Registration Dossier

Administrative data

Description of key information

Oral NOAEL (Rat): >1000 mg/Kg bw/day

Inhalation NOAEC (Rat): ≥ 10400 mg/m3

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: According to or similar to guideline study OECD 422: GLP
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
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
Males were treated from day 14 prior to the mating phase until the end of the mating phase and then killed, Females were treated from day 14 prior to mating, through day 4 of lactation and then killed.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males were treated from day 14 prior to the mating phase until the end of the mating phase and then killed, Females were treated from day 14 prior to mating, through day 4 of lactation and then killed.
Frequency of treatment:
7days/week
Remarks:
Doses / Concentrations:
0, 25, 150, or 1000 mg/kg/day (10 ml/kg dosing volume)
Basis:
other: gavage
No. of animals per sex per dose:
10 male, 10 female per group
Control group: 10 male, 10 female, 0.5% methylcellulose
Control animals:
yes
Observations and examinations performed and frequency:
Effects on general toxicity, neurobehavioral activity, clinical chemistry, and hematology were evaluated. Gross necropsies and histopathologic examination of tissues were conducted with emphasis on the male reproductive tract.
Sacrifice and pathology:
All surviving animals were sacrificed following dosing
Statistics:
Adult body and organ weight, food consumption, clinical chemistry, open field activity and hematologic data (raw or transformed) were compared using either parametric or nonparametric (Kruskal-Wallis) ANOVA depending on whether the data were found to be homogeneous or nonhomogeneous using Bartlett's homogeneity of variance procedure. If ANOVA analysis indicated significant differences, Dunnett's test and Mann Whitney's U test, for parametric and nonparemetric data, respectively, were used to analyze for differences between the various dose groups.
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 specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
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:
No deaths or clinical signs of toxicity or behavioral changes were noted. No significant differences in body weights or feed consumption were observed. Startle reflex, open field test, and forelimb grip reflex performance data also revealed no treatment-related findings.
There were also no treatment-related changes in hematology or blood chemistry parameters, organ weights or gross pathology. An apparent treatment-related, slight to moderate hyperplasia of the non-glandular mucosa of the stomach, associated with degeneration, hyperkeratosis and submucosal subacute inflammation and, in a few cases, with erosion, was seen in animals of all treated groups. This effect was considered an artifact of the dosing method and not directly related to the toxicity of the test material. No other treatment related histological changes were observed.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (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:
Based on these data, the no-observable- adverse effect level (NOAEL) for repeated dose toxicty was >= 1000 mg/kg/day, the highest dose tested.
Executive summary:

Groups of 10 male and 10 female Sprague Dawley rats were dosed with decane daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/kg/day. Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation.  Oral dosing of decane produced no evidence of any adverse effects on clinical observations, organ weights, gross pathology, neurobehavioral activity, clinical chemistry or hematology endpoints. Evidence of irritation of the nonglandular mucosa of the stomach was observed, but was considered an artifact of the dosing method and not attributed to the inherent toxicity of the test material.  Based on these data, the no-observable- adverse effect level (NOAEL) for repeated dose toxicty was >=1000 mg/kg/day, the highest dose tested. 

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report equivalent or similar to OECD guideline 408: GLP
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 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Principles of method if other than guideline:
According to EPA guideline 82-1
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley Inc.
- Age at study initiation: ca. 8 weeks
- Weight at study initiation: 238-295g (males); 180-236g (females)
- Housing: individual
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-76
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1990-12-17 To:1991-07-13
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Test material was mixed with corn oil to ensure a 10ml/kg dose volume at all dose levels.

Test material mixtures were administered by oral gavage at a dose volume of 10ml/kg. The control animals received carrier at a dose of 10ml/kg. The satellite group was dosed at the high dose level for the same duration as main test and allowed to recover for 28 days post-treatment.

VEHICLE
- Amount of vehicle (if gavage): 10ml/kg

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
7 days/week
Remarks:
Doses / Concentrations:
5000 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
2500 mg/kg
Basis:
actual ingested
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
10 animals/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Test material mixtures were administered by oral gavage at three different doses at a dose volume of 10ml/kg. The control animals received carrier at a dose of 10ml/kg. The satellite group was dosed at the high dose level for the same duration as the main test and allowed to recover for 28 days post-treatment.

- Post-exposure recovery period in satellite groups: 28 days post-treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily monday-friday and once daily on weekends and holidays

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: prior to dosing, the day of dose initiation, and weekly thereafter

OPHTHALMOSCOPIC EXAMINATION: Yes
at study initiation and during the final week of the main study

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at main study termination and on satellite animals on the day of recovery sacrifice
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals:all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at main study termination and on satellite animals on the day of recovery sacrifice
- Animals fasted: Yes
- How many animals: all

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
The following parameters were statistically analyzed for significant differences: mean hematology parameters, serum chemistry parameters, organ weights, organ to body weight ratios, body weights, mean food consumption. Comparisons were limited to within sex analysis. Statistical evaluation of equality of means was done by an appropriate one way analysis of variance and a test of ordered response in the dose groups. First, Bartlett’s test was performed to determine if the dose groups have equal variance. If the variances were equal, the testing was done using parametric methods, otherwise nonparametric techniques were used.

For the parametric procedures, a standard one way ANOVA using the F distribution to assess significance was used. If significant differences among the means were indicated, Dunnett’s test was used to determine which treatment groups differ significantly from control. In addition to ANOVA, a standard regression analysis for liner response in the dose groups and linear lack of fit were preformed.

For the nonparametric procedure the test of equality of means was performed using the Kruskal-Wallis test. If significant differences among the means was indicated, Dunn’s Summed Rank test was used to determine which treatment group differ significantly from control. In addition, Jonckheere’s test for monotonic trend in the dose response was performed.

The statistical t-test was used to compare the satellite group’s main study termination and recovery termination hematology and clinical chemistry values. In addition, the t-test was used to compare the satellite group's and the control group's relative organ weights. The t-test was also used to compare the high dose and satellite groups to ensure similar results in order to accurately evaluate the recovery effects.
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):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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
One male and 1 female died in the control group, 2 females died in the 2500 mg/kg dose group, 4 females died in the 5000 mg/kg dose group, 2 males and 3 females died in the satellite group. With the exception of one 2500 mg/kg female, all of the other 13 listed spontaneous deaths appear to be a result of dosing trauma and/or aspiration of test material (due to physical characteristics of test material and the high dosage volume).

The majority of animals in the control, low and mid dose groups displayed no observable abnormal clinical signs. Observations included but are not limited to scabs, maloccluded incisors, alopecia and staining of fur, dry/wet rales, dyspnea, nasal discharge. The type and incidence of abnormal clinical signs were similar between the high dose and satellite groups with a dramatic increase in incidence when compared to mid dose group. Clinical signs most frequently noted included swollen anus, ano-genital staining, emaciation, and alopecia. During the satellite recovery period, the incidence of abnormal signs decreased over time with an increase in the number of animals exhibiting no observable abnormalities.

BODY WEIGHT AND WEIGHT GAIN
Statistically significant decreases from controls at the p<=0.05 level of significance were noted for mid dose males on days 77, 84, 91 and termination and for the high dose males on Day 42. A statistically significant decrease (p<=0.01) was noted for the high dose group males on Day 49 and continued through the end of the treatment period. Statistically significant decreases were noted for mid dose females (p<=0.05) on day 91 and for high dose females on days 77 and 91. At termination both mid and high dose females displayed a statistically significant decrease in body weight.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Statistically significant increases in food consumption which were linearly related to dose were noted for males on Days 28 through 56 and Day 70 through termination. Significance levels were noted for both the mid and high dose males during these periods. These trends were also evident in the females where statistically significant increases in food consumption were noted on Days 21, 42, 49, and 63 through 95.

OPHTHALMOSCOPIC EXAMINATION
No treatment-related findings.

HAEMATOLOGY
A statistically significant increase in platelets which was linearly related to dose in both the males and females was observed. In addition the male animals displayed a linear dose related increase in white blood cells. The mid dose male values were noted to differ significantly from those of controls for hematocrit and hemoglobin at the p<=0.01 level of significance and mean corpuscular volume and mean corpuscular hemoglobin at the p<=0.05 level of significance.

CLINICAL CHEMISTRY
Statistically significant increases in males (p<=0.01) for urea nitrogen and gamma glutamyl transpeptidase for the high dose males and also the mid dose males for urea nitrogen. An increase for cholesterol was noted for the mid and high dose groups of both sexes (p<=0.01). An increase in alanine aminotransferase was also noted for the mid and high dose males (p<=0.01). Glucose levels were significantly lower than the control values (p<=0.01) for both sexes in the mid and high dose and for the male low dose (P<=0.05). A statistically significant increase in bilirubin in the high dose of both sexes was observed. Other parameters showing statistically significant differences from controls included creatinine, chloride, tryglycerides.

ORGAN WEIGHTS
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. Both the male and female relative kidney weights for all treated groups were significantly different from the control value (p<=0.01).

GROSS PATHOLOGY
Most frequently observed abnormalities include small and large intestine distension (mid and high dose groups); swollen anus (high dose groups), staining of the fur (mid and high dose groups).
Key result
Dose descriptor:
NOAEL
Effect level:
>= 5 000 mg/kg bw/day (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 No Observed Adverse Effect Level (NOAEL) following oral exposure to MRD-89-582 for 90-days is greater than or equal to 5000 mg/kg/day.
Executive summary:

MRD-89-582 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.  Based on the results, the No Observed Adverse Effect Level (NOAEL) for the 90-day study was greater than 5000 mg/kg/day.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Three read across studies available from structural analogues.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Referenceopen allclose all

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:
not specified
Species:
rat
Strain:
other: albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Shell Toxicology Laboratory Breding Unit
- Age at study initiation: 10-13 weeks
- Housing: three of one sex per cage
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum

During the period of the test the laboratory temperature varied between 19.4°C and 26.1°C and the relative humidity between 37% and 74%.
Barometric pressure was within the range 753 to 768 mm Hg


Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Details on inhalation exposure:
The atmospheres were generated by completely evaporating the solvent into the streams of ventilating air entering the chambers using micrometering pumps and vaporizers. The vaporizers consisted of electrically heated quartz tubes whose surface temperatures were adjusted during preliminary experiments to the minimal for complete evaporation of the solvent.

Each chamber was constructed of aluminum, with a volume of 1 m3 and was ventilated by air drawn from the laboratory through dust filters. The exhaust ducts from each chamber entered a common exhaust duct through which the air was drawn by a fan situated on the roof of the laboratory.

The total air flow rate through the main duct exhausting all four chambers was recorded continuously throughout the test by means of an electro—anemometer mounted in the duct. Slight adjustments were made as required to compensate for the effects of wind at the efflux point. The total flow rate was maintained at 2.0 + 0.03 m3 ∙min- 1. The individual flow rates through each chamber were balanced before the exposures began but were not checked further throughout the test since any significant changes would have been detected by the resulting changes in toxicant concentration. The flow rates were adjusted to 0.50 m3 ∙min- 1.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test atmospheres were analyzed sequentially by means of a total hydrocarbon analyzer fitted with a flame-ionisation detector (Beckman 109A). The analyzer was calibrated during the test by means of known concentrations of SHELLSOL TD, prepared in a Teflon FEP gas sampling bag.

The recorder traces from the analyser were examined daily and a ‘daily mean concentration’ value was estimated by visual inspection. The daily mean concentrations for each of the test atmospheres were then ‘pooled’ to give weekly mean concentrations. The overall means of the weekly mean concentrations are given below:
Nominal concentration Observed concentration
(mg/m3) (mg/m3) (ppm)
10400* 10186 SD 327 1444
5200 5200 SD 207 737
2600 2529 SD 116 359
*83% saturated.

The desired concentrations of solvent in the test atmospheres were reached within 10 mm of the start of each exposure period. They then stayed remarkably constant throughout the 6 h exposure period.
Duration of treatment / exposure:
Six hours/day
Frequency of treatment:
five days/week for 13 weeks
Remarks:
Doses / Concentrations:
0, 2600, 5200, 10400 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
6 animals/sex/dose (total of 12 animals/dose)
Control animals:
yes, sham-exposed
Details on study design:
The start and finish of the experiment was staggered in order that the optimum number of animals could be examined histopathologically after exposure. On each of four consecutive days, four male and four female rats per chamber were started on the experiment. The remaining two males and two females were started the next day. Thirteen weeks later, four male and four female rats per chamber were removed from the experiment for pathological examination on each of four consecutive days. The remaining two males and two females were removed the next day.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule for examinations: daily

DETAILED CLINICAL OBSERVATIONS: Yes


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption for each animal determined weekly: Yes


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: Yes / No / No data


WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly


OPHTHALMOSCOPIC EXAMINATION: No



HAEMATOLOGY: Yes
- Time schedule for collection of blood: 18h after the last 13 week exposure
- How many animals: all


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 18h after the last 13 week exposure
- How many animals: all



URINALYSIS: Yes / No / No data
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.


NEUROBEHAVIOURAL EXAMINATION: No



OTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes for all animals exposed to the high and medium concentrations, plus the control animals. Kidneys of low concentration males were also examined.
Other examinations:
Organ weights
After post-mortem examinations the following organs were weighed:
Brain
Liver
Heart
Spleen
Kidneys
Testes

Histopatholgy. Tissues taken for histological examination were:

Mammary gland (posterior site with skin)
Mesenteric lymph node
Pancreas
Stomach
Intestine at 5 levels
Caecum
Spleen
Liver (middle, left and triangular lobes)
Adrenals
Kidneys
Ovaries or testes
Uterus or prostate
Seminal vesicles
Urinary bladder
Thyroid (with oesophagus and trachea)
Trachea (mid course and bifurcation)
Heart
Lungs
Nasal cavity
Thymus
Eye and lacrimal glands
Salivary gland (submaxillary)
Brain
Spinal cord (thoracic)
Pituitary
Tongue
Sciatic nerves
Muscle (femoral)
Knee joint and femur
Plus any other macroscopic lesion in any tissues.
The samples marked were held in 4% neutral formalin and only processed for histological examination if indicated by clinical or other pathological findings.
Statistics:
Body and organ weights were analysed by covariance analysis using initial body weight as the covariate. Reported means were adjusted for initial body weight if a significant covariance relationship existed: where no significant covariance relationship was found, unadjusted means were reported.

Organ weights were further examined by covariance analysis using the terminal body weight as the covariate. The organ weight means are reported as adjusted for terminal body weight if a significant covariance relationship existed. Although not a true covariance analysis (because the terminal body weights are dependent upon treatment), the analysis does provide an aid to the interpretation of organ weights when there are differences in terminal body weights. The analysis attempts to predict what the organ weights would have been, had all the animals had the same terminal body weight.
Clinical, chemical and haematological parameters were examined using analysis of variance.

The analysis allowed for the fact that animals were multihoused. Differences in response can be affected by cage environment as well as by treatment but this effect is minimal in a study of this duration.
The significance of any difference between treated and control group means was tested using the Williams t test (1971, 1972). However, if a monotonic dose response could not be assumed Dunnett’s test (1964) 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:
not examined
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:
No deaths were recorded and clinical signs of toxicity were absent in the low and medium exposure groups; the high exposure groups were slightly lethargic when examined up to one hour after cessation of exposure. Body weight gain was slightly reduced in all female groups and in high exposure males. Water intake was increased in the high exposure males only.

Female aspartate amino transferase and alanine amino transferase were decreased in all female groups exposed to SHELLSOL-TD. No pathological changes were detected which could explain the observed decreases in these enzymes. In view of this lack of supporting evidence and the fact that the control values for these two parameters were high when compared with historical controls in the laboratory, these changes were not considered toxicologically significant.

Male alkaline phosphatase, potassium, chloride and albumin were increased at the high exposure level. These were considered to represent biological variation in the rat and were not considered treatment-related.

Male kidney weights were increased at all exposure levels. Hyaline intracytoplasmic inclusions and an increased incidence of tubular degeneration and/or dilatation were seen in the cortical tubules of all exposed males. These are a common effect observed in repeated-dose animal studies with hydrocarbon solvents. These kidney changes have been identified to result from an alpha2u-globulin-mediated process that because of its sex and species specificity, is not regarded as relevant to humans.

A low grade anemia was evident in all males exposed to SHELLSOL TD, characterized by slight reductions in haemoglobin, packed cell volume and total erythrocyte counts. Splenic weight was increased in the high concentration males. These changes were not seen in females and were not considered dose-related and therefore considered not toxicologically relevant.

Male and female liver weights were increased at the high and medium exposures, and male liver weights at the low exposures also. No lesions were identified histologically in the livers of treated animals that could account for the increased weight. This change was considered a physiological response to exposure rather than a toxic response and as such is not of toxicological significance.
Dose descriptor:
NOAEC
Effect level:
> 10 400 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 SHELLSOL TD is 10186 mg/m3 (actual) (1444 ppm) under the test conditions of this study.
Executive summary:

SHELLSOL TC was administered by inhalation to albino rats for 6 hours/day, 5 days/week for 13 weeks at nominal vapor concentrations of 10400 mg/m3, 5200 mg/m3, and 2600 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, male heart weights were increased at the highest exposure level and liver and kidney weights were increased in female rats at 10400 mg/m3.  In addition, the male rats exposed to SHELLSOL TC at all concentrations showed tubular degeneration and hyaline inclusion-droplets in the epithelium.  There was also scattered degeneration of the proximal renal tubules which showed cytoplasmic pallor and shrinkage. Occasionally the degenerate tubules were surrounded by a lymphocyte infiltrate. Many tubules also showed dilatation of the cortico-medullary junction, the dilated tubule being filled with a flocculent eosinophilic material. 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 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.  Histopathological examination did not reveal any abnormalities that were considered treatment related.  As there were no pathologic changes, changes in organ weights 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 10400 mg/m3.

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 April 1978 - 30 March 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. Limited documentation on animal housing, only 2 concentrations tested, exposure duration 84 days, no ophthalmological examination.
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
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass. 01887
- Age at study initiation: males 6 wks, females 7 wks
- Weight at study initiation: males 185 g mean (range 165-217 g); females 162 g mean (range 138-189)
- Fasting period before study: no
- Housing: paired in chamber, individual out of chamber
- Diet (e.g. ad libitum): Standard laboratory pellet diet (Purina Laboratory Chow) ad libitum (out of chamber only)
- Water (e.g. ad libitum): ad libitum (out of chamber only)
- Acclimation period: 13 days
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: not applicable, vapour
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chambers with 1 cubic meter total volume (760 L effective volume)
- Source and rate of air:
- Method of conditioning air:
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 134 L/min
- Air change rate: 8 per hour
- Method of particle size determination: not applicable, vapour


TEST ATMOSPHERE
- Brief description of analytical method used: Atmospheric sampling was performed using a Wilks Scientific Corp., Miran 1A Ambient Air Analyzer (long pathlength infrared). A calibration curve relating the absorption to the airborne concentration of the test material was prepared. On each exposure day, three samples were drawn from each exposure chamber (at about 1, 3, and 5 hours) and the exposure concentration calculated by comparing the absorption of this sample to the standard curve.
In addition, the composition of the test atmosphere was analyzed for homogeneity by gas chromatographic analysis of several charcoal-trapped vapour samples collected from each chamber during the 12-wk exposure period
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test atmosphere was analysed for concentration and homogeneity by measurement of the infrared spectrum and by gas chromatographic analysis, respectively. Based on the infrared analysis the animals were exposed to cumulative mean concentrations of 385 and 1200 ppm, respectively. Gas chromatographic analysis of the chamber atmosphere demonstrated that the test material composition was representative of the initial sample.
Duration of treatment / exposure:
12 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
400, 1200 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
35
Control animals:
yes, sham-exposed
Details on study design:
- Rationale for animal assignment (if not random): assigned to group by weight
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: incidence of abnormal signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (full recorded physical assessment)


BODY WEIGHT: Yes
- Time schedule for examinations: weekly, from 5 days prior to exposure through termination


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes (retro-orbital sinus)
- Time schedule for collection of blood: 4, 8, 12 weeks
- Anaesthetic used for blood collection: Yes (exsanguination under ether anesthesia)
- Animals fasted: Yes (fasted overnight prior to bleeding)
- How many animals: 10/sex/group (4 and 8 weeks), 15/sex/group (12 weeks, all survivors)
- Parameters examined: hemoblobin, hematocrit, erythrocyte count, clotting time, total and differential leukocytes


CLINICAL CHEMISTRY: Yes (retro-orbital sinus)
- Time schedule for collection of blood: 4, 8, 12 weeks
- Animals fasted: Yes (exsanguination under ether anesthesia)
- How many animals: 10/sex/group (4 and 8 weeks), 15/sex/group (12 weeks, all survivors)
- Parameters examined: blood urea nitrogen, serum glutamic pyruvic transaminase (SGPT), glucose, alkaline phosphatase


OTHER:
Organ weights and organ/body weight ratios determined in animals sacrificed at 4, 8 and 12 weeks (adrenals, brain (sans pituitary), gonads, kidneys, liver, lungs)
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: adrenals, brain (without pituitary), gonads, kidneys, liver, lungs
HISTOPATHOLOGY: Yes (control and 1200 ppm group): adrenals (2), bone marrow (sternal), brain (2 sections), eye, gonad, heart (with coronary vessels) intestine, colon, duodenum, ileum, kidneys (2), liver (2 sections), lung (2 sections), lymph node (mesenteric), mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin, spinal cord (cervical), spleen, stomach, thyroid, trachea, urinary bladder, uterus/prostate, gross lesions, tissue masses
Statistics:
Body weight, hematology and clinical chemistry parameters, organ weights and organ/body weight ratios were statistically evaluated. Mean values for all treatment groups were compared to the control group at each time interval (4, 8, and 12 weeks). Hematology and clinical chemistry parameters were compared by the F-test and Student's t-test. When variances differed significantly (F-test), Student's t-test was appropriately modified using Cochran's approximation (t'). Body weight, organ weight and organ/body weight ratios were compared to control according to Dunnett.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No treatment-related mortality occured (1 male of the 1200 ppm group was accidentally killed).
Several animals in all groups exhibited dry rales and red and mucoid nasal discharge (more numerous in the treated groups, but not clearly treatment-related), moist rales, excessive lacrimation, hair loss and chromodacryorrhea were found in a limited number of animals in all groups (not treatment-related)
1200 ppm: singular occurrences of excessive salivation, laboured, irregular breathing; yellow staining of the anogenital fur in 6 males and 35 females from wk 3 through 12
400 ppm: yellow staining of the anogenital fur in 2 females
Control: singular occurrences of excessive salivation and bleeding inside the ear; a limited number of animals with brown staining of the ano-genital region and soft stool; three observations (in one animal) of an abnormally dark red or red and yellow eye

BODY WEIGHT AND WEIGHT GAIN
1200 ppm: mean body weights in males significantly higher at wk 2 and significantly lower (p?0.05) from wk 8 through 11 than in controls
400 ppm: mean body weight and weight gains in males similar to control throughout the study, except wk 2 (significantly higher, p?0.01), in females mean body weights significantly depressed (p?0.01 and p?0.05) at wk 5 through 8.

HAEMATOLOGY
Several statistically significant (p < 0.05 and p < 0.01) decreases in mean hematocrit values of males and females of both treated groups at wk 4 and 8, statistically significant decreases (p?0.05) in mean hemoglobin values at wk 8 in the males of both treated groups and the females of the 400 ppm group at wk 4. Mean red blood cell values were significantly decreased in 1200 ppm males at wk 8 and 400 ppm females at wk 12. Since all values were within normal biological limits, these findings were not considered to be treatment-related.

CLINICAL CHEMISTRY
Mean SGPT levels were significantly (p?0.01) depressed in 1200 ppm males at wk 4, 400 and 1200 ppm males at wk 8, and in 1200 ppm females at wk 12. Mean blood urea nitrogen levels were significantly increased in the males of both treated groups at wk 8. Mean glucose levels were significantly (p?0.01 or p?0.05) increased in 400 ppm males at wk 8, decreased in 1200 ppm males at wk 12, and decreased in 1200 ppm females at wk 4 and 12. The observed effects were not considered to be treatment-related.

ORGAN WEIGHTS
Mean kidney weights and kidney/body weight ratios were significantly (p?0.05) higher in the 1200 ppm males at wk 8. In the 400 ppm males these values were also elevated, but not statistically significant. At wk 12, mean kidney weights and kidney/body weight ratios for 400 and 1200 ppm males were significantly (p?0.01) elevated, indicating a treatment-related response. The only other statistically significant (p?0.05) findings were elevated mean adrenal/body weight ratios for the 1200 ppm males at wk 4 and the 400 ppm females at wk 12.

GROSS PATHOLOGY
Microscopic evaluation of organs and tissues from the control and high level exposure groups revealed a mild tubular injury in the kidneys of some exposed male rats sacrificed after exposure for 8 and 12 wk. Other changes were unrelated to group or sex and were considered to be spontaneous.

HISTOPATHOLOGY: NON-NEOPLASTIC
See Gross Pathology
Key result
Dose descriptor:
NOAEC
Effect level:
1 200 ppm (nominal)
Sex:
male
Basis for effect level:
other: overall effects
Critical effects observed:
not specified

Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study.

The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males.

The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC.

Conclusions:
In a 12 -week inhalation study with rats the test substance hydrocarbons, C7 -C9, isoalkanes was tested. Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study.

The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males.

The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of ?2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC.

Renal effects were strictly limited to males, therefore the authors concluded an ?2u-globulin-related mechanism for the observed nephropathy. The observation was not considered for determination of the NOAEC.
Executive summary:

In a 12 -week inhalation study with rats the test substance hydrocarbons, C7 -C9, isoalkanes was tested. Significantly increased mean kidney weights and kidney/body weight ratios were observed in males at 400 ppm, which were considered to be treatment-related by the authors of the study. The kidney was confirmed as potential target organ for the test material-induced toxicity by the observation of mild tubular injury found in the histopathological examination of high dose males. The fact, that these effects were strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of ?2u-globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and therefore not relevant for risk assessment in humans. Therefore, these effects were not considered for the determination of the NOAEC. Renal effects were strictly limited to males, therefore the authors concluded an ?2u-globulin-related mechanism for the observed nephropathy. The observation was not considered for determination of the NOAEC.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 400 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Two key read across studies availablle from structural analogues.

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 are no data available for Hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics. However, data are available for structural analogues, Hydrocarbons, C7-C9, isoalkanes, <2% aromatics; Decane; Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics; Hydrocarbons, C10-C12, isoalkanes, <2% aromatics; and Hydrocarbons, C10-C13, n-alkanes, isoalkanes, cyclics, <2% aromatics. These data are read across 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

Decane

In a key OECD Guideline 422 screening reproductive/developmental toxicity study (Sasol, 1995), groups of 10 male and 10 female Sprague Dawley rats were dosed with decane daily by gavage at exposure levels of 0, 25, 150, or 1000 mg/Kg/day. Males were dosed from the 14th day prior to mating, during mating until the end of the mating period. Females were dosed from the 14th day prior to the start of the mating phase to day 4 of lactation. Oral dosing of decane produced no evidence of any adverse effects on clinical observations, organ weights, gross pathology, neurobehavioral activity, clinical chemistry or hematology endpoints. Evidence of irritation of the nonglandular mucosa of the stomach was observed, but was considered an artifact of the dosing method and not attributed to the inherent toxicity of the test material. Based on these data, the no-observable- adverse effect level (NOAEL) for repeated dose toxicty was >=1000 mg/Kg/day, the highest dose tested. 

Hydrocarbons, C10-C12, isoalkanes, <2% aromatics

A 90-day subchronic toxicity study was conducted in rats to assess the toxicity of Hydrocarbons, C10-C12, isoalkanes, <2% aromatics (ExxonMobil Corp., 1990). The test mixture was administered by oral gavage at a dose of 0, 100, 500, or 1000 mg/Kg, 7 days per week for a period of 13 weeks. The control animals received a carrier (corn oil) dose and a satellite group was dosed at 1000 mg/Kg, 7 days/week for 13 weeks and was then observed for reversibility, persistence or delayed occurrence of toxic effects for 28 days post-treatment. Observations were made as to the nature, onset, severity, and duration of toxicological signs. No treatment-related mortalities or clinical effects were observed. Animals in all dose group exhibited an overall mean weight gain. Minimal changes were noted in the haematology and serum chemistry values, however, all were considered to be either within normal biological variation or not adverse effects. The mean absolute and relative liver weights for both the 500 and 1000 mg/kg dose groups (both sexes) were significantly greater than the corresponding control values; however, these changes were found to be reversible following the 28 day recovery period. Slight increases in mean kidney weights were also noted in the 500 and 1000 mg/kg female dose groups, however, these changes were not considered to be adverse effects. All histopathological findings were minimal and no treatment related adverse effects were noted. Based on the data recorded in this study, the NOAEL was determined to be greater than 1000 mg/Kg.

Additionally, in order to comply with standard information requirements for Annex X substances, OECD Guideline 90-day sub-chronic (OECD 408) toxicity tests are proposed for structural analogues Hydrocarbons, C7-C9, isoalkanes, <2% aromatics (EC# 921-728-3), Hydrocarbons, C9-C11, isoalkanes, cyclics, <2% aromatics (EC# 920-134-1), and Isohexadecane (2,2,4,4,6,8,8-heptamethylnonane (EC# 224-506-8)). The testing proposals for the same have been presented in the lead registrant dossiers for these substances already submitted to ECHA. These studies will be conducted subsequent to ECHA's approval and this endpoint will be updated upon completion of the above studies.

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

In a key oral sub-chronic toxicity 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. 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. Based on the results, the No Observed Adverse Effect Level (NOAEL) for the 90-day study was greater than 5000 mg/Kg/day.

Inhalation

Hydrocarbons, C7-C9, isoalkanes, <2% aromatics

Systemic toxicity of hydrocarbons, C7-C9, iso-alkanes was assessed in a 12-week inhalation toxicity study in rats (ExxonMobil Chemical,1979). In this study, repeated exposure to 400 or 1200 ppm of the test substance for 6 hours/day, 5 days/week, for 12 weeks resulted in male rat kidney effects consistent with the alpha-2µ-globulin-induced nephropathy in male rats. There was no treatment-related mortality and clinical findings were unremarkable. Under the test conditions, the NOAEC (excluding male rat nephropathy) was determined to be >1200ppm.

The fact, that alpha-2µ-globulin-induced nephropathy was strictly limited to male rats and that the test substance belongs to a category of substances which are known for their ability to induce nephropathy in male rats due to their exclusive expression of alpha-2µ -globulin, the protein known to play the crucial role in the onset of this disease, the observed effects in the kidney have to be regarded as species-specific and are not relevant for risk assessment in humans.

Hydrocarbons C9-C11, isoalkanes, cyclics, <2% aromatics

In a sub-chronic inhalation toxicity study (ExxonMobil, 1978), the test material (hydrocarbons, C9 -C11, isoalkanes, cyclics, <2% aromatics) was administered by inhalation to Sprague-Dawley rats for 6 hours/day, 5 days/week for 12 weeks at nominal vapor concentrations of 300 ppm and 900 ppm to assess subchronic inhalation toxicity. Ten animals per sex per group were examined at 4 weeks, 8 weeks and all survivors were sacrificed and examined at 12 weeks. Male body weight gain was significantly decreased at 900 ppm. There were no treatment-related effects in any of the hematology and serum chemistry values. Liver and kidney weights were increased in male rats at 900 ppm, and adrenal weights were increased in female rats at 900 ppm. 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 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. Histopathological examination did not reveal any abnormalities that were considered treatment related. As there were no pathologic changes, changes in organ weight to body weight ratios 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 900 ppm (>=5220 mg/m3).

Hydrocarbons, C10-C12, isoalkanes, <2% aromatics

In a key sub-chronic toxicity study (Shell, 1980), the test material (Hydrocarbons, C10-C12, isoalkanes, <2% aromatics) was administered by inhalation to albino rats for 6 hours/day, 5 days/week for 13 weeks at nominal vapor concentrations of 10400 mg/m3, 5200 mg/m3, and 2600 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, male heart weights were increased at the highest exposure level and liver and kidney weights were increased in female rats at 10400 mg/m3. In addition, the male rats exposed to the test material at all concentrations showed tubular degeneration and hyaline inclusion-droplets in the epithelium. There was also scattered degeneration of the proximal renal tubules which showed cytoplasmic pallor and shrinkage. Occasionally the degenerate tubules were surrounded by a lymphocyte infiltrate. Many tubules also showed dilatation of the cortico-medullary junction, the dilated tubule being filled with a flocculent eosinophilic material. 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 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. Histopathological examination did not reveal any abnormalities that were considered treatment related. As there were no pathologic changes, changes in organ weights mentioned above were judged to have been compensatory rather than toxic effects. Based on these results, the No Observed Adverse Effect Concentration (NOAEC) was determined to be greater than or equal to 10400 mg/m3.

 

In a supporting sub-chronic toxicity study (ExxonMobil Corp., 1978), the test material (Hydrocarbons, C10-C12, isoalkanes, <2% aromatics) was administered by inhalation to rats at vapor concentrations of 300 or 900 ppm for 6 hours/day, 5 days/week for 12 weeks. No treatment-related effects on mortality were observed and there were no significant alterations in hematology or clinical chemistry parameters. Body weights were decreased and kidney weights were elevated in male rats at 300 and 900 ppm. Relative mean liver weights were elevated in males at 900 ppm, but no changes were noted in histopathology. Under the conditions of this study, the No Observed Adverse Effect Concentration (NOAEC) was determined to be greater than 900 ppm (> 5220 mg/m3).

 

In a supporting short-term toxicity study (Chevron Phillips, 1969), four rhesus monkeys were exposed to 4.2 mg/L of the test material (Hydrocarbons, C10-C12, isoalkanes, <2% aromatics) for 6 hours/day, for 3 days a week for 4 weeks. A total of 13 treatments were completed. There were no noted changes in behavior, clinical chemistry, hematological, or histopathological parameters. The NOAEC in primates was determined to be > 4.2 mg/L (> 4200 mg/m3).

Justification for classification or non-classification

Based on available read-across from structurally related substances, Hydrocarbons, C9-C11, n-alkanes, isoalkanes, <2% aromatics does not meet the criteria for classification for repeated dose toxicity (STOT-RE) under Regulation (EC) No 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).