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EC number: 233-126-1 | CAS number: 10042-59-8
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 996
- Report date:
- 1996
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 2-propylheptan-1-ol
- EC Number:
- 233-126-1
- EC Name:
- 2-propylheptan-1-ol
- Cas Number:
- 10042-59-8
- Molecular formula:
- C10H22O
- IUPAC Name:
- 2-propylheptan-1-ol
- Test material form:
- liquid
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Propylheptanol
- Analytical purity: 99.5% (GC)
- Lot/batch No.: CIW/E, Reg. No. 20 595
- Test substance No.: 94/279
- Stability under test conditions: by reanalysis after the in-life phase of the study; the stability of the test substance in the vehicle over a period of 3 hours was proven before the start of the study (as the emulsions were prepared daily and administered within this time period, the stability was guaranteed)
- Homogeneity: proven by visual inspection
- Storage condition of test material: room temperature; protected from light
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River GmbH, Germany
- Age at study initiation: 42 days
- Weight at study initiation: the body weight of the males was in the range of 100 - 124 g (group mean: 110 g) and the body weight of the females was in the range of 85 - 101 g (group mean: 94 g)
- Housing: single
- Diet: ground Kliba maintenance diet rat/mouse/hamster, 343 meal, supplied by Klingentalmuehle AG, Kaiseraugst, Switzerland; ad libitum
- Water: drinking water (from water bottles) were available ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Cremophor EL in doubly distilled water (approx. 5 mg/100 ml)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
To prepare the emulsion, Propylheptanol was weighed depending on the dose group, then the vehicle was filled up to the desired volume and subsequently mixed using an Ultra Turrax. During administration to the animals the test substance preparations were kept homogeneous with a magnetic stirrer. The test substance preparations were prepared daily.
The administration volume was 10 ml/kg body weight, based upon the latest individual body weight determination. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- At the beginning of the administration period the homogeneity of the test substance in the vehicle was checked at the low and high concentration; these analyses served also as concentration controls. Further concentration control analyses were carried out in samples from the mid dose drawn at the beginning of the administration period, and in samples from all doses drawn at the end of the administration period. Analytical checks of the concentrations revealed 89% - and 103% of the target concentrations. Although one value was only 89% of the target concentration (high dose at termination of the study), this was assessed as being acceptable.
- Duration of treatment / exposure:
- 3 months
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- other: yes, group #1: bi-distilled water, group #2: emulsifier (Cremophor EL in doubly distilled water (approx. 5 mg/100 ml))
- Details on study design:
- - Dose selection rationale:
Based upon the findings in a prenatal toxicity screening study with Propylheptanol (1580, 790 and 158 mg/kg body) the following doses were selected for the present study: 600 mg/kg body weight (as high dose with expected effects on body weight), 150 mg/kg body weight (as mid dose), 30 mg/kg body weight (as low dose)
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were examined for morbidity or mortality twice a day from Mondays to Fridays and once a day on Saturdays, Sundays and public holidays. Additionally, comprehensive clinical examinations were carried out before treatment, less than 1 hour after application and, if the animals showed clinical signs, 3 - 4 hours after application.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight was determined before the start of the administration period in order to randomize the animals. During the conduct of the study, the body weight was determined on day 0 (start of administration period) and thereafter at weekly intervals. The difference between the body weight on the respective day of weighing and the body weight on day 0 was calculated as body weight change.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption was determined weekly over a period of 7 days
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes
FOOD EFFICIENCY:
- Body weight gain in g/food consumption in g per unit time x 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Prior to the start and towards the end of the administration period the eyes of the animals were examined for any changes using an ophthalmoscope.
- Dose groups that were examined: test groups 0, 1 and 4
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood was taken from the retroorbital venous plexus in the morning.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: 10 animals per test group and sex
- Parameters checked: leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelets; the differential blood count was evaluated visually; clotting analyses: prothrombin time (Hepato Quick's test)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood was taken from the retroorbital venous plexus in the morning.
- Animals fasted: No
- How many animals: 10 animals per test group and sex
- Parameters checked: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, serum-gamma-glutamyltransferase, cyanide-insensitive Palmitoyl-CoA-oxidation, sodium, potassium, chloride, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium
URINALYSIS: Yes
- Time schedule for collection of urine: Urine was collected overnight.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (withdrawal of food and water in the metabolism cages)
- Parameters checked: volume, color, turbidity, nitrite, pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment
OTHER: At necropsy liver samples were collected for examinations in liver homogenate. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Means and standard deviations of each test group were calculated. As two control groups were used in this study (groups 0 and 1), comparison was performed using either group 0 as the reference control group (with which groups 1 to 4 were compared) or group 1 was taken as the reference control group (with which groups 2 to 4 were compared).
Food consumption, body weight, body weight change, food efficiency: Parametric one-way analysis using the F-test (ANOVA) (two-sided). If the resulting p-value was equal or less 0.05, a comparison of each group with the control group using the DUNNETT's test (two-sided) was performed for the hypothesis of equal means.
Clinical pathology parameters, except differential blood count: Parametric one-way analysis using the F-test (ANOVA) (two-sided). If the resulting p-value was equal or less 0.05, a comparison of each group with the control group was performed using DUNNETT's test (two-sided) for the hypothesis of equal means.
Urinalysis, except volume, color and turbidity: Pairwise comparison of each dose group with the control group using FISHER's exact test for the hypothesis of equal proportions.
Weight parameters: A comparison of each group with the control group using the DUNNETT's test (two-sided) was performed for the hypothesis of equal means.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- slight salivation in all males and females within one hour after administration
- urine-smeared anogenital region in 4 males and 6 females 3 - 4 hours after administration - Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- impairment of body weight in males, resulting in reduced values of 13 % (compared to control group 0) or 14% (compared to control group 1) on day 91
- impairment of body weight change in males, resulting in reduced values of 22 % (compared to control group 0) or 25 % (compared to control group 1) on day 91
- decreased mean terminal body weight in male rats (-16.7% or -14.1% when compared with control groups 0 or 1) and in female rats (- 8.2% when compared with control group 1) - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- impairment of food consumption in males (-18%; compared to both control group 0 and control group 1) and females (-10%; compared to both control group 0 and control group 1) - Food efficiency:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Food efficiency was statistically significantly impaired in high dose males on days 63 (compared to test group 0), 91 (compared to test group 1), in mid dose males on day 77 (compared to test group 0), in high and mid dose females on day 35 (compared to test group 1) and in high dose females on day 42 (compared to test group 1). Due to the lack of a dose-response relationship and the only isolated significances, this was assessed as being incidental.
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- decrease in platelets in both sexes - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- decrease in globulins and cholesterol in both sexes and in triglycerides in males, only
- increase in albumin, cyanide-insensitive palmitoyl-CoA-oxidation in the serum of both sexes - Urinalysis findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- decrease in urinary specific gravity in the females
- increase in urinary volume and transitional epithelial cells in the females, only, and increase in squamous epithelial cells in the urine of both sexes - Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Dose group 4 (600 mg/kg):
- increased mean absolute and relative liver weights in male (absolute weight: +26.2% / +28.1%, relative weight: +47.6% / +53.8%) and female rats (absolute weight: +31.2% / 24.6%; relative weight: +37.6% / 35.7%; when compared with either control group); indicative for peroxisomal proliferation
Dose group 3 (150 mg/kg):
- increased mean relative liver weight in female rats (+7.5% / +6.1%; when compared with either control group), revealing dose response relationship, but indicative for peroxisomal proliferation
- Comparison of dose group 3 with control group 1: The mean weights of the kidneys and the epididymides were significantly increased (p = 0.05) in group 3 (+5.1% for kidneys and +8.0% for epididymides). - Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related microscopic findings were noted in the liver (male and female rats), thyroid glands (male rats, only), and pituitary gland (male rats, only).
Dose group 4 (600 mg/kg):
- diffuse hypertrophy (grade 2) of the liver cells in male and female rats (indicative for peroxisomal proliferation)
- loss of fatty infiltration of the liver cells in male rats (In females, there was also no indication of fat storage, however, this finding was anyhow a very rare event even in control females of dose group 0 (two females were affected with minimal (= grade 1) fatty infiltration, only))
- diffuse hypertrophy (grade 2) of the follicular cells of the thyroid glands in seven male rats
- vacuolation of basophilic (thyrotropic) cells (grade 1, grade 2 or grade 3) in the glandular part of the pituitary gland of three male rats (that had slight diffuse hypertrophy of the follicular cells of the thyroid glands)
Dose group 3 (150 mg/kg):
- diffuse hypertrophy (grade 1) of the liver cells in one female rat (indicative for peroxisome proliferation) - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Effect levels
- Dose descriptor:
- NOAEL
- Remarks:
- (disregarding peroxisomal proliferation)
- Effect level:
- 150 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- food consumption and compound intake
- haematology
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 150 mg/kg bw/day (nominal)
- System:
- hepatobiliary
- Organ:
- liver
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- no
Any other information on results incl. tables
Body weight (g)
mg/kg 0# 0## 30 15 600
Males
Day 0 109.8 111.0 109.7 110.2 109.7
Day 28 206.1 215.8 215.7 205.2 197.4
Day 56 253.9 265.6 271.2 257.0 232.0
Day 91 284.6 293.7 302.1 285.3 246.6**
Females
Day 0 92.8 94.2 94.0 93.6 93.1
Day 28 142.3 145.0 142.5 142.2 142.3
Day 56 164.7 171.0 164.8 163.4 160.2
Day 91 174.5 180.5 175.0 175.5 171.2
* p<0.05, ** p <0.01 Dunnett's test + Anova
# = control; ## = vehicle control
Food consumption (g)
Mg/kg 0# 0## 30 15 600
Males
Day 7 15.3 15.6 15.6 15.6 15.3
Day 28 17.5 18.3 18.1 17.1 16.0*
Day 56 17.4 18.0 18.3 17.3 16.5
Day 91 15.8 15.7 15.8 15.1 12.9**
Females
Day 7 12.7 13.2 13.0 12.7 12.5
Day 28 13.7 13.7 13.3 13.8 12.4**
Day 56 13.8 14.0 13.4 13.5 12.9*
Day 91 10.7 11.3 1.1 11.6 10.4
* p<0.05, ** p <0.01 Dunnett's test + Anova
# = control; ## = vehicle control
Clinical pathology (including hematology, urinalysis)
Males day 87
mg/kg 0# 0## 30 150 600
PLT (Giga/l) 641 617 614 611 540**
Pal C0A (Mu/mg P) 4.50 5.21 5.49 6.64 43.27**
Alb (G/L) 36.11 35.31 35.80 38.03 41.86**
Glob (G/L) 33.97 33.38 34.07 33.52 28.24**
Trig (G/L) 2.60 2.34 2.21 2.24 1.76**
Chol (mM/L) 2.31 2.22 2.22 2.03* 1.38**
Urine ml 4.3 3.9 3.6 2.7 5.0
Females day 88
mg/kg 0# 0## 30 15 600
PLT (Giga/l) 608 605 598 614 428**
Pal C0A (Mu/mg P) 3.27 4.07 4.63 3.93 22.63**
Alb (G/L) 35.18 35.52 35.27 35.83 38.19**
Glob (G/L) 31.55 31.74 31.38 31.11 28.51
Trig (G/L) 1.09 1.06 0.97 0.97 1.47*
Chol (mM/L) 3.02 3.03 2.96 2.73 2.24**
Urine ml 1.7 1.5 2.4 2.1 5.2
* p<0.05, ** p <0.01 Dunnett's test + Anova
# = control; ## = vehicle control
Organ weights
Males
mg/kg 0# 0## 30 15 600
Liver weight
Absolute (g) 7.87 7.75 7.99 7.83 9.93**
Relative (%) 3.00 2.88 2.86 2.99 4.4**
Females
Liver weight
Absolute (g) 4.23 4.53 4.32 4.61 5.64**
Relative (%) 2.67 2.70 2.68 2.87* 3.67**
* p<0.05, ** p <0.01 Dunnett's test + Anova
# = control; ## = vehicle control
Applicant's summary and conclusion
- Conclusions:
- The no observed adverse effect level was 150 mg/kg body weigh/day in males and females disregarding liver effects due to peroxisomal proliferation.
- Executive summary:
The test substance was administered daily to groups of 10 male and 10 female Fischer F-344 rats by gavage as aqueous emulsion at doses of 0 ; 30 ; 150 and 600 mg/kg body weight/day for 3 months. Vehicle was Cremophor® EL in doubly distilled water (approx. 5 mg/100 ml) . Two control groups were used: One group received doubly distilled water (test group 0), the other group received the vehicle (test group 1) . The administration volume was 10 ml/kg body weight. Food consumption and body weight were determined weekly . The state of health was checked daily before
and after the administration of the test substance. Ophthalmological examinations were carried out before the beginning of the administration period and at the end of the study in the animals of both control groups and of the highest dose group. Clinicochemical and hematological examinations and urinalyses were carried out towards the end of the administration period . All animals were assessed by gross pathology, followed by histopathological examinations.
The following substance-related findings were obtained :
Dose group 4 (600 mg/kg) :
- slight salivation in all males and females within one hour after administration
- urine-smeared anogenital region in 4 males and 6 females 3 - 4 hours after administration
- impairment of food consumption in males and females
- impairment of body weight in males, resulting in reduced values of 13 % (compared to control group 0) or 14% (compared to control group 1) on day 91
- impairment of body weight change in males, resulting in reduced values of 22 % (compared to control group 0) or 25 % (compared to control group 1) on day 91
- decrease in platelets, globulins and cholesterol in both sexes and in triglycerides in males, only
- increase in albumin, cyanide-insensitive palmitoyl-CoA-oxidation in the serum of both sexes
- decrease in urinary specific gravity in the females
- increase in urinary volume and transitional epithelial cells in the females, only, and increase in squamous epithelial cells in the urine of both sexes
- decreased mean terminal body weight in male rats (when compared with control groups 0 or 1) and in female rats (when compared with control group 1)
- increased mean absolute and relative liver weights in male and female rats (when compared with either control group)
- diffuse hypertrophy of the liver cells in male and female rats
- loss of fatty infiltration of the liver cells in male rats
- diffuse hypertrophy of the follicular cells of the thyroid glands in seven male rats
- vacuolation of basophilic (thyrotropic) cells in the glandular part of the pituitary gland of three male rats
Dose group 3 (150 mg/kg) :
- increased mean relative liver weight in female rats (when compared with either control group)
- diffuse hypertrophy of the liver cells in one female rat
Dose group 2 (30 mg/kg) :
no substance-related effects
Thus, substance-related effects were seen at 600 mg/kg in both sexes and at 150 mg/kg in females, only . Main target organ was the liver, most probably related to a peroxisome proliferating potential of the test substance.
The no observed adverse effect level under the conditions of this study was 150 mg/kg body weigh/day in males and 30 mg/kg body weight in females.
Due to the fact that the effects in the liver are related to peroxisomal proliferation which is not a relevant effect for humans a NOAEL and LOAEL disregarding these effects was determined: NOAEL (disregarding peroxisomal proliferation): 150 mg/kg bw, LOAEL (disregarding peroxisomal proliferation): 600 mg/kg bw for both sexes.
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