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Key value for chemical safety assessment

Effects on fertility

Description of key information

Multigeneration studies were available for read across substance Docusate sodium (CAS 577-11-7) for assessment of reproductive and postnatal developmental function. In a first study, slight maternal/paternal toxicity were observed at 0.5 and 1% in the diet, however this was not confirmed in a second study. The test article was considered to have influenced the taste of the milk, for which adaptations were done in the second study. From both studies, it can be concluded that dosing Docusate sodium 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.
Based on the absence of reproductive findings in the repeated dose toxicity studies and the multigeneration studies, no further testing is needed.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
reliable (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

No test data were available for current substance, however read across data were available from Docusate sodium (CAS 577 -11 -7). Justification for read across within the category of Di-ester sulfosuccinates is documented in a separate document attached in Section 13.

Multigeneration studies

-A key study for reproductive toxicity was available for read across substance Docusate (CAS 577 -11 -7) sodium as a 3-generation toxicity study at dietary dose levels of 0.1, 0.5 and 1.0% in the diet (MacKenzie, 1986). The study was conducted according to OECD 416 and GLP guidelines, and was considered to be reliable, adequate and relevant. The test substance 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, the reduced body weight did not interfere with growth and development or reproductive performance, and the test substance 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. Based on the results of this study, when Docusate sodium was administered in the diet to three successive generations of rats, the no-observable-effect level (NOEL) for body weights of parental animals and offspring was 0.1%; the NOEL for reproductive parameters was 1.0% Docusate sodium, which was considered to correspond with approximately 750 mg/kg bw/day.

-In a supporting successive 2-generation generation study in rats, dietary doses of Docusate sodium (CAS 577 -11 -7) given were 0.5 and 1% (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 they were expected to cast their litters to avoid a bitter taste of the milk. When they were weaned, pups of these 3 litters were given diets containing the same levels of test material that their progenitors had been receiving. When pups were 3-4 months of age, they were in turn mated, and the process was repeated with their pups for a total of 3 generations. Pups of all litters, including those which died before weaning, were examined for gross defects. Autopsies were performed, however, only on pups from the first mating of the F2 animals. Those pups were killed at weaning. Immediately after death, the 2 males and 2 females which were the smallest or appeared least healthy of each litter were set aside, while the others were autopsied. 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.

Conclusion

Multigeneration studies with read across substance Docusate dodium (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. The test article was considered to have influenced the taste of the milk for which adaptations were done 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 repeated dose studies and the multigeneration studies no further testing is needed.



Effects on developmental toxicity

Description of key information
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 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 reproductive findings in the repeated dose toxicity studies and the multigeneration studies, 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:
reliable (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

No test data were available for current substance, however read across data were available from Docusate sodium (CAS 577 -11 -7). Justification for read across within the category of Di-ester sulphosuccinates is documented in a separate document attached in Section 13.

 

Teratogenicity testing

-A key study for prenatal developmental toxicity was performed in rats dosed from day 6-15 of gestation with read across substance Docusate sodium (CAS 577 -11 -7) 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. 

- As doscusate sodium has a long history of pharmaceutical and dietary supplement use, a 3-generation toxicity study in rat was requested by FDA and JECFA, which confirmed that docusate sodium would pose ro reproduction or teratological problems. The data were considered to adequately support safety in combination with information from prenatal developmental toxicity testing of docusate sodium and docusate calcdium, therefore a study in a second species was not considered necessary. In addition, the rabbit was not considered to be an adequate model due to its high gastro-intetinal sensitivity to surfactant properties, as demonstrated by diarrhoea followed by mortality in a repeated dose toxicity study. In conclusion, based on the evaluation of the outcome of the first species and other supporting informatoin, a second species for developmental toxicity was not considered necessary and waived according to REACH Annex IX section 8.7.2 column 2.

Conclusion 

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 was 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, no further testing is needed.


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.