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Toxicological information

Developmental toxicity / teratogenicity

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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:
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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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)

open allclose all
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
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

Applicant's summary and conclusion