Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1980
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report equivalent or similar to OECD guideline 413.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): BRIGHTSOL

- Other

Test animals

Species:
rat
Strain:
other: Albino
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory
- Age at study initiation: 10-13 weeks
- Fasting period before study:
- Housing: three of one sex/cage
- Diet (e.g. ad libitum): ad libitum, removed during exposure
- Water (e.g. ad libitum): ad libitum

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The atmospheres were generated by completely evaporating the solvent into the streams of ventilating air entering the chambers using micro metering pumps and vaporizers. The vaporizers consisted of electronically heated quartz tubes.
- Exposure apparatus: aluminum with a volume of 1m3
- Source and rate of air: exhausted duct through which air was drawn by a fan situated on the roof of the laboratory
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 1.8-2.0 m3/min
- Treatment of exhaust air: dust filters


TEST ATMOSPHERE
- Brief description of analytical method used: Analyzed continuously by means of a total hydrocarbon analyzer fitted with flame-ionization detectors.
- Samples taken from breathing zone: no

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyzed continuously by means of a total hydrocarbon analyzer fitted with flame-ionization detectors.
Duration of treatment / exposure:
6h/day, 5days/week for 13 weeks
Frequency of treatment:
6h/day, 5days/week for 13 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
1500 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3000 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
6000 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
18 rats /sex/dose
Control animals:
yes
Details on study design:
The start and finish of the experiment was staggered in order that the optimum number of animals could be examined at necropsy after exposure. On each of 6 consecutive days, 3 male and 3 female rats per dose were started on the experiment. Thirteen weeks later, 3 male and 3 female rats per dose were removed from the experiment for pathological examination on each of 6 consecutive days.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g/cage of 3 rats/week: Yes


WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- Anaesthetic used for blood collection: No
- How many animals: all


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- Animals fasted: No
- How many animals: all rats


URINALYSIS: Yes
control, low and high dose groups only
- Time schedule for collection of urine: following last exposure


NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Body and organ weights were analyzed by covariance analysis using the initial body weight as the covariate. Reported means were adjusted for initial body weight if a significant covariance relationship existed. Organ weights were further examined by covariance analysis using the terminal body weight as the covariate. The organ weight means were reported as adjusted for terminal body weight if a significant covariance relationship existed. Clinical chemical and hematological parameters were examined using analysis of variance. The significance of any difference between treated and control group means was tested using the Williams t-test. However, if a monotonic dose response could not be assumed, Dunnett’s test was used.

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):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No deaths were recorded during the experiment and the general health of the animals remained good throughout the period of exposure.

BODY WEIGHT AND WEIGHT GAIN
No significant differences in male body weights due to exposure. Female body weights, however, were significantly reduced from control at the high dose.

FOOD CONSUMPTION
Female food intake showed and early significant reduction from control at the high exposure level.


WATER CONSUMPTION
Some significant increases were seen in both males and females at the highest dose.


HAEMATOLOGY
Significant decrease in male reticulocytes at the high dose, all other red and white cell parameters were normal

CLINICAL CHEMISTRY
Significant decrease in female ALT values at all exposure levels. Male chloride was significantly reduced at the medium and high dose levels and female beta protein was increased at the high level.

URINALYSIS
Glucose and protein were present in the urine of many of the rats, but animals were fed during collection period, therefore this is not unexpected. Very low incidence of exposed rats with glycosuria compared with control rats.

ORGAN WEIGHTS
Increase in male kidney weights at all exposure levels and an increase in male liver weights at the medium and high dose exposures. Female liver weights were also increased compared with controls at the high dose level. The differences were slightly enhanced when results were adjusted for terminal body weight.

GROSS PATHOLOGY
Increased incidence of renal pallor and subcapsular granularity in the male rats exposed to high concentrations. No other changes observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys of male rats exposed to all concentrations of BRIGHTSOL contained multiple, hyaline, intracytoplasmic, inclusion-droplets in the epithelium of the proximal convoluted tubules and showed an increased incidence of focal cortical, tubular basophilia.

A low grade catarrhal inflammatory reaction was evident in the nasal cavities of the majority of rats exposed to the medium concentration. The lesions were confined to the olfactory epithelium and comprised mild mucosal and submucosal edema, focal congestion and diffuse low grade inflammatory cell infiltrates. Unilateral and bilateral lesions occurred.

Effect levels

Dose descriptor:
NOAEL
Effect level:
>= 6 000 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: No treatment-related mortality or significant adverse clinical effects occurred.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for BRIGHTSOL vapor following a 13-week inhalation exposure is greater than or equal to 6000 mg/m3
Executive summary:

BRIGHTSOL was administered by inhalation to albino rats for 6 hours/day, 5 days/week for 13 weeks at nominal vapor concentrations of 1500 mg/m3 and 3000 mg/m3, and 6000 mg/m3 to assess inhalation toxicity.  No mortality or treatment-related effects in any of the hematology and serum chemistry values were observed. Liver and kidney weights were increased in male rats at all exposure levels, and liver weights were increased in female rats at 6000 mg/m3. In addition, the male rats exposed to BRIGHTSOL at all concentrations contained multiple, hyaline, intracytoplasmic, inclusion-droplets in the epithelium of the proximal convoluted tubules and showed an increased incidence of focal cortical, tubular basophilia. The kidney effects observed in male rats are indicative of alpha-2u-globulin nephropathy. Alpha-2u-globulin nephropathy, also known as hyaline droplet nephropathy, results from the formation of complexes with a naturally occurring protein (alpha-2u-globulin) in the kidneys of male rats. These complexes can accumulate in the proximal renal tubules and may produce species-specific histopathological changes. These kidney effects are specific to male rats and are not considered to be of biological relevance to humans. Histopathological examination did not reveal any abnormalities that were considered treatment related. As there were no pathologic changes, changes in liver weight to body weight ratios mentioned above were judged to have been compensatory rather than toxic effects.  Based on these results, the No Observed Adverse Effect Level (NOAEL) was greater than or equal to 6000 mg/m3.