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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 from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: only 2 doses tested

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1976
Report Date:
1976

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: About 2 months
- Weight at study initiation: Not provided
- Fasting period before study: Not provided
- Housing: Individually in hanging wire mesh cages
- Diet (e.g. ad libitum): Wayne Lab Meal ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Not provided

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2°C
- Humidity (%): 50 ± 5%
- Air changes (per hr): Not provided
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: feed
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: 40% solution in corn oil

DIET PREPARATION
- Rate of preparation of diet (frequency): Not provided
- Mixing appropriate amounts with (Type of food): 1.0% and 2.0% admixed in Wayne Lab Meal
- Storage temperature of food: Not provided

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 40% solution in corn oil
- Amount of vehicle (if gavage):/
- Lot/batch no. (if required): Not provided
- Purity: Not provided
Details on mating procedure:
Not provided
Duration of treatment / exposure:
gestational days 6 through 15: dosing
Duration of test:
gestational days 6 through 15: dosing
gestational day 21: killing of the mothers and removing fetuses by cesarean section
Doses / concentrations
Remarks:
Doses / Concentrations:
1.0 % DSS , 2.0% DSS
Basis:

No. of animals per sex per dose:
22 female rats in dose 1.0% DSS
20 female rats in dose 2.0% DSS
Control animals:
yes, concurrent vehicle
Details on study design:
Not provided

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes (clinical condition and signs of illness)
- Time schedule: each day
- Cage side observations were not included.

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g
food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight
gain data: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Organs examined: Ovaries and uterine content


Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of resorptions: Yes
- Other:
Fetal examinations:
- External examinations: Yes (3336 of conceptuses)
- Soft tissue examinations: No
- Skeletal examinations: Yes (one half of the total number of fetuses)
- Head examinations: No
-Visceral examinations: Yes (one-half of the total number of fetuses were fixed in Bouin’s fluid for a detailed examination of visceral anomalies, using the slicing method of Wilson)

Statistics:
Maternal body-weight gains, maternal food consumptions and fetal weights were analyzed by Dunnett’s two-sided, multiple comparison test. Frequencies of resorptions and fetal abnormalities among litters were analyzed by the Mann-Whitney U test or the Chi-square test (with Yate’s correction), as appropriate.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
1 other: %
Based on:
act. ingr.
Remarks:
in the diet
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
1 other: %
Based on:
act. ingr.
Remarks:
in the diet
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

TABLE 1. Maternal and fetal results of pregnant rats given various amounts if DSS in their diets during   

                gestational days 6 through 15.

Parameter

Dose:      Control        

1.0% DSS

2.0% DSS

Maternal

Groups:            (I-A)

(II-A)

(II-B)

No. of pregnant rats

43

22

20

No. of pregnancies with total resorptions

0

0

1

No. of pregnancies with viable fetuses

43

22

19

Average weight gain of dams with viable fetuses(g):

 

 

 

Days 6 to 15

78

86

52*

Days 15 to 21

66

67

77

Avarage, apparent food intake of dams with viable fetuses (g/rat/day):

 

 

 

Days 6 to 15

22.5

24.8

21.4

Days 15 to 21

28.6

32.1

33.4

Calculated compound consumed (mg/kg/day)

--

1074

1988

Litters

 

 

 

Total number of:

implantations

 

411

 

203

 

219

Resorptions

(% occurence)

23

(5.6)

8

(3.9)

30*a

(13.7)

Dead fetuses

(% occurrence)

3

(0.7)

0

1

(0.5)

Viable fetuses

(% occurrence)

385

(93.7)

195

(96.1)

188

(85.5)

Fetal weight (g)

4.6

5.2

4.7

Litters size (viable fetuses)

8.9

8.9

9.9

External major malformations1:

No. of litters affected

(% occurrence)

 

 

0

 

 

0

 

 

5*

(25.0)

No. of fetuses affected

(% occurrence)

 

0

 

0

36*a

(20.2)

* Significantly different from control (p< 0.05)

a Significance by Chi-square, but not Mann-Whitney U test

1 Primarily, exencephaly varying degrees and associated anomalies (See TABLE 2)

    

TABLE 2. Morphological observations of fetuses delivered from rats given DSS in their diets on

                gestational days 6 through 15.

Morphology

Dose:        Control

1.0% DSS

2.0% DSS

External observations1:

Groups:    (I-A)

(II-A)

(II-B)

Total number examined

388a

195

189

Major anomalies:

  Adactyly

 

0

 

0

 

0

  Hemimelia

0

0

0

  Schistocelia

0

0

2

  Dome shaped head

0

0

0

  Cranial bubble (1-2mm)

0

0

9*

  Exencephaly

0

0

18*

  Exencephaly (cleft condition)

0

0

7*

  Anencephaly

0

0

0

  Spina bifida

0

0

6

  Macroglossia

0

0

0

  Micro- or anophtalmia

0

0

3

Defects:

  Hematoma (subcutaneous)

 

2

 

0

 

0

  Edamatous abdomen

0

0

0

  Tail short & curled

0

0

0

  Abducted fifth digit, left

   Rear foot

0

0

1

1 Fetuses may have more than one defect

a Fifty-four fetuses examined grossly only. (Shipment c valid as controls only)

      *Significantly different from control (p< 0.05) by Chi-square only

 

TABLE 3. Visceral observations of fetuses delivered from rats given DSS in their diets on gestation days

                 6 through 15.

Visceral observations

Dose:      Control

1.0 % DSS

2.0% DSS

Groups:       (I-A)

(II-A)

(II-B)

Total number of fetuses examined

165a

98

91

Defects1:

  Exencephalous   characteristics                     

 

0

 

0

 

11*

  Dilated lateral ventricles

1

3

5

  Microphtalmia

0

1

0

  Anolphtalmia

0

0

23*

  Retinal foldings

0

0

0

  Anotia or microtia

0

0

0

  Cleft palate

0

0

1

  Situs transversus – aorta, esophagus

  & stomach

1

0

0

  Intestinal agenesis

0

0

0

  Arch of aorta absent or right sided

0

0

0

  Diaphragmic hernia

0

0

1

  Dilated renal pelves

2

0

3

  Ectopic kidneys(s) &/or variation in size

1

0

0

  Renal agenesis

0

0

2

  Dilated ureters

6

0

3

  Adrenal agenesis

0

0

1

  Testes – ectopic or enlarged

1

0

1

  Hermaphroditism

0

0

3

1Fetuses may have more than one defect

aExcludes 1 fetus lost

*Significantly different from control (p<0.05) by Chi-square only

TABLE 4. Skeletal observations of fetuses delivered from rats given DSS in their diets on gestation days

                6 through 15.

 

Skeletal observations

Dose:      Control

1.0 % DSS

2.0% DSS

Groups:       (I-A)

(II-A)

(II-B)

Total number of fetuses examined

167a

97

98

Defects1:

  Cranial bones,

  incomplete to lack of ossification :

   Nasal                    

 

 

 

0

 

 

 

0

 

 

 

4

   Frontal

1

0

20*

   Parietal

1

1

19*

   Interparietal

1

2

18*

   Supraoccipital

0

0

15*

   Exoccipital

0

0

2

   Atlas

0

0

1

   Zygomatic

0

0

1

   Premaxilla

0

0

1

   Tympanic bullae

0

0

5

   Mandibles

0

0

1

   Hyoid

0

0

3

  Eye orbit, reduction

0

0

0

  Exoccipital, fused to atlas

0

0

0

  Vertebrla column, curved &/or open

0

0

5

  Vertebrae:

 

 

 

   misshapened &/or retarded 

   development

0

0

5

   thoracic, bipartite centra

2

1

5

   lumbar, bipartite centra

0

0

2

  Sternebrae:

 

 

 

   fused

0

0

0

   hypoplastic to absent

0

0

1

   one or two absent

1

0

0

   staircase

0

0

3

   bipartite

0

0

2

  Rib(s):

 

 

 

   accesory

6

5

5

   Absent or less developed

0

0

7*

   wavy

2

2

0

   fused

0

0

2

  Pelvic, hypoplastic to absent

0

0

0

  Brachydactyly

0

0

0

  Syndactyly

0

0

0

  Adactyly

0

0

0

  Hemimelia & small scapula

0

0

 0

1Fetuses may have more than one defect

aExcludes 1 fetus destroyed during cleaning process

*Significantly different from control (p<0.05) by Chi-square only

 

Applicant's summary and conclusion

Conclusions:
Subtoxic dietary levels of 1.0% DSS ingested on gestational days 6 through 15 showed no adverse effects on the various maternal or fetal parameters.
Near toxic or toxic dietary levels of 2.0% DSS produced significant incidences of resorptions(13.7%) and gross abnormalities either among litters ( 25.0%) or fetal populations ( 20.2%) as compared to non in the controls. These abnormalities consisted primarily of exencephaly of varying degrees with, at times, spina bifida, anophtalmia and associated skeletal defects. The visceral observations confirmed the significance of the exencephalous characteristics and anophtalmia for the group given dietary levels of 2.0% DSS. In this group, skeletal observations revealed a significant incidence of incomplete ossification to absence of the various cranial bones, a curved or open vertebral column, and a variety of defects of the vertebrae and ribs.
There were also significant depressions in maternal weight-gains in the 2.0% DSS-group .

Interpretation of the results of the present experiments, in which only maternally toxic or near toxic dietary doses induce teratogenicity, indicates no real hazard with the recommended human use of these surfactants.
Executive summary:

A prenatal developmental toxicity study was performed in rats dosed from day 6-15 of gestation with Docusate sodium dosed at dietary dose levels of 1.0 and 2.0 % in the diet. The study was conducted according to OECD 414 guideline, and was considered to be reliable, adequate and relevant. Subtoxic dietary levels of 1.0% showed no adverse effects on the various maternal or fetal parameters. Toxic dietary levels of 2.0% Docusate sodium produced significant depressions in maternal weight-gains and increased incidences of resorptions (13.7%) and gross abnormalities either among litters (25.0%) or fetal populations (20.2%) as compared to controls. These abnormalities consisted primarily of exencephaly of varying degrees with, at times, spina bifida, anophthalmia and associated skeletal defects. The visceral observations confirmed the significance of the exencephalous characteristics and anophthalmia for the group given dietary levels of 2.0%. In this group, skeletal observations revealed a significant incidence of incomplete ossification to absence of the various cranial bones, a curved or open vertebral column, and a variety of defects of the vertebrae and ribs. Interpretation of the results of the present experiment, in which only maternally toxic doses induce teratogenicity, indicates no real hazard with the recommended human use of these surfactants. The concentration of 1% in the diet is considered as maternal and developmental NOAEL. This dose level corresponded with a test article intake of 1074 mg/kg body weight, as calculated in the study.