Isopropylamine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to 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

Details on test material:

- Name of test material (as cited in study report): Isopropylamine (2-aminopropane)
- Substance type: organic
- Physical state: clear 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
- Age at study initiation: 54 days
- Weight at study initiation: 241-300g (males), 163-207 g (females)
- Fasting period before study: no
- Housing: individually
- Diet: ad libitum, Purina Rodent Chow (5002), except inhalation exposure
- Water: ad libitum, except inhalation exposure

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

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Routinely sampled five times per exposure at approximately one hour intervals. Test atmosphere was drawn through a MIRAN 1A General Purpose Gas Analyzer

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

6 h/d, 5d/wk

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

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during exposure and immediately after exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once weekly

BODY WEIGHT: Yes
- Time schedule for examinations: once weekly

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: all animals before first exposure, control and high exposure groups during last week of exposure

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day of scheduled necropsy
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: 15 per sex and group
- Parameters checked: 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 differentials, reticulocyte count s

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day of scheduled necropsy
- Animals fasted: Yes
- How many animals: 15 per sex and group
- Parameters checked: 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

IMMUNOLOGY: No

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All animals subjected to gross necropsy, organ weights were determined, and tissues were obtained: Internal cavities (abdominal, thoracic, cranial, and scrotal)
were opened, and organs were removed and examined


HISTOPATHOLOGY: Yes
Tissues Obtained (when present): aorta, adrenals, bone, brain, diaphragm, esophagus, eyes with optic nerve, gonads (ovaries. testes with
epididymides) , hearts intestine (duodenum, colon, ileum), kidneys, liver, lung, lymph nodes (thymic and mesenteric) , mammary gland, nasal passages, pancreas, pituitary, prostate, salivary gland (submaxillary) ,
sciatic nerve, seminal vesicle, skeletal muscle, skin, spinal cord, spleen, stomach, thymus, thyroid/parathyroid, trachea, urinary bladder, uterus, vagina, and gross lesions (at the discretion of the
pathologist).
All tissues from control and high level animals were examined microscopically; nasal passages from low and mid level females were also examined

Statistics:

Dunnett's Multiple Comparison Test, Mann-Whitney Test, with with Bonferroni Inequality Procedure, Fisher’s Exact Test with Bonferroni Inequality Procedure, (partially uncorrected) chi-square Test

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

A low level female and a high level male died approximately 12 weeks into the study. The reason for the death of the low level female could not be determined, but it was not thought to be treatment-related. The death of the high level animal was due to mechanical trauma and was not treatment-related.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weight of high exposure level males was reduced slightly (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. These effects were not considered as toxicologically relevant.

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 exposure level males. Erythrocyte parameters (RBC, HCT, HGB) were increased in all male exposure groups. The reticulocyte count was decreased in high level males. The MCHC values were decreased in all three female’exposure groups. However, the changes were minimal (<3.5%), not dose-related, and thus not considered to be treatment-related.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Serum glucose was decreased approximately 25% in high level females (197, 181, 193 and 147 mg/dL in control, low, mid and high exposure level, respectively). Males were unaffected (224, 221, 241 and 223 mg/dL, respectively). See Overall remarks for discussion.
The following effects were not considered by the authors as toxicologically relevant: Sodium was decreased in mid and high level females, but the changes were minimal (<1.4%) and not considered to be biologically significant. Increased serum potassium values in mid and high level males were not dose-related and thus not considered to be treatment-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.
Remark: Histology of organs was unremarkable.

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 may have been related to treatment was inflammation of the nasal mucosa in high level females.

Histopathological findings: neoplastic:

not examined

Effect levels

1

Key result

Dose descriptor:

NOAEC

Effect level:

500 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: systemic effects (excluding local effects)

2

Key result

Dose descriptor:

NOAEC

Effect level:

100 mg/m³ air

Sex:

male/female

Basis for effect level:

other: local effects: histopathology (nose)

Target system / organ toxicity

Key result

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the only toxicologically relevant effect observed in this study was local irritation of the respiratory tract at 500 mg/m3, with a NOAEC of 100 mg/m3.
The glucose reduction in high dose females was considered toxicologically not relevant, for details see Overall remarks above

Executive summary:

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/m3 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 treatment-related 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 (by the study authors) to be 100 mg/m3 in air.