Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 March 1998 to 17 March 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was not conducted under GLP conditions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
no guideline available
Guideline:
other: internal laboratory testing
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
T-6933
IUPAC Name:
T-6933
Details on test material:
- Name of test material (as cited in study report: T-6933
- Lot/batch no.: NB 11457-54
- Other: Molecular weight: 414 g/mol; Density: 1.65 g/ml

Test animals

Species:
rat
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
IN-LIFE DATES: From: 23 March 1998 To: 27 March 1998

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
not specified
Vehicle:
other: no vehicle
Details on inhalation exposure:
TEST ATMOSPHERE
- Brief description of analytical method used: standard target concentrations were analyzed by gas chromatography.
- Samples taken from breathing zone: Yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber test compound concentrations were nominally maintained within +/- 10% of the target concentrations
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days
Doses / concentrations
Remarks:
Doses / Concentrations:
10000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
3
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: no data
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS:No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT:
- Time schedule for examinations: daily before treatments an during the study period

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY:Yes
- Time schedule for collection of blood: at necropsy
- Animals fasted: No data
- Parameters checked in table No. 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Organ weights and organ weight ratios were assessed (see Table 2)
Sacrifice and pathology:
GROSS PATHOLOGY: No data

HISTOPATHOLOGY: Yes-liver, kidneys, testes, spleen. The brain was examined in 2 of the 3 animals.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY: All animals survived

BODY WEIGHT AND WEIGHT GAIN: The test animals gained an average of 36 +/- 4g during treatment; not significantly different than controls.

CLINICAL CHEMISTRY: Slight lowering of cholesterol (81% of control values) and a 74% (over the control) increase in lactate dehydrogenase may be indicative of some cell lysis.

ORGAN WEIGHTS: Liver weights were 15.4 +/- 1.6 g which was 20% greater than control values. Liver to body weight ratio averaged 0.06, which is 118% control values. Liver to brain weight ratios for two animals were 7.43 +/- 0.64, which is not significantly different. Average right kidney and testis weights were 1.32 g and 2.6 g, respectively, which were not significantly different than control.

HISTOPATHOLOGY: Mild tubular nephrosis was present in the renal medulla in one animal

Effect levels

Dose descriptor:
NOAEL
Effect level:
10 000 ppm
Sex:
male
Basis for effect level:
other: overall effects mortality; body weight; clinical chemistry; organ weights

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Following 5-day (6 hours/day) repeated inhalation exposure to T-6933 at 10000 ppm, the NOAEL was identified as 10000 ppm.
Executive summary:

The 5-day repeated dose inhalation toxicity of T-6933 was assessed in 3 male rats. Standard target concentrations for the compound was prepared and analyzed by gas chromatography (GC). Chamber air was monitored by GC and maintained within 10% of the target dose. The animals were exposed to 10000 ppm of T-6933 for 6 hours a day for 5 days, until the animals were euthanized by CO2 asphyxiation. Serum chemistry, body weights, organ weights (including organ to body weight ratios) and histology were evaluated in the study. No mortalities and no significant changes in body weights were observed. Liver weights were 20% greater in the treated animals versus the controls.Liver to body weight ratio was significantly increased, in which the test article caused an average 18% increase in the test animals versus control (non-treated) animals. Other organ weights and ratios were non-significant. In one animal, histopathology of the kidney revealed mild tubular nephrosis in the renal medulla. No other abnormalities were noted. Slight lowering of Cholesterol (81% of control values) was observed. Increases in lactate dehydrogenase (74% greater than control) may be indicative of some cell lysis, although no histopathological changes were seen in the liver, the NOAEL for T-6933 was identified at 10000 ppm.