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: According to 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)
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: Approximately 6 weeks
- Weight at study initiation: Males: 156.2-223.2 g; Females: 136.2-170.9 g
- Housing: Individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 16 days


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


IN-LIFE DATES: From: October 24, 1990 To: September 27, 1991
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The test material was diluted in vehicle at the following concentration to ensure a 5ml/kg dose volume at all dose levels:
-Group 2=0.1g/kg (2.0% w/v)
-Group 3= 0.5g/kg (10% w/v)
-Group 4 and 5= 1.0g/kg (20.0% w/v)

VEHICLE
- Amount of vehicle (if gavage): 5ml/kg
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
The test material mixtures and control were administered by oral gavage at a dose volume of 5ml/kg, 7 days per week for a period of 13 weeks.
Remarks:
Doses / Concentrations:
0.1g/kg (2.0w/v)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
0.5g/kg 10% w/v)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1.0g/kg (20% w/v)
Basis:
actual ingested
No. of animals per sex per dose:
All groups consisted of 20 mice (10males; 10 females)
Group 1=Control group (
Group 2= 0.1g/kg (2.0% w/v)
Group 3= 0.5g/kg (10% w/v)
Groups 4=1.0g/kg (20% w/v).
Group 5 (satellite)= 1.0g/kg (20% w/v).
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for selecting satellite groups: observed for reversibility, persistence or delayed occurrence of toxic effects
- Post-exposure recovery period in satellite groups: 28 days
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were made daily. Clinical laboratory studies were performed on all animals pre-dose, interim (day 32 for males, and day 33 for females), and at main study termination. For the satellite animals, clinical laboratory studies were also performed on the day of recovery sacrifice.


BODY WEIGHT: Yes
- Time schedule for examinations: prior to dosing (pretest), on the day of dose initiation (Day 0), and weekly thereafter. Body weights were also recorded at sacrifice or death.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to study initation and during the final week of the main study
- Dose groups that were examined: all dose groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pre-dose, interim (day 32 for males, and day 33 for females), and at main study termination. Also on day of recovery sacrifice for the satellite animals.
- Anaesthetic used for blood collection: Yes-methoxyflurane
- Animals fasted: yes
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pre-dose, interim (day 32 for males, and day 33 for females), and at main study termination. Also on day of recovery sacrifice for the satellite animals.
- Animals fasted: yes
- How many animals: all animals

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
The necropsy included an examination of the external surface of the body, all orifices, and the cranial, thoracic, and abdominal cavities and their contents. The kidneys, liver, ovaries, tested, adrenals, and brain were weighed prior to fixation.

HISTOPATHOLOGY: Yes
-erythrocyte count
-hematocrit
-hemoglobin
-leukocyte count
-mean corpuscular volume
-mean corpuscular hemoglobulin
-mean corpuscular hemoglobulin concentration
-platelets
-reticulocyte count

SERUM CHEMISTRY:
-total bilirubin
-albumin
-blood urea nitrogen
-calcium
-cholesterol
-creatinine
-electrolytes
-glucose
-total protein
-triglycerides
-phosphorous
-gamma glutamyl transferase
-serum aspartate aminotransferase
-serum alanine aminotransferase
Statistics:
The following parameters were statistically analyzed for significant differences:
-mean hematology parameters
-mean serum chemistry parameters
- mean organ weights
- mean organ to body weight ratios
- mean 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 for ordered response in the dose groups. Bartlett's test was performed first. If the dose groups had equal variance, a parametric method was used. Otherwise, nonparametric techniques were used.

Parametric procedures involved a standard one way ANOVA using the F distribution. If significant differences among the means were indicated, Dunnett’s test was used to determine significant differences from control. In addition, a standard regression analysis for linear response in the dose groups and linear lack of fit were performed.

Nonparametric procedures involved the test of equality of means using the Kruskal-Wallis test. If significant differences were indicated, Dunn’s Summed Rank test was used. 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 values. In addition, the t-test was used to compare the satellite group’s and the high dose group's relative organ weights. The t-test was also used to evaluate recovery.
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 specified
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic changes were observed in the kidneys and liver of male rats and in the livers of female rats. The treatment-related effects in the kidney were characterized predominantly by accumulations of hyaline droplets in the cytoplasm of the proximal tubules of the cortex. An increased incidence of multifocal cortical tubular basophilia with changes consistent with both degeneration and regeneration of the tubular epithelium also was present as well as dilated medullary tubules with granular casts. These renal changes were observed only in males in all doses necropsied immediately after the 90-day treatment period. The incidence and severity of these changes generally occurred in a dose-related manner. After the reversibility period, there were still residual changes but of a lesser degree. Dilated tubules with granular casts in the medulla and an increased incidence of multifocal cortical tubular basophilia were noted. No-treatment related microscopic changes were observed in the kidneys of the female rats.

Changes in the liver consisted of a minimal to slight centrilobular hepatocellular hypertrophy in the high dose male rats and in the female rats of the mid and high dose groups. The centrilobular areas were more prominent and the hepatocytes were larger with an increased amount of eosinophilic cytoplasm. Centrilobular hepatocellular hypertrophy was not observed in any of the satellite group rats.

OTHER FINDINGS
Two control female rats died prior to study termination. One rat had diffuse fibrinopurulent pleuropneumonia and pericarditis. These changes are believed to be related to a dosing accident with perforation of the esophagus in the thoracic cavity. The cause of death in the second control female included bacterial nephritis and an associated mucosal hyperplasia and distention of the ureter and urinary bladder.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: No treatment-related clinical in-life signs of toxicity and no mortality were observed at the highest dose tested.
Critical effects observed:
not specified

Microscopic changes in the male kidneys characterized by hyaline droplet accumulation in the cytoplasm of the proximal tubules of the cortex and an increased incidence of multi-focal cortical tubular basophila with changes consistent with both degeneration and regeneration of the tubular epithelium and dilated medullary tubules with granular casts are typical of a syndrome that occurs specifically in male rats and is unlikely to have a correlation to humans.  The syndrome, Alpha-2u-Globulin Nephropathy or Light Hydrocarbon Nephropathy is related to the accumulation of alpha-2u globulin in the lysosomes of the kidney.

 

Treatment-related microscopic change in the liver (centrilobular hepatocellular hypertrophy) of the mid-dose females and the high dose of both sexes in the absence of necrosis is typical of an adaptive change probably related to the livers' metabolism of large volumes of test material.  This observation is supported by the increase in relative liver weights in these animals which is typical of an adaptive change.

Conclusions:
Oral administration via gavage for 90 days produced no treatment-related clinical in-life signs of toxicity and no mortality at the highest dose tested. The no observable adverse effect level for MRD-90-868 is > 1000 mg/kg.
Executive summary:

A 90-day subchronic study was conducted in rats to assess the toxicity of MRD-90-868. 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. There were no deaths attributed to the oral administration of MRD-90-868 (two control group females died prior to termination).  The majority of animals in all groups displayed no observable abnormalities during the test period.  The most frequently noted observations included broken/maloccluded incisors, alopecia, and scabs, all of which were considered incidental.  Body weight, food consumption, and hematology data displayed no biologically significant trends for either males or females during the test period.  The most remarkable finding was a treatment-related microscopic change in the liver of the mid-dose females and the high dose of both sexes.  This change was minor and is typical of an adaptive change probably related to the livers metabolism of large volumes of test material and was reversible upon microscopic evaluation of the tissues from the satellite recovery group.  Microscopic changes were also observed in the male kidneys at all doses.  These changes are characteristic of kidney changes produced in male rats by hydrocarbons and are considered to be a male rat specific phenomenon without human significance.  Based on the data recorded in this study, the NOAEL for MRD-90 -868 is >1000mg/kg.

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:
One sub-chronic read across study available from structural analogues.

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:
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 conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
10 400 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
One key read across study 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, C15-C19, n-alkanes, isoalkanes, <2% aromatics. However, data are available for structural analogues, decane, Hydrocarbons, C10-C12, isoalkanes, <2% aromatics, and Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics. These data are read across to Hydrocarbons, C15-C19, n-alkanes, isoalkanes, <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

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

In another key 90-day sub-chronic study (ExxonMobil, 1991) conducted in rats the test material (hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics) 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. There were no deaths attributed to the oral administration of the test material (two control group females died prior to termination). The majority of animals in all groups displayed no observable abnormalities during the test period. The most frequently noted observations included broken/maloccluded incisors, alopecia, and scabs, all of which were considered incidental. Body weight, food consumption, and hematology data displayed no biologically significant trends for either males or females during the test period. The most remarkable finding was a treatment-related microscopic change in the liver of the mid-dose females and the high dose of both sexes. This change was minor and is typical of an adaptive change probably related to the livers metabolism of large volumes of test material and was reversible upon microscopic evaluation of the tissues from the satellite recovery group. Microscopic changes were also observed in the male kidneys at all doses. These changes are characteristic of kidney changes produced in male rats by hydrocarbons and are considered to be a male rat specific phenomenon without human significance. Based on the data recorded in this study, the NOAEL for hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, <2% aromatics is >1000mg/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, C14-C19, isoalkanes, cyclics, <2% aromatics (EC# 920-114-2), Hexadecane (EC# 208-878-9), 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.

Inhalation

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).

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

In a supporting sub-chronic toxicity study (Shell, 1980), the test material 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 Level (NOAEL) was greater than or equal to 6000 mg/m3.

Justification for classification or non-classification

Based on available read-across from structurally related substances, Hydrocarbons, C15-C19, n-alkanes, isoalkanes, <2% aromatics does not meet the criteria for classification for repeated dose toxicity (STOT-RE) according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (CLP).