Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

A key study for reproductive toxicity in rats by was available from an OECD 422 study with a liquid formulation containing 41.5% active ingredient of read across substance 'Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts', at dose levels of 100, 300 and 1000 mg act. ingr./kg bw/day. No reproductive toxicity effects were observed up to 1000 mg/kg bw. At the dose of 1000 mg/kg bw, decrease body weight and other systemic effects were observed, therefore NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive toxicity was 1000 mg/kg bw/day. Read-across from CAS no. 577-11-7 (Docusate sodium) three-generation study according to OECD TG 416 and GLP showed decreased body weights in P, F1 and F2 generations at 0.5 and 1% dietary concentrations (the latter corresponding with 750 mg/kg bw), however these were not considered adverse and were not associated with any other (reproductive) findings. In a second (supporting) two-generation study the highest concentration of 1% in the diet corresponding with 750 mg act. ingr./kg bw was NOAEL.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see attached read-across justification
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Slightly increased salivationwas noted in one male rat dosed at 1000 mg/kg bw/day.
No signs of clinical toxicity were noted in all female treatment groups.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No premature deaths were noted in the male and female rats treated with 100, 300 or 1000 mg/kg bw/ day.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slight reduction of body weight and body weight gain was noted in male and female rats dosed at 1000 mg/kg bw/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
oral gavage study
Slight reduction in food consumption was noted in male and female rats dosed at 1000 mg/kg bw/day
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Increased number of eosinophils in intermediate dose females on test day 15 lacking dose dependence (p≤0.05)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group (1000 mg/kg bw/day) a statistically significant (p≤0.01) increase (males: +66%; females: +46%)) was noted for the plasma activity of ALAT.
In the male high dose group (1000 mg/kg bw/day) a decrease in albumin on test day 15 (p≤0.01) was noted but not considered test-item related (slight alteration in comparison to control animals without biological relevance).
In the female intermediate dose group (300 mg/kg bw/day) an increase in bile acids on test day 15 (p≤0.05) was noted but not considered test-item related (lacking dose dependence).
Urinalysis findings:
not examined
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related influence was noted for the fore- and hindlimb grip strength in any male/female treatment group (100, 300 or 1000 mg/kg bw/day).
No test item-related influence was noted on the spontaneous motility of the rats in any of the treatment groups.
In the male low dose group (100 mg/kg bw/day) a decrease in hindlimb grip strength on test day 36 (p≤0.05) was noted but not considered test-item related (lacking dose dependence).
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related influence in observational screening was noted for any treatment group (100, 300 or 1000 mg/kg bw/day).
In the high dose males a statistically significant decreased mean body temperature was noticed in comparison to the control group. This was considered to be not test item related.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
No test item-related microscopic changes were seen in the reproductive organs for both males and females.
A test item-related squamous cell hyperplasia was noted in the forestomachs from 5/5 male and 5/5 female animals of the high dose group (1000 mg/kg bw/day). These test item-related stomach changes were localized in the zone adjoining the glandular stomach mucosa (forestomach or
non-glandular mucosa) and attained statistical significance for both sexes (p≤0.01). Occasionally the squamous cell hyperplasia with subsequent hyperkeratinization was associated with acute inflammation of the submucosa in the non-glandular stomach (for 2/5 males and 1/5 females).
Examination of the stomachs from the animals (5 per group) of the low- and intermediate dose groups (100 and 300 mg/kg bw/day) did not reveal any test item-related changes. As humans lack a forestomach, the relevance of these changes for humans is questionable.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
effects observed, non-treatment-related
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
No statistically significant differences were noted in the length of the pre-coital time between the control group and the treatment groups.
There were no statistically significant differences for the female fertility rates between the control and the treatment groups.
No test item-related influence was noted on the gestation length of the females in any of the treatment groups compared to the control group.
No statistically significant differences were noted in the number of corpora lutea between the control and the treatment groups of P0 dams.
No statistically significant differences were noted in the number of implantation sites between the control and the treatment groups of P0 dams.
No statistically significant differences were noted in the total number of born pups (alive and dead) or in the number of pups born alive between the control group and the treatment groups of P0 dams.
No test item-related differences were noted between the control group and the treatment groups of P0 dams with respect to the reproduction indices which were calculated from the above mentioned parameters (Fertility index, Gestation index, Birth index, Live birth index, Pre-implantaion losss and Post-implantation loss).
Parameters with statistically significant differences in comparison to the control group which were considered as to be not test item related:
-Increased Birth Index in low and intermediate dose females
-Increased Pre-implantation loss in low dose females
-Decreased Post-implantation loss in low and intermediate dose females
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No premature deaths were noted in the male and female rats treated with 100, 300 and 1000 mg/kg bw/day.
No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day).
A slightly increased salivation was noted in one male rat, no further signs of clinical toxicity were noted for the male and female rats of the high dose group (1000 mg/kg bw/day). No test item related influence was noted for the male and female rats of all treatment groups (100, 300 and 1000 mg/kg bw/day) during the observational and functional (grip strength and spontaneous motility) neurological
screenings.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
A slight reduction in body weight was noted for the male and female rats of the high dose group (1000 mg/kg bw/day). For the male rats the reduction in body weight was noted from test day 8 (4.4%) until test day 36 (5.5%) , statistically significant (p≤0.05) in comparison to the control group on test day 8. Body weight gain was accordingly reduced in the high dose group during the whole study, mostly pronounced and statistically significant at the end of the first test week on test day 8 (p≤0.01), with a reduction in body weight gain by 35.4% in comparison to the control group. During the further course of the study the differences in body weight gain between the high dose group and the control group declined, leading to a body weight gain at the end of the study of 42.1%, the control group revealed a body weight gain of 50.5%.
For the high dose female rats a slight, not statistically significant, reduction in body weight was noted of 3.7% and 3.4% was noted on test days 8 and 15 (pre-mating). Body weight gain was 6.6% on test day 8 and 10.6% on test day 15 in the high dose group in comparison to 10.7% (test day 8) and 14.6% (test day 15) in the control group. Body weight was decreased during the whole gestation period between 7.6% on gestation day 0 and 6.5% on gestation day 20, statistically significant (p≤0.05) on gestation days 7 and 14 with 9.7% and 7.9% decrease, respectively. A small reduction in body weight gain was noted in the high dose group on gestation day 0 (15% in comparison to 18%. On gestation day 20 body weight gain was nearly identical in the high dose group (59.7%) and the control group (59.4%). During lactation a slight but not significant reduction in body weight was noted in the intermediate dose female rats by 4.4 % on lactation day 0 and 5.6% on lactation day 4. In the high dose group the body weight was statistically significantly (p≤0.05) reduced on lactation days 1 and 4 by 9.1% and 9.5%. No noticeable differences were noted in body weight gain during the lactation period with 5.6% in the high dose group and 6.1% in the control group.

A slightly statistically significant (p ≤ 0.01) increase in relative food consumption by 10.3% was noted in the high dose males during the 2nd test week. This was caused by the reduced body weight of the rats of the high dose group.
A slightly statistically significant (p≤0.05) decrease in relative food consumption by 7.4% was noted in the high dose females during the first test week.

HAEMATOLOGICAL FINDINGS
No test item-related influences were noted between the control group and the treatment groups for the haematological parameters, i.e. the haemoglobin content, the number of erythrocytes, leucocytes, reticulocytes and platelets, the haematocrit value, the thromboplastin time (TPT, aPTT), the mean corpuscular volume (MCV), the mean corpuscular haemoglobin (MCH) and the mean corpuscular haemoglobin concentration (MCHC). No test item-related changes were noted in the relative and absolute differential blood counts.
Statistically significant increased number of eosinophils (p≤0.05) was noted in the intermediate dose females on test day 15. This was considered to be not test item related ( lacking dose dependence).

CLINICAL BIOCHEMISTRY
In the high dose male and female group (1000 mg/kg bw/day) a statistically significant (p≤0.01) increase was noted for the plasma activity of ALAT.
In males no test item related influence was noted for the plasma levels of globulin, the albumin/globulin ratio, bilirubin (total), cholesterol (total), creatinine, glucose, urea in blood, sodium, potassium,calcium, chloride, the activity of the alkaline phosphatise (aP), the activity of ASAT and the serum levels of the bile acids. Decreased albumin in the high dose males (p≤0.01) was considered to be not test item related (slight alteration in comparison to control animals without biological relevance and 4/5 individual values within range of LPT Background Data))
In females no test item related influence was noted for the plasma levels of albumin, of globulin, the albumin/globulin ratio, bilirubin (total), cholesterol (total), creatinine, glucose, protein (total), urera in blood, sodium, potassium, calcium, chloride, the activity of the alkaline phosphatase (aP) and the
serum levels of the bile acids. Increased bile acids in the intermediate dose females (p≤0.05) was considered to be not test item related (lacking dose dependence).

BEHAVIOUR (FUNCTIONAL FINDINGS)
The functional neurological screenings were performed on test day 36 for the male rats and between test days 40-50 for the female rats, 2 hours after dosing.
No test item-related influence was noted for the fore- and hindlimb grip strength in any male/female treatment group (100, 300 or 1000 mg/kg bw/day).
Hinglimb grip strength in low dose males was statistically significant decreased on test day 36 (p≤0.05) but lacking dose dependence and was considered to be not test item related.
No test item-related influence was noted on the spontaneous motility of the rats in any of the treatment groups. No test item-related influence on relative and absolute organ weights was noted for the rats treated with 100, 300 or 1000 mg/kg bw/day in comparison to the control group.
Statistically significant differences in the relative organ weights compared to the control, which are not considered to be test item-related were:
- increased relative weight of left gonads in low and high dose males (p≤0.05)
- increased relative weight of right kidney in high dose females (p≤0.05)
- increased relative weight of right adrenal in high dose males (p≤0.05)
Statistically significant differences in the absolute organ weights compared to the control, which are not considered to be test item-related were:
-decreased absolute brain weight in high dose males (p≤0.05)
-decreased absolute heart weight by 16.6% in high dose females (p≤0.05)

GROSS PATHOLOGY (PARENTAL ANIMALS)
Macroscopic inspection at autopsy for the males was performed on test day 37.
No test-item related findings were noted in the low and intermediate dose group (100 and 300 mg/kg bw/day).
However, one animal (no. 3) with a reduction in the size of the testes was noted in the control group.
At the low dose group (100 mg/kg bw/day) animal no. 21 showed a partly reddened thymus and animal no. 29 a thickened right prostate.
In the intermediate dose group (300 mg/kg bw/day) one animal (no. 49) with macroscopic changes in the stomach (yellowish contents, detachment of mucosa) was found.
All changes are considered to be not test item-related but spontaneous due to the low number of occurrence.
In the high dose group (1000 mg/kg bw./day) 2 animals with macroscopic changes in the stomach were noted: Animal no. 68 showed a whitish thickening in the cardia part of the stomach and in the stomach of animal no. 69 a yellowish content was noted.
These findings were considered to be test item-related, because they were associated with microscopic changes in the forestomach from the animals of the high dose group.
Macroscopic inspection at autopsy for the females was performed between test days 43 and 54.
No test-item related macroscopic changes were noted in any treatment group (100, 300 and 1000 mg/kg bw/day) in females.
In 2 of the 3 non-pregnant rats (nos 16 and 54) from the control and the intermediate dose group (300mg/kg bw/day) a thickened uterus was noted.
These findings were considered to be not test item-related but spontaneous due to the low number ofoccurrence.

NEUROPATHOLOGY (OBSERVATIONAL FINDINGS)
The observational screenings were performed on test day 36 for the male rats and between test days 40-50 for the female rats, 2 hours after dosing.
No test item-related influence was noted for any treatment group (100, 300 or 1000 mg/kg bw/day).
A decrease in mean body temperature (p≤0.05) in the high dose males on test day 36 was considered to be not test item related. The slight alteration in comparison to control animals was without biological relevance (only 0.4°C difference to controls)

HISTOPATHOLOGY (PARENTAL ANIMALS)
Histopathological examination performed on one testicle and one epididymis with special emphasis on the qualitative stages of spermatogenesis (proliferative, meiotic and spermiogenic phases) and histopathology of the interstitial testicular structure of all adult male animals of the highest dose group and the control group following H & E and PAS staining, did not reveal any test item-related effects.
No test item-related microscopic changes were seen in the reproductive organs for both males and females.
A pulmonary congestion was noted in the lungs from 4/5 male (control 0/5) and 5/5 female rats (control 4/5) of the high dose group (1000 mg/kg bw/day). As pulmonary congestion is occasionally seen in rats as a background finding, this change was not considered to be test item-related.
A test item-related squamous cell hyperplasia was noted in the fore-stomachs from 5/5 male and 5/5 female animals of the high dose group (1000 mg/kg bw/day). These test item-related stomach changes were localized in the zone adjoining the glandular stomach mucosa (forestomach or
13 the squamous cell hyperplasia with subsequent hyperkeratinization was associated with acute inflammation of the submucosa in the non-glandular stomach (for 2/5 males and 1/5 females).
Examination of the stomachs from the animals (5 per group) of the low- and intermediate dose groups (100 and 300 mg/kg bw/day) did not reveal any test item-related changes. As humans lack a fore-stomach, the relevance of these changes for humans is questionable.
All other microscopic changes observed were either coincidental, or lie within the normal background alterations which may be seen in untreated rats of this age and strain.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
All animals were successfully mated as determinated by positive sperm detection. No statistically significant differences were noted in the length of the pre-coital time between the control group and the treatment groups.
There were no statistically significant differences for the female fertility rates between the control and the treatment groups.
No test item-related influence was noted on the gestation length of the females in any of the treatment groups compared to the control group.
No statistically significant differences were noted in the number of corpora lutea between the control and the treatment groups of P0 dams.
No statistically significant differences were noted in the number of implantation sites between the control and the treatment groups of P0 dams.
No statistically significant differences were noted in the total number of born pups (alive and dead) or in the number of pups born alive between the control group and the treatment groups of P0 dams.
No test item-related differences were noted between the control group and the treatment groups of P0 dams with respect to the reproduction indices which were calculated from the above mentioned parameters (Fertility index, Gestation index, Birth index, Live birth index, Pre-implantation loss and Post-implantation loss).
Parameters with statistically significant differences in comparison to the control group which were considered as to be not test item related:
-Increased Birth Index in low and intermediate dose females (p≤0.05)
-Increased Pre-implantation loss in low dose females (p≤0.05)
-Decreased Post-implantation loss in low and intermediate dose females (p≤0.05).
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
read-across test substance
Sex:
male/female
Remarks on result:
other: highest dose tested
Dose descriptor:
NOAEL
Remarks:
general toxicity
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
read-across test substance
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
clinical biochemistry
gross pathology
histopathology: non-neoplastic
Details on results:
No P1 generation: screening study
Clinical signs:
not examined
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
No test item-related differences were noted between the survival index of the control group and the treatment groups.
No live born pup from the control group and the low and intermediate dose groups died between lactation day 1 and 4, leading to a survival index of 100% for these groups.
In the high dose group (1000 mg/kg bw/day) 9 of 10 dams revealed a survival index of 100%, whereas all 3 live born pups from dam no. 77 were found dead without milk on lactation day 2, leading to a survival index of 0.0% for dam no. 77 and a survival index of 97.6% for the pups of the high dose group. This small decrease in the survival index of the pups of the high dose group was regarded as to be spontaneous.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test item-related influence was noted on the mean litter weight of the pups in all treatment groups.
No test item-related influence was noted on the total litter weight of the pups in all treatment groups.
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
Sexual maturation:
not examined
Description (incidence and severity):
Pups were sacrificed on day 4 of lactation.
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
The external examinations of the pups at sacrifice on day 4 of lactation revealed no test item-related external visible changes or gross abnormalities after treatment of the parental animals with 100, 300 or 1000 mg/kg bw/day. No milk was noted in the stomachs of the 3 dead pups from dam no. 77. This observation was spontaneous and considered as not test-item related.
Histopathological findings:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
VIABILITY (OFFSPRING)
No test item-related influence was noted on the survival rate of the pups.
No live born pup from the control group and the low and intermediate dose groups died between lactation day 1 and 4, leading to a survival index of 100% for these groups.
In the high dose group (1000 mg/kg bw/day) 9 of 10 dams revealed a survival index of 100%, whereas all 3 live born pups from dam no. 77 were found dead without milk on lactation day 2, leading to a survival index of 0.0% for dam no. 77 and a survival index of 97.6% for the pups of the high dose group. This small decrease in the survival index of the pups of the high dose group was regarded as to be spontaneous.

BODY WEIGHT (OFFSPRING)
No test item-related influence was noted on the mean litter weight of the pups in all treatment groups.
No test item-related influence was noted on the total litter weight of the pups in all treatment groups.

GROSS PATHOLOGY (OFFSPRING)
The external examinations of the pups at sacrifice on day 4 of lactation revealed no test item-related external visible changes or gross abnormalities after treatment of the parental animals with 100, 300 or 1000 mg/kg bw/day. No milk was noted in the stomachs of the 3 dead pups from dam no. 77. This observation was spontaneous and considered as not test-item related.

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
read-across test substance
Sex:
male/female
Basis for effect level:
other: development of F1 offspring
Remarks on result:
other: highest dose tested
No F2 generation: screening study
Reproductive effects observed:
not specified

Table 1. Fertility and Reproductive parameters Parental generation

Parameter

Group 1

Control

Group 2

100 mg/kg

Group 3

300 mg/kg

Group 4

1000 mg/kg

No. of females evaluated for pre-coital time

10

10

10

10

Mean precoital interval (days)

4.5

3.4

3.9

2.6

No. of females evaluated for fertility

10

10

10

10

Number of pregnant dams

8

9

9

10

Fertility index (%)

80

90

90

100

No. of females evaluated for gestation length

8

9

9

10

Gestation length (days)

22.0

22.2

22.2

22.1

Number of dams with live pups

8

9

9

10

Gestation Index (%)

100

100

100

100

Corpora lutea(total)

110

137

129

142

Corpora lutea(mean)

13.8

15.2

14.3

14.2

Implantation sites (total)

110

131

128

139

Implantation sites (mean)

13.8

14.6

14.2

13.9

Number of pups at birth (total)

96

125

123

127

Number of pups at birth (mean)

12.0

13.9

13.7

12.7

Birth Index (mean %)

90.4

95.5

95.9

90.1

Birth Index (total# %)

87

951

96 1

90.1

Number of stillbirths

0

0

1

0

No. of dams with stillborn pups

0

0

1

0

Number of live born pups (total)

96

125

123

126

Number of live born pups (mean)

12.0

13.9

13.7

12.6

Live birth index (mean %)

100.0

100.0

100.0

97.5

Live birth index (total#1 %)

100

100

100

99

Pre-implantation loss (mean %)

0.0

4.4

0.7

1.9

Pre-implantation loss (total#2  %)

0.0

4.42

0.8

2.1

Post-implantation loss (mean %)

9.6

4.5

4.1

11.2

Post-implantation loss (total#3 %)

12.7

4.62

3.92

9.4

Number of runts

0

0

0

0

Number of malformed pups

0

0

0

0

# based on the total No. of implantation sites and total No. of pups at birth (alive and dead)

#1 based on the total No. live born pups and total No. of pups at birth (alive and dead)

#2 based on the total No. corpora lutea and total No. of implantation sites

#3 based on the total No. implantation sites and toal number of live born pups

1 p≤0.05 Chi2-test

2 p<0.05 Chi2-test

Conclusions:
Read-across test substance NOAEL (no-observed-adverse-effect level) for reproductive toxicity: >= 1000 mg/kg bw/day, p.o.
Executive summary:

The aim of the study was to obtain information on possible effects of the read-across test item on general toxicity, reproduction and/or development according to OECD guideline 422. The test item was administered orally by gavage to rats at dose levels of 100, 300 and 1000 mg active ingredient/kg bw/day. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 37 for the male rats and between lactation day 4 and 7 for the female rats.

Effects on the parental generation (general toxicity)
No test item-related premature death was noted in any treatment group (100, 300 and 1000 mg test item/kg bw/day).

No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg test item/kg bw/day). A slightly increased salivation was noted in one male rat, no further signs of clinical toxicity were noted for the male and female rats of the high dose group (1000 mg test item/kg bw/day). A slight reduction in body weight was noted for the male and female rats of the high dose group (1000 mg test item/kg bw/day). For the male rats the reduction in body weight was noted from test day 8 (4.4%) until test day 36 (5.5%) and for the female rats from gestation day 0 (7.6%) until lactation day 4 (9.5%). The body weight at autopsy was reduced accordingly.

Effects on reproduction parameters and organs

No test item-related influence was noted on the reproduction parameters in any treatment group (100, 300 and1000 mg/kg bw/day).

Microscopic examination revealed no changes in the reproductive organs from the male and female rats of the high dose group (1000 mg/kg bw/day).

Effects on the F0-generation

NOAEL (no-observed-adverse-effect level): 300 mg/kg bw/day, p.o.

Effects on reproductive toxicity

NOAEL (no-observed-adverse-effect level): >=1000 mg/kg bw/day, p.o.

 

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliable quality (Klimisch 2)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproductive screening

No test data were available for current substance, however read across data were available from 'Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts'. Justification for read across within the category of N-containing sulphosuccinates (N2 subcategory) is documented in a separate document attached in Section 13.

- A key study for reproductive toxicity was performed by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013e). The test item (liquid formulation) containing 41.5% active ingredient was administered orally by gavage to rats at dose levels of 100, 300 and 1000 mg act. ingr./kg bw/day for for at least 28 days in male rats and at least 39 days in females. No test item-related premature death was noted in any treatment group. No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day), whereas slightly increased salivation was noted in one male rat as the only finding at 1000 mg/kg bw/day. A slight reduction in body weight was noted for the male and female rats dosed at 1000 mg/kg bw/day. Other parameters such as neurological observations, haematology and serum chemistry are discussed in the repeated dose toxicity section.

No test item-related influence was noted on the reproduction toxicity parameters in any treatment group (100, 300 and 1000 mg/kg bw/day).

Microscopic examination revealed no changes in the reproductive organs from the male and female rats of the high dose group (1000 mg/kg bw/day). NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive toxicity was >= 1000 mg/kg bw.

 

Multigeneration studies

Further data on reproductive toxicity were available from read across substance Docusate sodium (CAS No. 577-11-7). Justification for read across with the category of Di-ester sulphosuccinates is documented in a separate document attached in Section 13.

 - A key 3-generation toxicity study at dietary dose levels of 0.1, 0.5 and 1.0% in the diet (MacKenzie, 1986) conducted according to OECD caused a reduction in body weights at the dose levels of 0.5 and 1% in the diet for parental males of all generations and for F1 and F2 females. Pup weights at the 0.5% and 1.0% dose levels were lower than those of the control in all three generations, however this did not interfere with growth and development or reproductive performance, and had no adverse effects at levels on the reproductive function of either sex in any generation up to 1%. There were no other effects on parental or reproductive parameters. The NOEL for body weights of parental animals and offspring was 0.1%; the NOEL for reproductive parameters was 1.0%, which was considered to correspond with approximately 750 mg/kg bw/day.

- In a supporting 2-generation toxicity study in rats, 0.5 and 1% were given in the diet (Levinskas & Shaffer, 1970). In the first mating of the F0 generation and the second mating of the F2 generation, pups were weaned directly onto the diets which were being fed to their parents. In the other 3 matings of this study, dams were given a control diet on the day before delivery to avoid a bitter taste of the milk. Pups of all litters were examined for gross defects. Autopsies were performed, however, only on pups from the first mating of the F2 animals. Portions of all major organs were taken for histopathology processing and examination from one male and female from each litter. The other male and female were skinned and eviscerated, and the carcasses cleared, and the skeletons stained and examined for defects. In both the first mating of the F0 generation and the second mating of the F2 generation, the fertility and gestation indices were high and comparable. The viability index was good, albeit slightly down for the F3b pups, while the lactation index was depressed for both of these matings. In addition, the mean weight of the pups at weaning decreased with increasing concentrations of test material in the diet of the dams. In the second mating of the F0 animals, the viability and lactation indices and the mean weight of the test pups at weaning still showed decreases relative to the control values. However, in the 2 subsequent matings, all indices for the dosed animals were numerically high and compared favorably with the corresponding control values. Also, the mean weight of the pups at weaning was essentially similar for all groups. Consequently, it is concluded that diets containing 1% or less had no adverse effect on the reproduction and lactation performance of rats. The lowering of the survival rate and the mean body weight of the F1a and F3b pups is attributed to an impairment of nutrition as a result of the taste which is believed to have been secreted into the milk of the dams. Microscopic study of tissues showed findings which were similar in all groups. In processing the skeletons, the presence of an extra sternebrae in the sternum between the 5th and 6th sternebrae was not considered to parental exposure of test material. It is concluded that feeding of test material to rats from weaning through reproductive age for successive generations at levels of 1%, or less, did not produce lesions or anomalies in the offspring which could be attributed to the compound.

In conclusion, 2 multigeneration studies with read-across substance CAS no. 577 -11 -7 (Docusate sodium) showed that there were no reproductive findings.

 

Conclusion

An oral gavage reproductive screening study with read across substance Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts showed NOAEL of 300 mg/kg bw for paternal/maternal toxicity, whereas 1000 mg/kg bw was NOAEL for reproductive and developmental toxicity.

Multigeneration studies with read across substance Docusate sodium (CAS 577-11-7) showed slight maternal/paternal toxicity at 0.5 and 1% in the diet, however this was not confirmed in the second study. From both studies, it can be concluded that the substance up to 1% in the diet did not lead to effects on fertility or postnatal development; this concentration corresponds with 750 mg/kg bw/day, which is higher than the NOAEL for paternal/maternal toxicity.

Based on the absence of reproductive findings in the screening study, the repeated dose studies and the multigeneration studies with structural similar substances, no further testing is needed.

 

Justification for selection of Effect on fertility via oral route: key study

Effects on developmental toxicity

Description of key information

Developmental toxicity was not observed in the oral combined repeated dose and reproduction/

development screening study according to OECD guideline 422 with read across substance Butanedioic

acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]

ethyl]esters, disodium salts. Rats were dosed at 100, 300 and 1000 mg act. ingr./kg bw/day. No test item

related influence was noted on the survival rate and the mean and total body weights of the pups. External

examination of the pups revealed no visible changes related to the test item. NOAEL for systemic toxicity

was 300 mg/kg bw/day, whereas NOAEL for reproductive and developmental toxicity was >= 1000

mg/kg bw.
Prenatal developmental toxicity was tested by dietary administration of read across substance Docusate

sodium in rats from day 6 to 15 of gestation. 1% in the diet was a maternal and developmental NOAEL,

whereas at 2% in the diet visceral and skeletal anomalies were observed, which were considered

secondary to maternal toxicity. This was confirmed in a similar study with Docusate calcium given at

subtoxic and toxic dose levels, where the same could be observed.
Based on the absence of developmental findings in the screening study and teratogenicity study, no

further testing is needed.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
see attached read-across justification
Reason / purpose for cross-reference:
read-across source
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Among rats given dietary levels of 2.0% DSS, there were significant depressions in maternal weight-gains.
Rats fed diets containing 1.0% level of DSS showed no significant maternal effects on the various parameters.
Food consumption and compound intake (if feeding study):
no effects observed
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:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
Rats fed diets containing 1.0% level of DSS) showed no significant maternal effects on the various parameters. Among rats given dietary levels of 2.0% DSS, there were significant depressions in maternal weight gains.
Number of abortions:
no effects observed
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
In the 2.0% DSS group 1 pregnancy with total resorptions was observed (No statistical significance). No pregnancy with total resorptions was observed in the control or 1.0% DSS group.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Among rats given dietary levels of 2.0% DSS, there were significant increases in the number of resorptions of 13.7% as compared to the control frequency of 5.6%.
Dead fetuses:
no effects observed
Description (incidence and severity):
0.5% occurrence of dead fetuses was seen in the 2.0% DSS group versus 0.7% in the control group. No dead fetuses were observed in the 1.0% DSS group.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: 2.0% in the diet
Key result
Dose descriptor:
NOAEC
Effect level:
1 other: %
Based on:
act. ingr.
Remarks:
in the diet
Basis for effect level:
body weight and weight gain
early or late resorptions
Key result
Dose descriptor:
NOAEL
Effect level:
1 074 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Remarks:
read-across test substance
Basis for effect level:
body weight and weight gain
early or late resorptions
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): There is no postnatal evaluation in an OECD 414 study.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There is no significant reduction in viable fetuses in the dosed animals animals compared to control animals.
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
Description (incidence and severity):
There is no postnatal evaluation in an OECD 414 study.
External malformations:
effects observed, treatment-related
Description (incidence and severity):
Near toxic or toxic dietary levels of 2.0% DSS produced significant incidences of gross abnormalities either among litters (25.0%) or fetal populations (20.2%) as compared to none in the controls. These abnormalities consisted of cranial buble, exencephaly, spina bifida (not significant), microphtalmia or anophtalmia (not significant).
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
The visceral observations confirmed the significance of the exencephalous characteristics and anophtalmia for the group given dietary levels of 2.0% DSS.
Other effects:
effects observed, treatment-related
Description (incidence and severity):
In the 2.0% DSS group, skeletal observations revealed a significant incidence of variations including 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.
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
See Table 1-4.
Key result
Dose descriptor:
NOAEC
Effect level:
1 other: %
Based on:
act. ingr.
Remarks:
diet
Sex:
male/female
Basis for effect level:
external malformations
visceral malformations
other:
Remarks on result:
other: secondary to high maternally toxic dose
Key result
Dose descriptor:
NOAEL
Effect level:
1 074 mg/kg bw/day
Based on:
act. ingr.
Remarks:
diet
Sex:
male/female
Basis for effect level:
external malformations
visceral malformations
other: skeletal variations
Abnormalities:
effects observed, treatment-related
Localisation:
external: cranium
skeletal: skull
skeletal: rib
visceral/soft tissue: central nervous system
visceral/soft tissue: eye
Description (incidence and severity):
only at 2.0% dietary level.
Developmental effects observed:
yes
Lowest effective dose / conc.:
2 other: %
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Table 1. Maternal and fetal results of pregnant rats given various amounts if DSS in their diets during  gestational days 6 through 15.

Parameter

 Control        

1.0% DSS

2.0% DSS

Maternal

Group  (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

Average, 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

 Control

1.0% DSS

2.0% DSS

External observations1:

Group (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

Group  (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

 

Conclusions:
Subtoxic dietary levels of 1.0% read-across substance docusate sodium 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 controls. Interpretation of the results of the present experiments, in which only maternally toxic dose levels induce teratogenicity, indicates no real hazard with the recommended human use of these surfactants.
Executive summary:

Prenatal developmental toxicity was studied in rats dosed from day 6 to day 15 of gestation by dietary administration of read-across substance docusate sodium at dose levels of 1.0 and 2.0 % in the diet. Subtoxic dietary levels of 1.0% showed no adverse effects on the various maternal or fetal parameters. Near toxic or 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 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%. 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 significant depressions in maternal weight gains in the 2.0% DSS-group. Interpretation of the results of the present experiment, in which only maternally toxic dose levels 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 1074 mg/kg body weight, as calculated in the study.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Reliable quality (Klimisch 2)
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental screening

No test data were available for current substance, however read across data were available from 'Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) and C18unsaturated)alkyl))amino]ethyl]esters, disodium salts'. Justification for read across within the category of N-containing sulphosuccinates (N2 subcategory) is documented in a separate document attached in Section 13.

Supporting data for absence of developmental toxicity were available from an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013e). The test item was administered orally by gavage to rats with a formulation containing 41.5% active ingredient at dose levels of 100, 300 and 1000 mg act. ingr./kg bw/day for at least 28 days in male rats and at least 39 days in females. No test item-related premature death was noted in any treatment group. No signs of clinical toxicity were noted for the male and female rats of the low and intermediate dose groups (100 and 300 mg/kg bw/day), whereas slightly increased salivation was noted in one male rat as the only finding at 1000 mg/kg bw/day. A slight reduction in body weight was noted for the male and female rats dosed at 1000 mg/kg bw/day. Other parameters such as neurological observations, haematology and serum chemistry are discussed in the repeated dose toxicity section. No test item-related influence was noted on the developmental toxicity parameters in any treatment group (100, 300 and 1000 mg/kg bw/day).

Microscopic examination revealed no changes in the reproductive organs from the male and female rats of the high dose group (1000 mg/kg bw/day). No test item related influence was noted on the survival rate and the mean and total body weights of the pups. External examination of the pups revealed no visible changes related to the test item. NOAEL for systemic toxicity was 300 mg/kg bw/day, whereas NOAEL for reproductive and developmental toxicity was >= 1000 mg/kg bw.

 

Teratogenicity testing

Further data on prenatal developmental toxicity were available from read across substance Docusate sodium (CAS No. 577-11-7). Justification for read across with the category of Di-ester sulphosuccinates is documented in a separate document attached in Section 13. - A key study for prenatal developmental toxicity was performed in rats dosed from day 6-15 of gestation with read across substance Docusate sodium dosed at dietary dose levels of 1.0 and 2.0 % in the diet (Roell et al., 1976). 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. - As supporting information, prenatal developmental toxicity was also studied in rats by dietary administration of Docusate 'calcium' (DCS) at dose levels of 0.5, 1.0, 1.5 and 2.0 % in the diet as well as by oral gavage at 250, 500, 750 and 1000 mg/kg bw (Roell et al., 1976). Subtoxic dietary levels of 0.5 and 1.0% Docusate calcium 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 1.5 and 2.0% DCS produced significant incidences of resorptions and gross abnormalities consisting primarily of exencephaly of varying degrees with spina bifida, anophthalmia and associated skeletal defects. However, dietary levels of 2% of DCS fed to pregnant rats for 3 days (days 6-8, 8-10 or 10-12) did not produce teratogenic response. Also, DCS given to pregnant rats by oral intubation at maternally subtoxic doses (250-750 mg/kg) and a slightly toxic dose (1000 mg/kg) did not lead to malformations, however the incidence of resorptions was increased at the 2 toxic doses. Likewise doses of 500 and 750 mg/kg given by gavage from day 6-15 produced an increase in resorptions at the highest dose without a teratogenic effect. Since only maternally toxic doses fed on gestational day 6-15 produced embryotoxic and teratogenic effects, it is concluded that no real hazard exists.

In conclusion, both a prenatal developmental toxicity with read across substance Docusate sodium and with read across substance Docusate calcium were negative for teratogenicity at non-toxic dose levels.

 

Conclusion

An oral gavage reproductive screening study with read across substance 'Butanedioic acid, 2(or 3)-sulfo-, 4-[2-[(1-oxo(C12-C18(even numbered) andC18unsaturated)alkyl) amino]ethyl]esters, disodium salts' showed NOAEL of 300 mg/kg bw for paternal/maternal systemic toxicity, whereas 1000 mg/kg bw was NOAEL for reproductive and developmental toxicity.

Prenatal developmental toxicity was tested by dietary administration of read across substance Docusate sodium in rats from day 6 to 15 of gestation. 1% in the diet was a maternal and developmental NOAEL corresponding to 1074 mg/kg bw, whereas at 2% in the diet visceral and skeletal anomalies were observed, which were considered secondary to maternal toxicity. This was confirmed in a similar study with Docusate calcium given at subtoxic and toxic dose levels, where the same could be observed.

Based on the absence of developmental findings in the screening study and teratogenicity study with structurally similar substances, no further testing is needed.

 

Justification for selection of Effect on developmental toxicity: via oral route: Supporting study

Justification for classification or non-classification

Based on these results and according to CLP (No. 1272/2008 of 16 December 2008), the test item does not have to be classified and has no obligatory labelling requirement for reproductive and developmental toxicity.

Additional information