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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
8 June - 15 July 1993
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted in 1981
Deviations:
yes
Remarks:
Administration comprised only period of organogenesis.
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Alcohols, C12-14, ethoxylated, sulfates, sodium salts
EC Number:
500-234-8
EC Name:
Alcohols, C12-14, ethoxylated, sulfates, sodium salts
Cas Number:
68891-38-3
Molecular formula:
not applicable, UVCB
IUPAC Name:
Alcohols, C12-14(even numbered), ethoxylated < 2.5 EO, sulfates, sodium salts
Details on test material:
- Name of the test material: Alcohols, C12-14, ethoxylated, sulfates, sodium salts (1 - 2.5 moles ethoxylated)
- EC number: 500-234-8
- CAS number: 68891-38-3
- Name of test material (as cited in study report): Sodium laurylethersulfate
- Ethoxylation degree: No data
- Physical state: Colourless to yellowish paste
- Analytical purity: 70.1% a.i.
- Lot/batch No.: 198/3
- Storage condition of test material: At RT

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
CD
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Wiga Sulzfeld, Germany
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: approx. 204 g
- Number of animals: 96, primiparous time-mated females
- Housing: Individually in Makrolon Type M3 cage (Ebeco, 44579 Castrop-Rauxel, Germany) with standard softwood bedding (ARWI-Center, 45307 Essen, Germany)
- Diet: Pelleted Altromin Maintenance Diet 1324, ad libitum
- Water: Community tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 23
- Humidity (%): 42 - 66
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 8 June 1993 To: 15 July 1993

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
Aqua dest.
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared daily by dissolving appropriate amounts of the test material in water yielding a final concentration of 1, 3, and 10% corresponding to 100, 300 and 1000 mg/kg bw/day, respectively.

VEHICLE:
- Concentration in vehicle: 1, 3 and 10%
- Amount of vehicle: 10 mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The formulation was analysed by "Henkel TTA-Zentrale Analytik" in the time from 21 - 30 June 1993 (study number TTA 93-6431). The concentrations of the test substance in aqua dest. based upon the results of the determination of the dry sediment confirmed the active content of 70.1% of the test substance.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
The females were mated at the supplier with an accurate day of mating. They were received at the testing facility on day 0 of gestation.
The mated animals (number) were delivered:
June 08, 1993 (24)*
June 09, 1993 (24)
June 23, 1993 (24)
June 24, 1993 (18)
June 25, 1993 (16)**
*: on delivery 3 animals dead, 1 animal died one day later
**: 15 females used in study
Duration of treatment / exposure:
Day 6-15 (incl.), post coitum
Frequency of treatment:
daily, 7 days/week
Duration of test:
Until Day 20 post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
corrected for a.i. content of test material
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
corrected for a.i. content of test material
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
corrected for a.i. content of test material
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose selection is based on the results of an earlier toxicoligical investigation. Rats (10 animals/dose/sex) were orally exposed to 100, 500 and 1000 mg/kg bw/day for 28 days (BASF, 1985, TBD870334). Adverse effects (lesions in the mucosa of the forestomach) were observed at 500 and 1000 mg/kg bw/day. In addition, alterations in hematology and clinical chemistry parameters were observed in the mid- and high-dose group animals when compared to the controls. Therefore, 100, 300 and 1000 mg/kg bw/day were selected as the dose levels for the pre-natal developmental toxicity study since the females in this study were dosed on only 10 consecutive days (Day 6 - 15, inclsive, post coitum).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS AND MORTALITY: Yes
- Time schedule: twice daily
- Cage side observations included: mortality, signs of reaction to treatment and symptoms of illness

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 16 and 20 post coitum

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on Day 20 post coitum by an overdose of ether
- Organs examined: all maternal organs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes

Examinations included: Gravid uterus weight, number of corpora lutea, implantations and early/late resorptions

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 early resorptions: Yes
- Number of late resorptions: Yes
Blood sampling:
Not performed.
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No
Statistics:
If the variables could be assumed to follow a normal distribution, the Dunnett-Test, based on a pooled variance, was applied for the comparison between the treated groups and the control group.
The Steel-Test was applied when the data could not be assumed to follow a normal distribution.
Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomised without loss of information (Bonferroni-Holm-corrected).
Indices:
No information reported.
Historical control data:
No data reported.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
No test substance-related symptoms were observed in any animal at any dose level.
Mortality:
no mortality observed
Description (incidence):
No deaths occured in any dams of the control and treatment groups.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gains were essentially similar in all groups and comparable with the controls.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not specified
Description (incidence and severity):
The following parameter relevant to ED were examined:
- gravid uterus weight, placenta weight
- number of corpora lutea / implantations
- number of early and late resorptions
- pre-implantation loss, post-implantation loss
- number of live and dead fetuses
- sex ratio
- fetal weights
- fetal abnormalities (skeletal, visceral and external)
For details, please refer to the respective result section.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No effect on gravid uterus weight and placental weight.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic changes were noted in the dams of the control and treatment groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
In the mid-dose group (300 mg/kg bw/day), the mean value of the pre-implantation loss was decreased (level 5%). The finding was considered incidental and in the normal range.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
corrected for a.i. content of test material
Basis for effect level:
other: No treatment-related adverse effects observed up to and including the highest dose tested.
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
With the exception of the male group 2 (slight mean decrease) the weights of live fetuses exhibited no significant differences on a litter and individual basis. Mean weight between the control group and the treatment group was comparable.
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
In the high-dose group (1000 mg/kg bw/day), the mean value of the total males was increased (level 5%) and that of the total females decreased (level 5%). These findings were considered to be incidental and in the normal range.
Changes in sex ratio:
effects observed, non-treatment-related
Description (incidence and severity):
In the high dose group (1000 mg/kg bw/day), the mean value of total males was increased (5%) and the corresponding value for total females decreased. This finding was considered incidental and within the normal range.
Changes in litter size and weights:
no effects observed
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No macroscopical findings were noted at external examination of fetuses which were considered to be an effect of the treatment with the test article. In group 4, there was one foetus with paleness.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Retardations were noted in group 3 and 4. The finding "two sternebrae, non ossified" (p<0.05) is not a negative effect of the substance because a decrease indicates a more developed embryonic stage than in the other fetuses. It was considered incidental. Incidences were 14-12-18-4 for the control, 100, 300 and 1000 mg/kg bw/day group, respectively.
Furthermore, the retardation effect of the "hyoid, incomplete ossified" (p<0.01) is also incidental and not dose-related. Incidences were 1-3-16-3 in the control, 100, 300 and 1000 mg/kg bw/day group, respectively. Only singular litters were affected. The incidental character of this variation is emphasised by the fact the values were within the normal range of variation of this strain.
No variations were observed.
No malformations were observed in treated groups.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects.
The incidences of the most common findings are listed below:
Hydronephrosis: 24/150, 31/156, 21/173 and 34/161 affected foetuses in Group 1, 2, 3 and 4, respectively.
Waved ureter: 11/150, 7/156, 8/173 and 19/161 affected foetuses in Group 1, 2, 3 and 4, respectively.
Dilatation of ureter: 9/150, 8/156, 4/173 and 18/161 affected foetuses in Group 1, 2, 3 and 4, respectively.
There was no dose-response and therefore, no relationship to treatment was inferred.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
corrected for a.i. content of test material
Sex:
male/female
Basis for effect level:
other: No treatment-related effects observed.
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In the present prenatal developmental toxicity study compliant with OECD 414 (with deviations) and GLP, rats were dosed orally at doses 100, 300 and 1000 mg/kg bw/day during gestation day 6-15. The results of this study showed that repeated oral administration of the test substance to pregnant rats caused no symptoms of cumulative toxicity and did not reveal any embryotoxic or teratogenic potential up to a dose level of 1000 mg/kg bw/day.