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Diss Factsheets

Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2 Jul 1991 - 29 Aug 1991
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (analytical purity of test substance not specified, only 2 dose levels, only organogenesis covered (days 6-15 of gestation))

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
(analytical purity of test substance not specified, only 2 dose levels, only organogenesis covered (days 6-15 of gestation))
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Sorbitan monolaurate, ethoxylated
EC Number:
EC Name:
Sorbitan monolaurate, ethoxylated
Cas Number:
Molecular formula:
Molecular formula cannot be given as substance is a mixture.
Sorbitan monolaurate, ethoxylated (1-6.5 moles ethoxylated)
Details on test material:
- Name of test material (as cited in study report): Polyoxyethylene sorbitan monolaurate, polysorbate 20
- Physical state: Colorless, viscous liquid
- Analytical purity: not reported
- Lot/batch No.: Lot No. 05241, Batch 01)
- Stability under test conditions: Stable as bulk chemical, when stored for 2 weeks, protected from light, at temperatures up to 25 °C
- Composition of test material, percentage of components: A colorimetric assay indicated 74 ± 1% fatty acid esters and 26 ± 1% carbowaxes

Test animals

Details on test animals or test system and environmental conditions:
- Strain details: Crl:CD BR VAF/Plus
- Source: Charles River Laboratories, Inc., Raleigh, NC, USA
- Age at study initiation: females: ca. 8 - 10 weeks, males: ca. 10 - 12 weeks
- Identification: unique tail tattoo or ear tag
- Weight at study initiation: females: 220-275 g
- Housing: Individually housed in solid-bottom polycarbonate cages with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ, USA ) and Ab-Sorb-Dri cage litter {Laboratory Products, Garfield, NJ, USA)
- Diet: Pelleted Purina Certified Rodent Chow (#500Z, (Ralston Puri. Co., St. Louis, Missouri, USA), ad libitum
- Water: deionized/filtered water, ad libitum
- Acclimation period: 7 days

- Temperature (°C): 21
- Air changes (per hr): 12 - 14.1 - 24.4
- Humidity (%): 51 - 69
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
A predetermined amount of the test substance was weighed into volumetric flask or a tared, calibrated beaker. The appropriate amount of water was added in order to achieve the desired concentration. Formulations were shaken or stirred to achieve a visibly homogeneous mixture. Each concentration of the test substance was formulated independently (twice during the study) in order to provide sufficient quantities for dosing.

- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Prior to administration, each formulation was analysed to ensure a concentration between 90 and 110% of the target concentration by UV/VIS Spectrometry
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: over night
- Further matings after two unsuccessful attempts: yes, sperm-negative females were returned to the male's cage and checked for sperm on successive mornings until insemination occurs or the treatment groups were filled, whichever came first
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
From Gestation Day 6 through 15
Frequency of treatment:
daily, 7 days/week
Duration of test:
20 days
Doses / concentrations
Doses / Concentrations:
500 and 5000 mg/kg bw
actual ingested
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The designated exposure levels were based upon the literature review as included in the study report.


Maternal examinations:
- Time schedule: at least once (more often if necessary) on the mornings of GD 0 through 20; more often than once per day, if necessary.

- Time schedule for examinations: on the mornings of GD 0, 3, 6 through 15, 18 and 20, and immediately following sacrifice on GD 20.

- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: On GD 0, 3, 6, 9, 12, 15, 18 and 20

- Sacrifice on gestation day 20
- Organs examined: liver, heart and kidney (right) was weighed and stored in 10% neutral buffered formalin for optional histopathology.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
Statistical procedures for selected experimental end-points was based on SAS software (SAS Institute, 1989a; 1989b, 1990a, 1990b, 1990c) available through the RTJ Computer Applications Center. Except for nominal scale measures, data were reported as Mean ± SEM. An alpha level of 0.05 was applied to all group-wise, pair-wise or trend tests.
A Test for Linear Trend was used to determine the significance of the dose-response relationship. Analysis of variance(ANOVA) was used to determine the significance of dose effects. When a significant (p<0.05) main effect for dose occurs, Dunnett’s Test (one-tailed) and Williams' Test was used to compare each substance-treated group to the vehicle control group for that measure; a one-tailed test was used, except that a two-tailed test was used for maternal organ and body weight parameters, maternal food and water consumption, fetal body weight, and percent males per litter. An arcsine-square root transformation was performed on all litter-derived percentage data prior to analysis by ANOVA.
Nonparametric Analyses: Nominal scale measures were analysed by chi-Square Test for independence for differences among treatment groups, and by a Test for Linear Trend on Proportions. When Chi-Square revealed significant (p<0.05) differences among groups, then a one-tailed fisher’s Exact Test was used for pair wise comparisons between each substance-treated group and the vehicle control group.
Historical control data:
Historical control data from teratologic Investigations in CD Rats at Research Triangle Institute

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: decreased weight gain

Details on maternal toxic effects:
No mortality was observed in any dose group. Signs of toxicity for individual animals during the in-life phase of the study were limited to regional hair loss, and alopecia, but these were not indicative of compromised maternal health.

Average maternal body weight (GD 0, 3, 6, 9, 12, 15, 18 or 20) did not differ among treatment groups, nor was there a treatment related change in maternal weight gain during gestation (absolute or corrected). Maternal weight gain during treatment was decreased by 14% at 5000 mg/kg bw/day relative to the vehicle control group, but no effect was noted at 500 mg/kg bw/day.

There were no treatment-related effects upon the following maternal organ weights: gravid uterine weight (absolute), liver weight (absolute or relative), kidney weight (absolute or relative), and heart weight (absolute or relative)

Maternal relative food intake was comparable among treatment groups throughout gestation.
Maternal water intake was comparable across groups during the pre- and post-treatment periods, but was elevated by 14% during the treatment period (GD 6 to 15) at 5000 mg/kg bw/day relative to the vehicle control group.

No differences among groups were noted for the number of corpora lutea per dam. The number of implantation sites per dam or the percent preimplantation loss per litter.

Resorptions occurred with an incidence of 4.1%, 4.2% and 0.9% per litter for the control, low and high dose groups, respectively. By comparison, the average historical incidence (n=203 litters) was 5.4% resorptions per litter. No significant effects were noted for the percent litters with at least one resorption, percent males per litter, fetal body weight (males, females or both) or percent adversely affected fetuses per litter (i.e. nonlive implants or malformed fetuses). The percent litters with one or more resorbed or adversely affected implants was not affected.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
> 5 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No late fetal deaths and no litters with 100% prenatal mortality were found in this study. No effect was noted for live litter size. The overall incidence of malformations in this study did not differ among treatment groups (4.3%, 5.0% and 8.1% per litter in the vehicle through high dose groups, respectively). The percent fetuses per litter with external or visceral malformations or with anatomical variations also did not differ among groups, nor did the percent litters with one or more fetuses with malformations (external, visceral, skeletal or all types combined) or variations. The increasing trend for percent fetuses with skeletal malformations per litter (i.e .0%, 0% and 0.7% skeletally malformed fetuses per litter, respectively) was considered as insufficient evidence of an adverse effect on skeletal development. Only two fetuses exhibited bipartite vertebra in the thoracic region, which is a common finding in this species and strain. Thus, it was not regarded as treatment-related.

Effect levels (fetuses)

Dose descriptor:
Effect level:
> 5 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion