Butanedioic acid, sulfo-, C-C16-18-alkyl esters, disodium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL (reproductive toxicity) = 120 mg/kg bw/d              

NOAEL (parental/maternal toxicity) = 60 mg/kg bw/d

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

120 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch 1

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 reproductive screening study was performed with the registered substance, the substance was evaluated based on information with a read-across substance C12 -18 sulfosuccinate.

A key study for reproductive screening was performed with a read-across substance (C12 -18 sulfosuccinate) by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013a). The test item was a solid formulation (containing >93% active ingredient) which was administered as a watery solution orally by gavage to rats at dose levels of 60, 120 and 300 mg act. ingr./kg bw/day for for at least 28 days in male rats up to 54 days in female rats. Paternal/maternal toxicity was observed at 120 and 300 mg/kg bw in males. No test item-related influence was noted on the reproduction toxicity parameters at 60 and 120 mg/kg bw. The high number of 5 pregnant dams with a total loss of implantation sites in the high dose group (300 mg/kg b.w./day) led to a statistically significant reduction in the gestation index, in the mean number of implantation sites per dam, in the mean number of born pups per dam and in the birth index. Accordingly, the implantation loss index was statistically significantly increased in the high dose group. The high percentage of stillbirths led to a statistically significantly reduced live birth index in the high dose group (300 mg /kg b.w./day). Test item related effects were also noted on the pups from the 3 remaining dams of the high dose group (300 mg/kg b.w./day), expressed by a statistically significantly reduced survival rate during the lactation period, a statistically significant reduction in the mean litter weight and in the total litter weight per dam on lactation day 1 and 4.

In conclusion, general parental toxicity was higher than reproductive toxicity, and the reproductive findings were considered to be secondary to the paternal/maternal toxicity. NOAEL-levels were as follows: 60 mg/kg bw for paternal/maternal toxicity (based on clinical signs, reduced body weight, food consumption, organ weights and changes in biochemical parameters at the high dose levels) and 120 mg/kg bw for reproductive toxicity (based on reduced gestation index, birth index, live birth index and increased post implantation loss at the high dose levels).

Effects on developmental toxicity

Description of key information

No screening study was performed with the registered substance, the substance was evaluated based on information with a read-across substance C12 -18 sulfosuccinate.

A combined reproductive/developmental screening study according to OECD 422 which was performed with a read-across substance (C12 -18 sulfosuccinate) did not reveal external visible changes up to highest tested dose of 300 mg/kg bw. Decreased number of pups alive on day 4 of lactation and decreased viability index were observed, as well as decreased body weight of the pups both on day 0 and day 4. NOAEL for paternal/maternal toxicity was 60 mg/kg bw/day, whereas NOAEL for developmental toxicity was 120 mg/kg bw. The developmental findings were considered secondary to the paternal/maternal toxicity.

Based on the absence of developmental findings in the screening study with the read-across substance, no further testing is needed.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 074 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

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

Supporting data for absence of teratogenicity and developmental toxicity was available from following studies:

- A combined oral repeated dose and reproduction/development screening study was conducted with registered substance according to OECD guideline 422 (Hansen, 2013a). The test item was a solid formulation (containing >93% active ingredient) which was administered as a watery solution orally by gavage to rats at dose levels of 60, 120 and 300 mg act. ingr./kg bw/day for for at least 28 days in male rats up to 54 days in female rats. Paternal/maternal toxicity was observed at 120 and 300 mg/kg bw in males.No test item-related influence was noted on the reproduction toxicity parameters at 60 and 120 mg/kg bw. In the high dose group (300 mg/kg b.w./day)the total litter weight per dam of the 3 dams with live born pups was reduced on lactation day 1 and on lactation day 4 by 42 and 56%, respectively. A statistically significantly (p≤0.01) decreased viability index between day 4 and day1 was also noted in this dose group.The external examinations of the pups revealed no test item-related external visible changes in any of the treatment groups, except for ‘no milk in the stomach’ in pups which were found dead during the lactation period.

NOAEL-levels were as follows: 60 mg/kg bw for paternal/maternal toxicity (based on clinical signs, reduced body weight, food consumption, organ weights and changes in biochemical parameters at the high dose levels) and 120 mg/kg bw for developmental toxicity (based on a reduced viability index at the high dose levels).

- A combined reproduction-teratogenicity study was available for read across substance CAS No. 37294 -49 -8 (disodium C-isodecyl sulphonatosuccinate) in 2 generations (Tegeris and Underwood, 1975). The test item containing +-50% active ingredient was fed to Charles River CD Sprague-Dawley rats at 1% and 4% in the diet, while the control group received normal diet. The original females were allowed to deliver their first 2 litters (F1a & F1b), while the third litters were used for teratological evaluation and partial histology on 5 pairs per group (F1c). Females were allowed to rest 20 days between weaning and their next breeding. All litters were standardized to 8 newborn to equalize the maternal stress.
- F1a pups were examined to calculate Fertility Index (FI), Viability Index (VI) and Lactation Index (LI); they were discarded at weaning.
- F1b pups were examined to calculate Fertility Index (FI), Viability Index (VI) and Lactation Index (LI), with part of them that were studied postmortem (autopsy and 5 pairs per group for histology) and the other part were selected for second generation breeding, leading to F2a (discarded at weaning) and F2b (teratological examination and partial histology on 5 pairs per group).
- F1c were used for teratological evaluation an d partial histology on 5 pairs per group.

Although data suggest that the test material under the conditions of this experiment is not teratogenic in the rat it does, however, appear to depress the rate of body weight gain in the pups at 4% in the diet. The number of live born pups , and related to this Fertility Index (FI), Viability Index (VI) and Lactation Index (LI) also decreased at 4%. There were no histological effects on the gonads. NOEL for teratogenicity is 3000 mg/kg (4% in the diet); NOAEL for embryotoxicity is 750 mg/kg (1% in the diet).

In conclusion, both a combined reproductive/developmental screening study with registered substance and a combined reproduction-teratogenicity study with read across substance CAS No. 37294 -49 -8 did not indicate potential for developmental toxicity.

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 all., 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 registered substance showed NOAEL of 60 mg/kg bw for paternal/maternal toxicity, whereas 120 mg/kg bw was NOAEL for reproductive and developmental toxicity. The latter was based on reduced gestation index, (life) birth index and No. of pups and increased post-implantation loss at 300 mg/kg bw.

A combined reproduction-teratogenicity study with read across substance CAS No. 37294-49-8 (disodium C-isodecyl sulphonatosuccinate) in 2 generations resulted in a NOAEL for embryotoxicity of 750 mg/kg (1% in the diet) and a NOEL for teratogenicity of 3000 mg/kg (4% in the diet).

Prenatal developmental toxicity was tested by dietary administration of read across substance CAS No. 577-11-7 (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 seen at systemic toxic dose level and 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 teratogenicity study, and taking into account that same metabolic and toxicological behavior can be expected for structural similar substances, no further testing is needed.

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

Justification for classification or non-classification

Based on the results of a read-across substance and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), the registered substance does not have to be classified and has no obligatory labelling requirement for reproductive and developmental toxicity.