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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
propylidynetrimethanol, ethoxylated, esters with acrylic acid and its reactions products with dibutylamine
EC Number:
606-330-7
Molecular formula:
Not specified UVCB - Reaction product of ethoxylated (0-7 EO) propylidenetrimethanol with acrylic acid and dibutylamine (propylidenetrimethanol with acrylic acid : dibutylamine = 5:1)
IUPAC Name:
propylidynetrimethanol, ethoxylated, esters with acrylic acid and its reactions products with dibutylamine
Details on test material:
- Name of test material (as cited in study report): Laromer LR 8869
- Physical state: colorless, clear liquid
- Analytical purity: for details see analytical report no. 11L00263
- Purity test date: 2012-01-11
- Lot/batch No.: 110009P040
- Expiration date of the lot/batch: 2012-07-4
- Stability under test conditions: verified for at least 7 days
- Storage condition of test material: at room temperature, light protected, avoid temperatures above 25°C

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany, male and female rats were derived from different litters to rule out sibling mating
- Age at study initiation: (P) 10-11 wks;
- Weight at study initiation: (P) Males: 294 g; Females: 197 g, on average
- Fasting period before study: no
- Housing: individually (except during overnight mating and lactation) in Makrolon type M III cages
- Diet (e.g. ad libitum): Kliba maintenance diet mouse-rat “GLP” meal, ad lib.
- Water (e.g. ad libitum): tap water ad lib.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr):15

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:The test substance was applied as suspension, which was prepared at least once a week. An appropriate amount of the test substance was weighed, and corn oil was added up to the desired volume. The suspension was kept homogenous during administration by stirring with a magnetic stirrer.

The administration volume was 4ml/kg b.w.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test substance is poorly soluble in water.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in corn oil for a period of 7 days at room temperature was proven before the start of the study (BASF Project No. 11L00386).
For homogeneity and concentration control analyses, each 6 samples of all concentrations was drawn at the start of the study and towards the end of the administration period. Homogeneity was confirmed, all concentrations measured were within 90-110% of the target concentration.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight for a maximum of 14 days, or until pregnancy was proven
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): single
Duration of treatment / exposure:
males: 36 days
females: 51 days
Frequency of treatment:
daily, except to animals being in labor
Duration of test:
males: 36 days
females: 51 days
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300, 1000mg/kg (high dose was reduced to 600mg/kg on day 19)
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of a range-finding study - no severe signs of toxicity were observed in animals treated with 1000mg/kg of the test substance for 14 days.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on workdays, daily on weekends and public holidays
- Cage side observations: check for moribund animals, pertinent behavioral changes, signs of overt toxicity, parturation, littering and lactation behavior of the dams

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the first administration, weekly thereafter
- The following parameters were examined: abnormal behavior during “handling”, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, impairment of gait, lacrimation, palpebral closure, exophthalmus, feces (appearance/consistency), urine, pupil size

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, weekly thereafter with the following exceptions for females: During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20. Females with litter were weighed on the day of parturition (PND 0) and on PND 4.

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, except during mating

WATER CONSUMPTION: Monitored by daily visual inspection

OTHER (for details see entry for this study in the repeated dose section):
- Functional observation battery and motor activity measurement of 5 males and females per group 2 days prior to sacrifice
- Urinanalysis in 5 males and females per group one day prior to necropsy
- Clinicochemical and hematological examinations 5 males and females on the day of necropsy after fasting for 16h
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: No
- Number of implantation sites: Yes
Fetal examinations:
All surviving pubs were subjected to postmortem examinations: external examination and macroscopic examination of organs.
Indices:
For the males, mating and fertility indices were calculated for F1 litters according to the following formulas:
Male mating index (%) = number of males with confirmed mating (vaginal sperm detected in females) / number of males placed with females x100
Male fertility index (%) = number of males proving their fertility (implants in utero) / number of males placed with females x100

For the females, mating, fertility and gestation indices were calculated for F1 litters according to the following formulas:
Female mating index (%) = number of females mated (vaginal sperm detected) / number of females placed with males x100
Female fertility index (%) = number of females pregnant (implants in utero) / number of females mated (vaginal sperm or implants in utero) x100
Gestation index (%) = number of females with live pups on the day of birth / number of females pregnant x100

Pubs
Live birth index (%) = number of liveborn pups at birth / total number of pups born x100
Viability index (%) = number of live pups on day 4 after birth / number of live pups on the day of birth x100

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Of the high dose animals, one male and one female were found dead, and one female was sacrificed in moribund condition. Piloerection, smeared fur, respiratory sounds, poor general state, hunched posture, and semiclosed eyelids were observed in single animals of this group at different time points. Pathology revealed erosion/ulcer in the forestomach of all male and 9/10 female high dose animals, mild to severe diffuse or focal hyperplasia with hyperkeratosis in the forestomach of all animals, and mild to severe submucosal edema in the forestomach of 8 male and 3 female animals. Animals receiving 300mg/kg b.w. showed comparable signs of local irritation in the forestomach, though the incidence was clearly reduced. No clinical signs were noted in this group and in low dose animals, which also showed no local irritation in the stomach. Reproductive performance was unaffected in all groups.

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 600 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 300 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 600 mg/kg bw/day
Basis for effect level:
other: no embryotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Reproductive performance was unaffected in all groups. No deviations from control animals were observed in the pubs from all groups. Thus the NOAEL for fertility and developmental toxicity was set to 600mg/kg b.w.

Applicant's summary and conclusion