased in all three female expsoure groups. However, the changes were minimal (< 3.5%), not dose related and thus not considered to be treatment related.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

Serum glucose was decreased approx. 25% in high level females. Sodium was decreased in mid and high level females but the chnages were minimal (< 1.4%) and not considerd to be biologically relevant. Increased serum potassium values in mid and high level males were not dose related and thus not considered to be tretament related.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The absolute and relative adrenal weights were significantly increased (approximately 18 and 22%, respectively) in high level females. Absolute spleen weights were significantly decreased (approximately 15%) in high level males.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The only microscopic change which occurred at a statistically significant incidence was inflammation of the nasal mucosa in high level females.

Histopathological findings: neoplastic:

not examined

Effect levels

1

Dose descriptor:

NOAEC

Effect level:

500 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: systemic effects (excluding local effects)

2

Dose descriptor:

NOAEC

Effect level:

100 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local effects: histopathology (nose)

Target system / organ toxicity

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/m³ air

System:

respiratory system: upper respiratory tract

Organ:

nasal cavity

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

yes

Applicant's summary and conclusion

Conclusions:

In conclusion, exposure to the test material showed microscopic changes in the nasal passages as well as decreases in body weights and serum glucose occurred at the high exposure level. No unequivocal effect was noted below this level. Therefore, the no observed adverse effect level is considered to be 100 mg IPA/cubic meter in air.

Executive summary:

In the subchronic toxicity study, four groups of 15 males and 15 females each were exposed for 6 hrs/day, 5 days/wk for approximately 13 weeks. Mean analytical exposure concentrations were 20, 101, and 499 mg IPA per cubic meter in air. The mean body weight of high exposure level males was reduced throughout much of the study. The only significant change in hematology and clinical chemistry values which appeared to be treatmentrelated was a decrease in serum glucose (high level females) .

There was no gross pathology change which was considered to be treatment-related. The only microscopic change which may have been related to treatment was inflammation of the nasal mucosa in high level females. Because of these microscopic changes as well as decreases in body weights and serum glucose values in high level animals, the no observed adverse effect level is considered to be 100 mg IPA/cubic meter in air.