Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Repeated Dose Oral 90d - NOAEL ≥ 500 mg/kg bw/day for rats (OECD 408); BMDL = 1857 mg/Kg bw/day

Repeated Dose Inhalation 90d – NOAEC ≥ 6000 mg/m3 for rats (similar to OECD TG 413)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
1study available from structural analogue. BMDL level determined and presented in the additional information section.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
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.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
no
Species:
rat
Strain:
other: Albino
Details on test animals or test system 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

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
Remarks:
Doses / Concentrations:
1500mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3000 mg/m3
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
6000mg/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.
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.
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.

Dose descriptor:
NOAEC
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.
Critical effects observed:
not specified
Conclusions:
The NOAEC for BRIGHTSOL vapor following a 13-week inhalation exposure is greater than or equal to 6000mg/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 Concentration (NOAEC) was greater than or equal to 6000 mg/m3.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
6 000 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
1 supporting sub-chronic study available from structural analogue

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There is no data available for repeated dose toxicity for Hydrocarbons, C14 -C15, n-alkanes, <2% aromatics. However, read across data is available for structural analogues Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, <2% aromatics and Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics. This data is read across to Hydrocarbons, C14-C15, n-alkanes, <2% aromatics based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Oral: 

Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, <2% aromatics

In a key study (ExxonMobil, 1991), the test material (Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, <2% aromatics) was administered

by oral gavage to rats at concentrations of 500, 2500 and 5000 mg/kg, 7 days a week for 13 weeks to assess the subchronic toxicity. An additional group of animals, dosed at 5000 mg/kg/day, was held for 4 weeks to assess reversibility. No treatment-related mortality was observed; however, male body weights were decreased while food consumption increased in the 2500 and 5000 mg/kg dose groups. Liver weights were elevated in male and female rats at 2500 and 5000 mg/kg/day. Adrenal weights were significantly increased in male and female rats at 5000 mg/kg and in female rats at 2500 and 5000 mg/kg. Testes weights were elevated in male rats at 5000 mg/kg. Kidney effects occurred in males at all dose levels, and 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 tubule 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.

Dose-related changes in hematology or serum chemistry parameters were observed and were consistent with the changes seen in the liver. Histological findings of hepatocellular hypertrophy (liver cell enlargement) were seen in livers of both sexes in all dose groups. These findings are believed to have been a compensatory response and not an indication of toxicity. Additionally, these liver effects were reversible and occurred only at high doses that are not typical of hydrocarbon exposures for humans. Other treatment-related effects were mucosal thickening and other signs of irritation of the stomach and anus which appear to be the direct result of high dose intubation of a the locally irritating test substance. These effects are believed to have been a compensatory response to local irritation and not an indication of toxicity. All treatment-related effects were reversible within the 4-week recovery period. Basedon a significant increase in ALT levels in the 2500 and 5000 mg/kg/day treatment groups in male rats,theNo Observed Adverse Effect Level (NOAEL) for the 90-day study was greater than 500 mg/Kg/day.

This NOAEL value is dependent on doses selected in the study and may not represent a true biological threshold. In order to circumvent the problem of dose-selection bias, benchmark analysis was used to determine a benchmark dose for this study, using individual ALT dose–response values in male rats as the critical effect. Since the minimal level of change in the endpoint (increased serumALT) that would be considered biologically significant was known (2–4-fold increase compared to concurrent control values), this value was used as the Benchmark response in the derivation of a BMDL, although the BMDL value using the EPA default BMR of 1SD from the mean was providedfor comparison. The use of the 1SD default for the BMR resulted in an overly conservative BMDL value, 3-fold lower than would have been predicted using the NOAEL/ LOAEL approach. When the BMR was more accurately defined in terms of a 2-fold minimum level of change over the control mean, the estimated BMDL value was 1857 mg/Kg/day.

 

Additionally, OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents) tests are proposed for structural analogues, Hydrocarbons, C14 -C19, isoalkanes, cyclics, <2% aromatics, Hexadecane, and Isohexadecane. This data is read across to Hydrocarbons, C14 -C15, n-alkanes, <2% aromatics based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

This endpoint will be updated subsequent to ECHA's approval of the testing proposals and availability of data upon completion of the studies.

Inhalation:

Hydrocarbons, C11 -C14, n-alkanes, isoalkanes, cyclics, <2% aromatics

The test material (Hydrocarbons, C11 -C14, n-alkanes, isoalkanes, cyclics, <2% aromatics) was administered by inhalation to albino rats for 6 hours/day, 5 days/week for 13 weeks at nominal vapor concentrations of 1500 mg/m3and 3000 mg/m3, and 6000 mg/m3to 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 the test material 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 Concentration (NOAEC) was greater than or equal to 6000 mg/m3.

Justification for classification or non-classification

Based on available data, Hydrocarbons, C14 -C15, n-alkanes, <2% aromatics do not meet the criteria for classification for repeated dose toxicity (STOT-RE) under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).