1-Heptanol, 2-propyl-, 1,1'-carbonate

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-07-16 to 2011-10-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study. OECD guideline was followed.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

adopted 03 Oct 2008

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Version / remarks:

Commission Regulation (EC) No 440/2008 of 30 May 2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Experimental Toxicology and Ecology BASF SE

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

bis(2-propylheptyl) carbonate

EC Number:

627-085-2

Cas Number:

1238449-42-7

Molecular formula:

C21H42O3

IUPAC Name:

bis(2-propylheptyl) carbonate

Test material form:

other: liquid

Test animals

Species:

rat

Strain:

other: Crl:WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age at study initiation: 41 - 43 days
- Weight at study initiation: mean 157.4 g
- Fasting period before study: 16 hours
- Housing: The rats were housed together (5 animals per cage) in polysulfonate cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70 %
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light from 06.00-18.00 h, 12 hours dark from 18.00-06.00 h

IN-LIFE DATES: From: 2011-11-02 To: 2011-12-08

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: ground maintenance diet

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: For each concentration, the test substance was weighted out and mixed with a small amount of food. Then corresponding amounts of food, depending on test group, were added to this premix in order to obtain the desired concentrations.

DIET PREPARATION
- Rate of preparation of diet (frequency): daily
- Mixing appropriate amounts with (Type of food): Mixing was carried out for about 10 minutes in a laboratory mixer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The mean values of Dipropylheptylcarbonate (Cetiol P5) in Ground Kliba maintenance diet mouse/rat “GLP” meal were found to be in the range between 90-110% of the nominal concentrations.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1500, 5000, 15000 ppm
Basis:
nominal in diet

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Dose selection rationale: The oral route was selected since this was proven to be suitable for the detection of a toxicological hazard.

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: on day 0 (start of the administration period) and thereafter at weekly intervals

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
Food consumption was determined weekly over a period of 1 day and calculated as mean food consumption grams per animal and day.
The mean daily intake of test substance (group means) was calculated based upon individual values for body weight and mean food consumption per cage.

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: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes (water consumption)
- Time schedule for examinations: daily

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes
- How many animals: all groups

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 29
- Animals fasted: Yes
- How many animals: all groups

URINALYSIS: Yes
- Time schedule for collection of urine: on day 26
- How many animals: all animals

NEUROBEHAVIOURAL EXAMINATION: Yes / No / No data
- Time schedule for examinations: weekly
- Dose groups that were examined: all animals
- Battery of functions tested: grip strength / motor activity

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Organ weight: Anesthetized animals, Adrenal glands, Brain, Epididymides, Heart, Kidneys, Liver, Ovaries, Prostate, Seminal vesicles with coagulating glands, Spleen, Testes, Thymus, Thyroid glands, Uterus with cervix

Other examinations:

none

Statistics:

Statistics of clinical pathology:
- Blood parameters:
For parameters with bidirectional changes: Non-parametric one-way analysis using KRUSKAL-WALLIS test. If the resulting pvalue was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians
For parameters with unidirectional changes: Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians
- Urinalysis parameters: Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians
- Weight parameters: Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY: No animal died. No test substance-related, adverse findings were observed in male and female animals of test groups 1-3 (1500, 5000 and 15000 ppm).

BODY WEIGHT AND WEIGHT GAIN: No test substance-related changes of body weight and body weight change values were observed for male and female animals in any test group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): All recorded values were within the biological range typical for this strain of rats.

WATER CONSUMPTION: Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

HAEMATOLOGY: No treatment-related changes among hematological parameters were observed. In males of test groups 2 and 3 (5000 and 15000 ppm) absolute and relative eosinophil counts were higher compared to controls. Low eosinophil counts in the study controls were the reason for this statistically significant deviation. All values of the mentioned test groups were within historical control ranges (absolute eosinophil counts 0.05-0.17 Giga/L, relative eosinophil counts 1.1-2.8%). Therefore, these alterations were regarded as incidental and not treatment-related.

CLINICAL CHEMISTRY: No treatment-related changes among clinical chemistry parameters were observed. In males of test group 1 (1500 ppm) total protein and globulin values were higher compared to controls, but the increase was not dose-dependent. In females of test group 3 (15000 ppm) urea and creatinine concentrations were lower compared to controls. These values were also not dose-dependently decreased and the means were within historical control ranges (urea 5.74-8.94 mmol/L; creatinine 47.0-56.7 μmol/L). Therefore, all mentioned alterations of clinical chemistry parameters were regarded as incidental and not treatment-related.

URINALYSIS: No treatment-related changes among urinalysis parameters were observed. In males of test group 3 (15000 ppm) urinary keton body levels were higher compared to controls. This was the only alteration of clinical pathology parameters and therefore it was regarded as maybe treatment-related, but not adverse (ECETOC, Technical Report No. 85, 2002).

PATHOLOGY: Regarding pathology, the target organs were kidneys, liver and thyroid glands. In the kidneys, minimal proximal tubular cell hypertrophy was observed in 4 of 5 males of test group 3 (15000 ppm). This finding correlated with the increased organ weight (120% absolute and 118% relative) and was considered to be adverse. The increased relative kidney weight in males of test group 2 (5000 ppm) was not accompanied by histopathological changes and therefore considered to be adaptive. In the liver, minimal diffuse hepatocellular hypertrophy was noted in all male and female animals of test group 3 (15000 ppm) and in 3 of 5 males of test group 2 (5000 ppm) correlating with an increase in organ weight. This finding was also considered to be adaptive and non-adverse due to the absence of any degenerative cellular alterations. In the thyroid gland, minimal follicular cell hypertrophy/hyperplasia was observed in 2 of 5 male and 1 of 5 female animals of test group 3 (15000 ppm), which was considered to be
treatment-related and possibly secondary to the hepatocellular hypertrophy in the same test group. It was assumed to be of no relevance to humans, although a definite statement cannot yet be made at this point.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

415 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: in diet: 5000 ppm

2

Dose descriptor:

NOAEL

Effect level:

1 351 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: in diet: 15000 ppm

Target system / organ toxicity

Critical effects observed:

not specified