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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1991
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP - Guideline study, tested with the source substance hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, < 2% aromatics. In accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes

Test material

Constituent 1
Reference substance name:
Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, < 2% aromatics
EC Number:
917-725-1
IUPAC Name:
Hydrocarbons, C11-C14, n-alkanes, isoalkanes, cyclics, < 2% aromatics
Details on test material:
- Name of test material (as cited in study report): MRD-90-868
- Physical state: colorless liquid
- Analytical purity: assumed to be 100% pure
- Lot/batch No.: Batch No. I
- Storage condition of test material: Room temperature

Test animals

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

Administration / exposure

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.
Doses / concentrationsopen allclose all
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

Examinations

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, testes, 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.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not 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.

Effect levels

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.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.