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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)
Deviations:
yes
Remarks:
Administration comprised only period of organogenesis.
GLP compliance:
yes
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

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
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
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).

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.
Dermal irritation (if dermal study):
not examined
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
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
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:
no effects observed
Other effects:
no effects observed

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 effects observed.

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
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:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The statistically significant differences were considered to be incidental. The finding "two sternebrae, non ossified" is not a negative effect of the substance because a decrease indicate a more developed embryonic stage than in the other fetuses. The retardation effect of the "hyoid, incomplete ossified" is also incidental and not dose-related. 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.
Visceral malformations:
no effects observed
Other effects:
no effects observed

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.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
The results of this study showed that repeated oral administration (Day 6-15 post coitum) of the test substance to pregnant rats caused no symptoms of cumulative toxicity and does not reveal any embryotoxic or teratogenic potential up to a dose level of 1000 mg/kg body weight/day.