Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study, similar to the OECD Guideline

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)
Deviations:
yes
Remarks:
-whole body exposure; no urinalysis performed; the test substance characterization & stability data were not developed according to GLP.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
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
Details on test material:
- Name of test material (as cited in study report): Isopropylamine
- Physical state: liquid
- Analytical purity: 99.77%
- Lot/batch No.: LP-606

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, NY
- Housing: Individual suspended stainless steel cages over paper bedding. Animals receiving inhalation exposures were individually housed in all-wire cages.
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 35-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure chamber: Ten-cubic meter New York University style stainless steel chambers with pyramidal tops and bottoms
- Exposure apparatus: a pressurized tank through a capillary tube into a Laskin-style nebulizer located in the top of the chamber. The concentration of the test material in the inhalation chamber was controlled by regulating the pressure in the tank headspace, and consequently, the flow rate of the test material into the nebulizer.
- Method of holding animals in test chamber: the animals were positioned on the middle four rows of the cage racks and they were rotated weekly through the cage positions to insure that all animals received similar exposure to the test material.
- Temperature, humidity, pressure in air chamber: monitored continuously and recorded approximately every 30 minutes

TEST ATMOSPHERE
- Brief description of analytical method used: Infrared spectroscopy
- Samples taken from breathing zone: no; the concentration in the chamber was routinely sampled five times per exposure at approximately one hour intenals.

VEHICLE (if applicable)
- Justification for use and choice of vehicle: no vehicle
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test atmosphere was drawn through a MIRAN 1A General Purpose Gas Analyzer. The analytical method used was infrared spectroscopy.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 h/d, 5d/wk
Doses / concentrations
Remarks:
Doses / Concentrations:
20, 101, and 499 mg/m3
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale:

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes, mortality and moribundity
- Time schedule: twice daily, but also during exposure period

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION: No data

FOOD EFFICIENCY: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: performed on all animals before exposures began, and on control and high level animals during the last exposure week

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once during the study and once at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, food was withheld overnight before blood collection
- How many animals: 15/sex/dose level
- Parameters examined: Red blood cell count (RBC), white blood cell count (WBC), platelet count (PLT), hematocrit (Hct), level of hemoglobin (Hgb), and red blood cell indices [mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC)], leukocyte counts, reticulocyte count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once during the study and once at the end of the study
- Animals fasted: Yes
- How many animals: 15/sex/dose level
- Parameters examined: albumin, total protein, blood urea nitrogen (BUN), total bilirubin, glucose, glutamic pyruvic transaminase (D-GPT/ALT),
alkaline phosphatase, glutamic oxaloacetate transaminase (D-GOT/AST), creatinine, cholesterol (Chol), calcium, phosphorus, chloride, sodium, and
potassium. Globulin was determined by subtraction of albumin from the total protein value.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, performed in all animals , organ weights determined (adrenals, brain, heart, kidneys, liver, spleen, testes with epididymides)
HISTOPATHOLOGY: Yes, all tissues were examined microscopically (aorta, adrenals, bone, brain, diaphragm, esophagus, eyes with optic nerve, gonads, heart, intestine, kidneys, liver, lung, lymph nodes, mammary gland, nasal passages, pancreas, pituitary, prostate, salivary gland, sciatic nerve, seminal vesicle, skeletal muscle, skin, spinal cord, spleen, stomach, thymus, thyroid, parathyroid, trachea, urinary bladder, uterus, vagina.
Statistics:
Dunnett’s Multiple Comparison Test, Mann Whitney Test, Mann Whitney Test with Bonferroni Inequality Procedure, Fisher’s Exact Test with Bonferroni Inequality Procedure, Bartlett’s Test to evaluate homogeneity of variances, Analysis of Variance to determine if the sample (group) means could be considered as an estimate of a common population, and Grubb’s Test to detect outliers

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
not considered as toxicologically relevant
Mortality:
mortality observed, treatment-related
Description (incidence):
not considered as toxicologically relevant
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
reduced body weight in females dosed with 500 mg/m3
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:
effects observed, treatment-related
Description (incidence and severity):
moderate decrease in serum glucose (high level females)
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increased for the adrenals in high dose females
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
treatment-related; local effects
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: 2 animals died during the study but it was not treatment related

BODY WEIGHT AND WEIGHT GAIN: The mean body weight of high exposure level males was reduced (approximately 6-9%) throughout most of the study. Slight (approximately 4-6%) body weight reductions were also noted in high level females during weeks 6-13.

OPHTHALMOSCOPIC EXAMINATION: No effects

HAEMATOLOGY/CLINICAL CHEMISTRY: minimal, non-dose related changes were seen in some hematological parameters (<3.5%) and some blood clinical parameters (<1.4%). The changes were not considered treatment related. At 500 mg/m3 a significant decrease in serum-glucose level of females was recorded.

ORGAN WEIGHTS: increased absolute and relative adrenal weights in high level females, probably treatment-related and may have been a non-specific response to stress; reduced spleen weights in high level males were attributed, at least partly, to the decreased body weights in the animals.

GROSS PATHOLOGY/HISTOPATHOLOGY: slight increases in centrilobular hepatocellular hypertrophy and individual hepatocellular necrosis in livers of high dose males, were not considered treatment-related. The mononuclear cell infiltrate occurred in kidneys of high dose females (small number) was considered spontaneous. At 500 mg/m3 inflammation of nasal mucosa was seen in female animals.

Effect levels

Dose descriptor:
NOAEC
Effect level:
100 mg/m³ air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: histopathology local effects (nose); decreased body weights and decreased serum glucose of high level females

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In this repeated dose inhalation toxicity the local NOAEL was set at 100 mg/m3 due to inflammation in the nasal mucosa seen at the higher tested dose.
Executive summary:

In this 90-day toxicity study, male and female Sprague-Dawley rats (15 animals/dose) were exposed for 6 hrs/day, 5 days/wk for approximately 13 weeks to ispropylamine (IPA) vapours. Mean analytical exposure concentrations were 20, 101, and 499 mg IPA per cubic meter in air. The results revealed reduced mean body weights of male animals in the high exposure group throughout most of the study period. The only significant change in hematology and clinical chemistry values, which were considered treatment-related was a decrease in serum glucose (high dose group females). Increased absolute and relative adrenal weights were seen in high level females, probably treatment-related and may have been a non-specific response to stress; reduced spleen weights in high level males were attributed, at least partly, to the decreased body weights in the animals. No treatment-related gross pathological changes were detected.The only relevant microscopic change observed was inflammation of the nasal mucosa in females tested with 499 mg/m3. The NOAEL of the study was set at 100 mg/m3.