Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with 2-propanamine

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Unavailable - orginal study report date 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

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

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

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 ensure 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 intervals.

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

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

Details on study design:

- Dose selection rationale: not specified

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, non-treatment-related

Description (incidence and severity):

Not specified.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Two animals died during the study but it 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 (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.

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

Description (incidence and severity):

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.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

At 500 mg/m3 a significant decrease in serum-glucose level of females was recorded.

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):

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 pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

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.

Histopathological findings: neoplastic:

no effects observed

Effect levels

Key result

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:

no

Applicant's summary and conclusion

Conclusions:

Inflammation of the nasal mucosa decreased body weights and serum glucose were observed in females at 499 mg/m3. The NOAEC was therefore determined to be 100 mg/m3.

Executive summary:

In a subchronic inhalation toxicity study (equivalent to OECD guideline 413), 2-propanamine (99.77% purity) was administered to 15 SD rats/sex/concentration via inhalation (dynamic whole body) exposure to concentrations of 0, 20, 101 or 499 mg/m³ for 6 hours per day, 5 days/week for a total of 13 weeks.

 

The results revealed a reduction in the average body weight of the male animals in the highly exposed group for most of the study period. The only significant change in haematology and clinical chemistry values, which was considered treatment-related, was a decrease in serum glucose (females in the high dose group). An increase in absolute and relative adrenal weights was observed in females in the high-dose group, probably treatment-related and may have been a non-specific response to stress; the decrease in spleen weights in males in the high-dose group was attributed, at least in part, to the decrease in body weight of the animals. No gross treatment-related pathological changes were detected, the only relevant microscopic change observed being inflammation of the nasal mucosa in the females tested at 499 mg/m3.The NOAEC is 100 mg/m3 based on histopathology local effects decreased body weights and serum glucose observed in females in the high-dose group.

This subchronic inhalation toxicity study in the rats is acceptable and satisfies the guideline requirement for a subchronic inhalation study OPPTS 870.3465; OECD 413 in the rats.