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Key value for chemical safety assessment

Effects on fertility

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 data were available for the registered substance, but read across data were available from category member CAS No. 90268-36-3 ( Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts). Justification for read across with the subgroup of mono-ester sulfosuccinates is documented in a separate document attached in Section 13.

A key study for reproductive screening was performed by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013b). 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 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. At the dose of 300 mg/kg bw, decreased values were observed for gestation index, No. of corpora lutea, implantation sites, pups born (alive and dead), and (life) birth index. Post-implantation loss was statistically increased. 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).

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 and 120 mg/kg bw for reproductive toxicity.

 

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 sulfosuccinates 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, sulfo-, 1-C12-18-alkyl esters, disodium salts (CAS 90268-36-3) 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.

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 no further testing is needed.


Short description of key information:
A key study for reproductive toxicity was performed with read across substance CAS No. 90268-36-3 (Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts) in rats by means of an OECD 422 study with a test substance containing >93% active ingredient at dose levels of 60, 120 and 300 mg/kg bw/day. NOAEL-levels were 60 mg/kg bw for paternal/maternal toxicity and 120 mg/kg bw for reproductive toxicity. Reproductive findings included decreased gestation index, No. of corpora lutea, implantation sites, pups born (alive and dead), and (life) birth index. The reproductive findings were considered to be secondary to the paternal/maternal toxicity.
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. .

Justification for selection of Effect on fertility via oral route:
Key study for reproductive toxicity screening. The study was selected as it had a lower NOAEL than the multigeneration toxicity studies with read across substance.

Effects on developmental toxicity

Description of key information
A  combined reproductive/developmental screening study according to OECD 422, which was performed with read across substance CAS No. 90268-36-3 (Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts), did not reveal  external no 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 forpaternal/maternal toxicity was 60 mg/kg bw/day, whereas NOAEL for developmental toxicity was 120 mg/kg bw. The developmetnal findings were considered secondary to the paternal/maternal toxicity. 
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 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 was 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.
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:
Klimish 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

Weight of evidence for absence of teratogenicity and developmental toxicity was available from following studies:

- A study for reproductive screening was performed with read across test substance CAS No. 90268-36-3 ( Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts) by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013b). 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. At the dose of 300 mg/kg bw, a decreased number of pups alive on day 4 of lactation and decreased viability index were observed. The body weight of the pups both on day 0 and day 4 were statistically decreased compared to controls.

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).

- Combined reproduction-teratogenicity study with read across test item CAS No. 37294-49-8 ( Disodium C-isodecyl sulphonatosuccinate) in 2 generations (Tegeris and Underwood, 1975c). 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. a. F1a pups were examined to calculate Fertility Index (FI), Viability Index (VI) and Lactation Index (LI); they were discarded at weaning. b. 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). c.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 withread across substance CAS No. 90268-36-3 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 read across substance  Butanedioic acid, sulfo-, 1-C12-18-alkyl esters, disodium salts (CAS 90268-36-3) showed NOAEL of 60 mg/kg bw for paternal/maternal systemic 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.

Combined reproduction-teratogenicity study with read across test item Disodium C-isodecyl sulphonatosuccinate (CAS No. 37294-49-8) in 2 generations resulted in 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 Docusate sodium (CAS 577-11-7) 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, combined study and teratogenicity study, 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 these results and according to the EC Directive (No.93/21/EEC) and CLP (No. 1272/2008 of 16 December 2008), the test substance does not have to be classified and has no obligatory labelling requirement for reproductive and developmental toxicity.