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

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.31 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Remarks:

BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany

Limit test:

no

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

Details on test material:

- Name of test material (as cited in study report): Dipropylheptylcarbonate
- Test substance No.: 11/0101-1
- Batch: CB03400026
- Physical state/appearance: Liquid, colorless

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Germany
- Age at study initiation: 10-12 weeks
- Housing: individually in Makrolon type M III cages (BECKER & CO., Castrop-Rauxel, FRG; floor area about 800 cm²) with dust free wood bedding. For enrichment, wooden gnawing blocks were offered (Typ NGM E-022, supplied by Abedd® Lab. and Vet. Service GmbH, Vienna, Austria).
- Diet: ground Kliba maintenance diet mouse/rat "GLP", meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water: Tap water ad libitum
- Acclimation period: 6 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12 (6.00 pm - 6.00 am dark; 6.00 am - 6.00 pm light)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The oily test substance preparations were prepared at the beginning of the administration period and thereafter at maximum intervals of 7 days, which took into account the period of established stability. To prepare the dose solutions, the specific amounts of test substance were weighed, topped up with corn oil in an Erlenmeyer flask and intensely shaken until completely dissolved.

ADMINISTRATION VOLUME:
4 mL/kg bw/d

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany. Analytical verifications of the stability of the test substance in corn oil for a period of 7 days were carried out prior to the study in a similar batch (Project No.: 01Y0101/11Y019). Samples of the test substance preparations were sent to the analytical laboratory at the beginning of administration for verification of the concentrations. Given that the test substance is completely miscible with corn oil, solutions were considered to be homogenous without further analysis.

Details on mating procedure:

The animals were paired by the breeder (“time-mated”); the day of evidence of mating (= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”.

Duration of treatment / exposure:

The test substance preparations were administered to the animals once a day orally by gavage, from implantation to one day prior to the expected day of parturition (GD 6 to GD 19), always at approximately the same time in the morning.

Frequency of treatment:

daily

Duration of test:

3 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300, 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

25 females

Control animals:

yes, concurrent vehicle

Examinations

Maternal examinations:

Mortality was checked twice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-20). The animals were examined at least once daily for clinical symptoms by cage-side examination for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. If such signs occurred, the animals were examined several times daily (GD 0-20). The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20. All animals were weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20. The body weight change of the animals was calculated based on the obtained results. Furthermore, the corrected body weight gain was calculated after terminal sacrifice (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6). Dams were sacrificed on gestation day 20 under isoflurane anesthesia by cervical dislocation, in randomized order. After the dams had been sacrificed, they were necropsied and assessed for gross pathology. Uterus and ovaries were removed for subsequent examination.

Ovaries and uterine content:

- Weight of the unopened uterus
- Number of corpora lutea
- Number and distribution of implantation sites classified as:
1) Live fetuses
2) Dead implantations:
a) Early resorptions (only decidual or placental tissues visible or according to SALEWSKI from uteri from apparently non-pregnant animals and the empty uterus horn in the case of single horn pregnancy)
b) Late resorptions (embryonic or fetal tissue in addition to placental tissue visible)
c) Dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened)
- Conception rate and pre- and postimplantation losses were calculated.

Fetal examinations:

At necropsy each fetus was weighed, sexed, and external tissues and all orifices were examined macroscopically. The sex was determined by observing the distance between the anus and the base of the genitalia. Furthermore, the viability of the fetuses and the condition of placentae, umbilical cords, fetal membranes, and fluids were examined. The placentas were weighed and their individual weights were recorded. Thereafter, the fetuses were sacrificed by a subcutaneous injection of pentobarbital (Narcoren®; dose: 0.1 mL/fetus). After these examinations, approximately one half of the fetuses per dam were eviscerated, skinned and fixed in ethanol; the other half were placed in Harrison’s fluid for fixation. The fetuses fixed in Harrison’s fluid were examined for any visceral findings according to the method of BARROW and TAYLOR. After this examination these fetuses were discarded. The skeletons of the fetuses fixed in ethanol were stained according to a modified method of KIMMEL and TRAMMELL. Thereafter, the skeletons of these fetuses were examined under a stereomicroscope. After this examination the stained fetal skeletons were retained individually.

Statistics:

- Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight: simultaneous comparison of all dose groups with the control group using the DUNNETT-test (two-sided) for the hypothesis of equal means.
- Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings: pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions.
- Proportions of fetuses with malformations, variations and/or unclassified observations in each litter: pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians.

Indices:

- Conception rate (%): 100 x number of pregnant animals / number of fertilized animals
- Preimplantation loss (%), for each individual pregnant animal which underwent scheduled sacrifice: 100 x (number of corpora lutea - number of implantations) / number of corpora lutea
- Postimplantation loss (%), for each individual pregnant animal which underwent scheduled sacrifice: 100 x (number of implantations - number of live fetuses) / number of implantations

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Details on maternal toxic effects:
None of the dams died untimely and the clinical observations revealed no toxicologically relevant difference between the animals receiving the test substance and controls.
The following test substance-related, adverse effects/findings were noted:

Test group 3 (1000 mg/kg bw/d):
Dams
• Slightly reduced food consumption from GD 6-20, attaining statistical significance on GD 15-17; if calculated for GD 6-19 4% less food consumption.
• Statistically significantly reduced mean body weight gain on GD 6-10 (30% below control)
and GD 15-17 (17% below).
• Statistically significantly reduced corrected body weight gain (12% below control).
• No test substance-related adverse effects on gestational parameters

Test group 2 (300 mg/kg bw/d):
• No test substance-related adverse effects on dams, gestational parameters or fetuses

Test group 1 (100 mg/kg bw/d):
• No test substance-related adverse effects on dams, gestational parameters or fetuses

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

2

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Details on embryotoxic / teratogenic effects:
The following test substance-related, adverse effects/findings were noted:

Test group 3 (1000 mg/kg bw/d):
• No test substance-related adverse effects on gestational parameters
Fetuses
• No test substance-related adverse findings

Test group 2 (300 mg/kg bw/d):
• No test substance-related adverse effects on dams, gestational parameters or fetuses

Test group 1 (100 mg/kg bw/d):
• No test substance-related adverse effects on dams, gestational parameters or fetuses

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified