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Toxicological information

Repeated dose toxicity: inhalation

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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

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 / concentrationsopen allclose all
Dose / conc.:
20 mg/m³ air (analytical)
Dose / conc.:
101 mg/m³ air (analytical)
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

open allclose all
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)
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.