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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:
supporting study
Study period:
02. Jul 1980 - 02. Oct 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
1. Food consumption was not determined 2. No measurement of blood clotting potential was performed 3. No individual data were available to the reviewer. This hampers the evaluation of the results. 4. The slight decrease in liver weight seen at 0.2 mg/L was not accompanied by histopathological or clinical chemistry findings 5. A quality assurance statement was included

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Principles of method if other than guideline:
see details in remarks on material and methods
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
CAS 75-64-9 (tert-butylamine), purity 99.5%.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Portage, MI)
- Age at study initiation: 49 days
- Weight at study initiation: 222-250 g (males), 169-186 g (females)
- Housing: individually
- Diet: Ralston Purina Rodent Chow 5002, ad libitum
- Water: tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 ± 2°F
- Humidity (%): 35-60%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
- Type of exposure: inhalation
- Particle size: not applicable (vapour)
- Air changes: 10/hour
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
4 samples per exposure day by infrared spectrophotometer
Distribution: 5 samples at different locations in the test chamber (3 times during the study)
Duration of treatment / exposure:
13 weeks (62 exposure days)
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.2, 0.5, 2.01 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
15
Control animals:
yes
Details on study design:
- Nominal concentration: the amount of test material metered into the test chamber per unit of time divided by the air-flow per unit of time
- Actual concentration: as determined by analyses

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily prior and after exposure; during exposure for activity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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 data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 13
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes, 22 h
- How many animals: 10
- Parameters examined:Red Blood Cell Count ( RBC), White Blood Cell Count ( WBC), Leukocyte Differentials Hemoglobin ( HGB), Hematocrit ( HCT), Mean Corpuscular Volume ( MCV), Mean Corpuscular Hemoglobin ( MCH), Mean Corpuscular Hemoglobin Concentration ( MCHC).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 13
- Animals fasted: Yes, 22 h
- How many animals: 10
- Parameters examined: Alkaline Phosphatase (ALP), Total Bilirubin, Blood Urea Nitrogen (BUN), Glucose, Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic Pyruvic, Transaminase (SGPT), Total Protein

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; heart, lungs, nasal turbinates, trachea, salivary gland, liver, pancreas, oesophagus, stomach, duodenum, jejunum, ileum, ceacum, colon, mammary gland, kidneys, urinary bladder, skeletal muscle, bone and bone marrow (femur), spleen, thymus, lymphnodes (mesenteric), thyroid, testes, epididymides, prostate, ovaries,uterus, pituitary, adrenals, brain, skin and eyes

HISTOPATHOLOGY: Yes; gross lesions and organs mentioned under macroscopy for control and high dose animals; bone marrow and nasal turbinates from low and mid dose groups
Other examinations:
Organ weights: adrenals, brain, heart, liver, spleen, pituitary, kidneys, testes
Statistics:
Dunnett's test, Mann-Whitney test, Fisher's exact test, Kolmogorov-Smirov (one-tailed test)

Results and discussion

Results of examinations

Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
ACTUAL DOSE RECEIVED:
Nominal (mg/L): 0.20, 0.50, 2.04
Actual (mg/L): 0.20, 0.50, 2.01
Distribution: uniformly

MORTALITY:
- Number of deaths at each dose (time): High dose: 2 males (day 43), 1 female (day 45), 1 female (day 59); 2 males and 5 females killed in extremis (between day 48 and 73)

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:

Clinical Signs During Exposure:
- At 0.2 mg/L: hypoactivity (>=25%) during first exposure
- At 0.5 mg/L: hypoactivity during first exposure (>=25%), irritation of nose and eyes (>=25%), respiratory difficulties (>=25%) during first exposure
- At 2.0 mg/L: hypoactivity (>=25%) during first exposure, hypoactivity (>=75%), irritation of nose and eyes (>=100%), respiratory difficulties (>=75%) throughout the study

Clinical Signs Before and After Exposure:
- At 0.2 mg/L: nasal discharge (2/10), breathing problems and sneezing (1/10), alopecia
- At 0.5 mg/L: incidental: nasal discharge, nose and eye irritation, listlessness, piloerection, alopecia
- At 2.0 mg/L: in general: irritation of nose and eyes, breathing problems, sneezing, listlessness, distended abdomen, alopecia; Incidental: corneal opacity, chromodacryorrhea, fur dicoloration, piloerection, salivation, behavioral abnormalities, hyperactivity, hypoactivity, ataxia, dicolored urine, urine stained fur and a mass (1/5 females) respiratory difficulties (75%) throughout the study

Body weight gain:
- Significant decrease at 0.5 (week 3 females only) and 2.0 mg/L (all animals) (dose related)

Haematology:
- RBC/WBC: not evaluated due to technical problems 2.0 mg/L
- Neutrophils: significant increase
- Lymphocytes: significant decrease

Clinical chemistry:
- At 0.2 mg/L glucose: significant increase (males)
- At 0.5 mg/L glucose: significant increase (males)
- At 2.0 mg/L glucose: significant increase (males and females)
- ALP: significant increase (males and females)
- ASAT: significant increase (males and females)
- ALAT: significant increase (females)
- BUN: significant increase (males)

MACROSCOPIC/MICROSCOPIC EXAMINATIONS:

Organ weights:
- At 0.2 mg/L: liver: significant decrease abs/rel (males)
- At 0.5 mg/L liver: significant decrease abs (males); pituitary: significnat decrease abs/rel (females)
- At 2.0 mg/L liver: significant decreasse abs/rel (males and females); adrenals: significant increase abs/rel (males and females); brain, heart, kidney: significant decrease abs (males), significant increase rel (males and females); pituitary: significant decrease abs (females)/significant increase rel (males); spleen: significant decreased abs/rel (males); testes: significant decrease abs/significant increase rel (males)

Gross pathology:
- At 2.0 mg/L In general: emaciation, gaseous distension of the intestine

Histopathology:
- At 2.0 mg/L in general: chronic inflammation of the nasal passages and the upper respiratory tract (infiltration of lymphocytes), myeloid hyperplasia (increased proportion of neutrophilic leukocytes in bone marrow)
- No nasal lesions were found in the middle and low dose group
- The gonads were examined histologically in the highest dose group: no effects found

Effect levels

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Dose descriptor:
NOEC
Effect level:
0.2 mg/L air (analytical)
Sex:
female
Dose descriptor:
NOAEC
Effect level:
< 0.2 mg/L air (analytical)
Sex:
male
Basis for effect level:
other: 0.2 mg of TBA/liter of air appears to be a "minimal effect" level.
Remarks on result:
not determinable
Remarks:
no NOAEC identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

The highest "no-effect" exposure level for female rats receiving a maximum of 62 six-hour exposures of TBA vapor was 0.2 mg/liter of air. Although there was no "no-effect" exposure level established for male rats, 0.2 mg of TBA/liter of air appears to be a "minimal effect" level.

Applicant's summary and conclusion