Tall-oil fatty acids salts of condensation products of tall-oil fatty acids with diethanolamine and triethanolamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across from GLP-compliant guideline study performed with similar substance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS Sprague Dawley rats, strain Crl:CD(SD)
- Source: Charles River (UK) Ltd.
- Age at study initiation: approx. 70 days (Day 0 of gestation)
- Weight at study initiation: 227-278 g
- Fasting period before study: none
- Housing: one cage per animal during gestation
- Diet (e.g. ad libitum): ad libitum (pelleted diet)
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: five days before commencement of pairing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12 h light, 12 h dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil allows good dispersion of test substance, experience from other gavage studies
- Concentration in vehicle: 50, 150, 500 mg/ml
- Amount of vehicle (if gavage): 2 ml/kg body weight

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Chemical analysis of test material formulations by high performance liquid chromatography (HPLC/UV) using an external standard technique.
- Concentrations (verified for first and last preparation) of the test material formulations were confirmed at each dose level.
- Chemical analysis confirmed that the prepared formulations were within 4% of the corresponding nominal concentration.

Details on mating procedure:

- M/F ratio per cage: 1 : 1 with identified stock males
- Length of cohabitation: until positive evidence of mating was detected
- Proof of pregnancy: ejected copulation plugs and vaginal smears were checked for presence of sperm; when positive then referred to as day 0 of pregnancy

Duration of treatment / exposure:

females were treated from Day 6 to Day 19 (inclusive)

Frequency of treatment:

once daily

Duration of test:

animals were killed on Day 20 after mating

No. of animals per sex per dose:

20 animals per group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on result of reproduction toxicity screening study

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 3 and 6-20 after mating

FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
- Food consumption for each animal determined for days: 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: detailed necropsy and macroscopic examination of tissues

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 early resorptions: Yes
- Number of late resorptions: Yes
- Number of fetuses: 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:

The analyses were carried out using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
The following data types were analysed at each timepoint separately:
Body weight, using absolute values and gains over appropriate study periods
Gravid uterine weight and adjusted body weight
Food consumption, over appropriate study periods
Litter size and survival indices
Fetal, placental and litter weight

A sequence of statistical tests was used for body weight, gravid uterine weight, food consumption, corpora lutea, implantations, live young, fetal, placental and litter weight data.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:no effects

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The incidence of major and minor visceral and skeletal abnormalities and skeletal variants showed no relationship to treatment.

Across all treated groups there was a slightly higher incidence of incompletely ossified hyoid and 13/14 14/14 short supernumerary ribs compared to concurrent control but was within Historical Control Data (HCD) (see attachment "historical control data").

At 1000 mg/kg/day there was also a slightly higher incidence of incompletely ossified sacrocaudal vertebrae compared to concurrent control but again this was within HCD.

These findings are therefore considered to be unrelated and incidental, showing no clear treatment relationship.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: embryotoxicity

3

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

There was no effect of WS400128 on body weight and body weight change as well as food consumption during gestation (Tables 2, 3, 4 in the attachment "result tables from OECD 414 study with WS400128).

There was no effect of WS400128 on implantations, early or late resorptions, live young or sex ratio (Table 5 in the attachment "result tables from OECD 414 study with WS400128).

There was no effect of treatment on placental weight or litter weight (Table 6 in the attachment "result tables from OECD 414 study with WS400128).

The incidence of major and minor visceral and skeletal abnomalities ans skeletal variants showed no relationship to treatment (Tables 7, 8, 9 in the attachment "result tables from OECD 414 study with WS400128).

As outlined in the „Validity Assessment Report“ for the read-across approach (see IUCLID Section 13) read-across from testing data obtained with the UVCB substance WS400128 is considered appropriate for the safety evaluation as well as classification and labelling of the UVCB substance WS400136 based on the close chemical similarity between the two substances.

Applicant's summary and conclusion

Conclusions:

As outlined in the „Validity Assessment Report“ for the read-across approach (see IUCLID Section 13) read-across from testing data obtained with the UVCB substance WS400128 is considered appropriate for the safety evaluation as well as classification and labelling of the UVCB substance WS400136 based on the close chemical similarity between the two substances.

The NOAEL for maternal toxicity, embryo-fetal survival, growth and development of 1000 mg/kg/day as derived with the read-across source substance WS400128 also can be used for the read-across target substance WS400136 for the regulatory purposes of REACH.