Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

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:
High quality (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
A key study with registered substance was performed by means of an oral combined repeated dose and reproduction/development screening study according to OECD guideline 422 (Hansen, 2013d). 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, as well as gross and histopathology are discussed in the repeated dose toxicity section 7.5.
No test item-related influence was noted on the reproductive 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). NOAEL for paternal/maternal 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 subgroup of Di-ester sulphosuccinates is documented in a separate read-across justification 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.

 

Conclusion

An oral gavage reproductive screening study with registered substance showed a NOAEL of 300 mg/kg bw for paternal/maternal systemic toxicity, whereas 1000 mg/kg bw was NOAEL for reproductive and developmental toxicity as well as for neurotoxicity. Multigeneration studies with read across substance Docusate sodium (CAS No. 577-11-7) showed slight maternal/paternal toxicity at 0.5 and 1% in the diet, however this was not confirmed in a 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 NOAEL for paternal/maternal toxicity. Based on the absence of reproductive findings in the screening study and the repeated dose toxicity studies and availability of multigeneration studies, no further testing is needed.

 


Short description of key information:
A key study for reproductive toxicity was performed in rats by means of an OECD 422 study with a liquid formulation containing 41.5% active ingredient given by oral gavage 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.

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, in which rats were dosed at 100, 300 and 1000 mg act. ingr./kg bw/day with the registered test substance.  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 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 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
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
High (Klimisch 1)
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

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, 2013d) with the registered test item. 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 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 paternal/maternal toxicity was 300 mg/kg bw/day, whereas NOAEL for 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 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.  

 

Conclusion

An oral gavage reproductive screening study with registered substance 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 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 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.  


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

Justification for classification or non-classification

Based on the 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.