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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 20, 2007 - August 10, 2007
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the following guidelines - OECD Guideline No. 422 (1996) and USEPA OPPTS 870.3650 (2000) and complied with the Principles of GLP.

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
other: OECD 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test)
GLP compliance:

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): Methyl Polyhydroxymethyl Stearate (Imperial Monomer)
- Molecular formula (if other than submission substance): UVCB- not applicable
- Molecular weight (if other than submission substance): UVCB- MW of primary components range from 270- 389 g/mole.
- Smiles notation (if other than submission substance): UVCB- not applicable
- InChl (if other than submission substance): not specified in the report
- Structural formula attached as image file (if other than submission substance): UVCB- not applicable
- Substance type: Mixture of functionalized fatty acid methyl esters (FAMEs) which may be derived from a variety of natural seed oils.
- Physical state: Waxy solid at room temperature
- Analytical purity: > 95.2 % as summed concentration of five primary components
- Impurities (identity and concentrations): water, approx. 0.4%
- Composition of test material, percentage of components:
Methyl Palmitate: 9.68 %
Methyl Stearate: 17.8 %
Methyl Hydroxymethyl Stearate: 38.6 %
Methyl Dihydroxymethyl Stearate: 26.7 %
Methyl Trihydroxymethyl Stearate: 2.37 %
- Isomers composition: The balance of unassigned composition can be attributed to both minor isomers of the primary components, as well as trace components resulting from physical/chemical processing of the unrefined natural oil feedstock.
- Purity test date: 22 August 2005
- Lot/batch No.: 200500200-25-4
- Characterisation expiration date: 07 September 2007
- Radiochemical purity (if radiolabelling): not applicable
- Specific activity (if radiolabelling): not applicable
- Locations of the label (if radiolabelling): not applicable
- Expiration date of radiochemical substance (if radiolabelling): not applicable
- Stability under test conditions: Stable
- Storage condition of test material: At room temperature in the dark under nitrogen

Test animals

Crj: CD(SD)
Details on test animals or test system and environmental conditions:
- Source: Charles River Laboratories Inc. (Portage, Michigan)
- Sex: Male and female
- Age at study initiation: 8 weeks
- Weight at study initiation: not specified in the report
- Fasting period before study: not specified in the report
- Housing: Acclimation - group housed in two-three animals/cage, experimental - singly, except during breeding (one male and one female)
- Diet (e.g. ad libitum): ad libitum, animals were provided LabDiet Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, Missouri) in meal form.
- Water (e.g. ad libitum): ad libitum, drinking water obtained from the municipal water department
- Acclimation period: at least one week prior to start of the study.

- Temperature (°C): 22°C with a tolerance of ± 1 C (and a maximum permissible excursion of ± 3°C)
- Humidity (%): 40-70%
- Air changes (per hr): 12-15 times/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/dark

IN-LIFE DATES: From: June 30, 2007 To: August 10, 2007

Administration / exposure

Route of administration:
oral: gavage
corn oil
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS: The test material was administered in a corn oil vehicle, such that a dose volume of 4 ml/kg body weight yielded the targeted dose. Dose volumes were adjusted using the most current body weight. Dose solutions were prepared approximately biweekly throughout the study period, and were used within the stability limits.

- Justification for use and choice of vehicle: Solubility and recommended as a vehicle by various regulatory agencies
- Concentration in vehicle: 25mg/ml, 125mg/ml and 250 mg/ml
- Amount of vehicle (if gavage): max volume = 4 ml/kg
- Lot/batch no. (if required): not specifed in the report
- Purity: not specifed in the report

Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Analysis to determine concentration of the test material of all dosing solutions from the first mix of the main study was initiated prior to the start of dosing. The low- and high-dose solutions from the first mix of the main study were analyzed to confirm homogenous distribution of the test material concurrent with dose confirmation. Analyses were conducted using GC-FID.
Details on mating procedure:
- M/F ratio per cage: 1 male:1 female
- Age at mating of the mated animals in the study: 10 weeks
- Length of cohabitation: two weeks
- Proof of pregnancy: [sperm in vaginal smear and/or plug positive] referred to as [day 0] of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): singly
- Any deviations from standard protocol: no
Duration of treatment / exposure:
Females were dosed once daily for two weeks prior to breeding, through breeding (two weeks), gestation (three weeks), and through postpartum day 4 or 5. Females were necropsied on postpartum day 5 or 6. Males were dosed two weeks prior to breeding and continuing through breeding (two weeks) until necropsy (test day 34).
Frequency of treatment:
Once daily
Duration of test:
- Male animals: All surviving animals (fasted) were submitted for necropsy after at least four weeks of exposure
- Maternal animals: All surviving animals (fasted) were terminated on LD 5 or 6, or at least 24 days after the end of the mating period for females not producing a litter.

Doses / concentrationsopen allclose all
Doses / Concentrations:
0 (vehicle)
analytical conc.
Doses / Concentrations:
25 mg/L
analytical conc.
Mean measured conc: 24.8 mg/L
Doses / Concentrations:
125 mg/L
analytical conc.
Mean measured conc: 123.0 mg/L
Doses / Concentrations:
250 mg/L
analytical conc.
Mean measured conc: 247.0 mg/L
No. of animals per sex per dose:
12 males + 12 females
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The effects of treatment were limited to minor, nonadverse changes in the liver. Specifically, male and female rats administered 1000 mg/kg/day had increases in absolute and relative liver weights. The higher liver weights in males corresponded to an increase in the incidence of very slight hypertrophy of centrilobular and midzonal hepatocytes with altered tinctorial properties (increased eosinophilia of hepatocytes) at this dose level. No such correlate was observed for females.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity
Dose descriptor:
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
There were no effects on prenatal/early neonatal growth and survival of the offspring.

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion