Reaction products resulting from the esterification of Sorbitol with C8 – 18 (even) and C18 unsaturated fatty acids in the ratio of 1:1

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions Analytical purity of test substance not reported

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2007

Report date:

2007

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

yes

Remarks:

analytical purity of test substance not reported, no skeletal examination of offspring performed;

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Sorbitan stearate

EC Number:

215-664-9

EC Name:

Sorbitan stearate

Cas Number:

1338-41-6

Molecular formula:

C24H46O6

IUPAC Name:

1,4-anhydro-6-O-stearoyl-D-glucitol

Details on test material:

- Name of test material (as cited in study report): Sorbitan, monooctadecanoate
- Physical state: light yellow crystalline pellet
- Analytical purity: no data
- Storage condition of test material: stored in a sealed box under the room temperature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 10 weeks
- Weight at study initiation: males (g): 385.3 ± 18.2 - 386.6 ± 16.8, females (g): 220.4 ± 9.6 - 224.8 ± 7.8
- Housing: metal wire mesh cages (220x270x190 mm)
- Diet (ad libitum): CE-2, Clea Japan
- Water (ad libitum): tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.0 - 24.5
- Humidity (%): 55.0 - 65.5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12 (7 a.m. to 7 p.m.)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: serial dilutions in water were prepared

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to the main study, analytical measurements were performed (GC).

Details on mating procedure:

- M/F ratio per cage: 1/ 1
- Length of cohabitation: max. 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

2 weeks before mating until day 4 of lactation ~42 days

Frequency of treatment:

once daily

Duration of test:

offspring were euthanized on day 4 of lactation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 40, 200, 1000 mg/kg bw/d
Basis:
nominal in water

No. of animals per sex per dose:

females: 0, 40, 200 and 1000 mg/kg/d: 12 animals

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: preliminary range-finding study (pilot project number: R-04-004) 0, 500, 1000 and 2000 mg/kg
- Other: Post-exposure recovery period in satellite groups: 14 days

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 1 time daily during the breeding and recovery period and twice daily during the treatment period before and after administration

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
pregnant females: day 0, 7, 14, 21, 28, 35, 42 during treatment and day 0 and 4 of lactation
[position, posture, spontaneous movement, noise, tremor, ease of retrieval, ease of handling, heart beat, body temperature, fur, skin, visible mucous membranes, tearing, bulging eyes, pupil diameter, Postural position, exploratory behavior, grooming, vocalizations, straub tail reaction, walking, stereotypic behavior, bizarre behavior, tremors, piloerection, eye fissure]

BODY WEIGHT: Yes
- Time schedule for examinations:
pregnant females: 1, 7, 14, 21, 28 before the copulation, 0, 7, 14, 20 after the copulation and 0, 4, 5 after delivery
females in satellite group: 1, 7, 14, 21, 28, 35, 42 during treatment and 1, 7, 14, 15 during recovery

FOOD CONSUMPTION:
females: between days 1-2, 7-8, 14-15 before pregnancy, 0-1, 7-8, 14-15, 20-21 during pregancy and 3-4 during lactation

FOOD EFFICIENCY:
- Body weight gain in g: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on day 4 post partum
- Organs examined: see repeated dose toxicity study under 7.5.1

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: No
- Head examinations: No

Statistics:

Fisher´s exact test, Mann-Whitney U-grade test, Student´s t-test, Aspin-Welch test, Bartlett test, Dunnett multiple comparison method, Kruskal-Wallis test

Indices:

Implantation index, gestation index, offspring viability index, birth index, live birth index, delivery index, sex ratio on day 0

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)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
VIABILITY (OFFSPRING)
40 mg/kg: all pups from two dams (FB02005, FB02007) were dead, all pups from FB02012 didn't suckle on day 1 of lactation and 9 pups were dead, but 4 pups were alive until day 4 of lactation. No deaths in the higher dose groups.

CLINICAL SIGNS (OFFSPRING)
1000 mgkg: one pup with a filamentous tail
It happens naturally in this species, therefore, it was not caused by the test material

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Number of pups up to day 4 lactation

Dose (mg/kg)	0	40	200	1000
Number of pregnant females	11	11	12	12
Number of pregnant females with live newborns	11	11	12	12
Day 0 of lactation (at birth) Number of newborns	14.2±1.9	13.3±2.4	13.3±2.7	13.3±2.8
Day 4 of lactation Number of live pups	13.8±1.9	10.3±6.1	12.7±3.6	13.3±2.8

Number of live pups in 40 mg/kg showed slightly decreased but it was not statistically significant.

Morphological observations of pups

Dose (mg/kg)	0	40	200	1000
Dead pups
Number of dead pups (including missing pups)	4	33	7	0
Number of dead pups with external changes	0	0	0	0
Number of dead pups with visceral changes	0	0	0	0
Live pups
Number of newborns examined (Day 0 of lactation; at birth)	153	134	152	160
No. of newborns with external changes	0	0	0	1
Types and number    Filamentous Tail	0	0	0	1
Number pups examined (Day 4 of lactation; at necropsy)	152	113	152	160
No. of newborns with external changes	0	0	0	1
Types and number   Filamentous Tail	0	0	0	1
No. of pups with visceral changes	0	0	0	0