Docusate sodium

Carcinogenicity

Description of key information

Docusate sodium was tested up to 1% dietary concentrations in standard rats  for 2 years and in a special rat model for colorectal carcinogenesis for 20 weeks . Both models did not result in increased tumour findings Docusate sodium was tested up to 1% dietary concentrations in standard rats  for 2 years and in a special rat model for colorectal carcinogenesis for 20 weeks . Both models did not result in increased tumor findings up to at a slight toxic dose level  of 1% showing decreased body weight. NOAEL for toxicity was 0.5% dietary concentration (250 mg/kg bw/day) and NOAEL for tumorigenicity was 1% in the diet (500 mg/kg bw/day).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

other: publication

Adequacy of study:

supporting study

Study period:

1948

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Limited information on materials & methods available.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

not specified

Species:

rat

Strain:

Osborne-Mendel

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation:21 days
- Housing: individual cages
- Diet (e.g. ad libitum): Ground commercial rat biscuits with 1 % added codliver oil ad libitum
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
controlled temperature and humidity

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: rotary batch mixer

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Ground commercial rat biscuits with 1% added codliver oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Two-year experiment: 2 year

Frequency of treatment:

daily

Dose / conc.:

0.25 other: % nominal in diet

Dose / conc.:

0.5 other: % nominal in diet

Dose / conc.:

1 other: % nominal in diet

No. of animals per sex per dose:

2-year experiment: 12 males per dose +12 males as control

Control animals:

yes, concurrent no treatment

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION :
- Food consumption for each animal determined : Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all but a few
HISTOPATHOLOGY: Yes, not all

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

During the fast growing period of the first 12 weeks of the experiment the growth rates of the group of rats on diets containg 1% sodium dioctyl sulfosuccinate were slightly less than that of the control group.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No dislike for the food containing sodium dioctyl sulfosuccinate was evidenced by a decreased food intake in any group of animals.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No gross pathological changes attributable to treatment

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No microscopic pathological changes attributable to treatment

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Dose descriptor:

NOAEL

Remarks:

toxicity

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Table 1. Mean gain in weight of male rats given sodium dioctyl sulfosuccinate in their diet for a year

Dosage, %	No. of animals	Mean Gain in Weight, g	Standard Error of Mean, g
0.25	10	436.0	± 15.5
0.5	10	441.3	± 14.5
1	10	395.8	± 11.6 p<0.001
Control: 0	11	471.9	± 13.2

 

Conclusions:

Effects on growth and mortality: no effects on mortality, there was a highly significant (p<0.001) difference in body weight gain between the control group and the 1% dose group .
Pathology: there were no changes whatever attributable to treatment.

Executive summary:

Docusate sodium was administered for 2 years to rats at concentrations of 0.25, 0.5 and 1% in the diet. At 1%, there were no effects on mortality, bu there was a significant (p<0.001) decrease in body weight gain between the control group. No effects were observed at the 0.25 and 0.5% dose level, corresponding with 125 and 250 mg/kg bw/day. There were no dose related changes in tumour incidences up to 1%, corresponding with at least 500 mg/kg bw/day .

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

other: publication

Adequacy of study:

supporting study

Study period:

1948

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Limited information on materials & methods available.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Details on test animals or test system and environmental conditions:

Inbred male F344 rats were divided into two groups of 84 each and fed the following diets: ground chow and 5% corn oil (control group) and ground chow, 5% corn oil, and 1% DSS (experimental group). All rats received high-dose DMH base (1,2-dimethylhydrazine ), 20 mg/kg/week sc for 20 weeks. Twenty rats per group were killed after 3, 4, 5, and 6 months. Duodenum, small intestine, colon, and rectum were dissected out. Each tumor was measured for size and location and evaluated histologically.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Duration of treatment / exposure:

20 weeks

Frequency of treatment:

daily

Dose / conc.:

1 other: % nominal in diet

No. of animals per sex per dose:

20 rats/period

Control animals:

yes, concurrent vehicle

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

decrease in tumors

Details on results:

The percentage of rats bearing tumors in the control and experimental groups did not differ significantly. In each rat there were fewer gastrointestinal tumors in the DSS-fed group of all histologic types combined, at all organ sites, at 5 and 6 months. This difference between the control and DSS-fed rats reached the level of statistical significance for tumors of the duodenum, colon, and rectum and for total gastrointestinal tumors at the 5th month.

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Table 1. Mean gain in weight of male rats given sodium dioctyl sulfosuccinate in their diet for a year

Dosage, %	No. of animals	Mean Gain in Weight, g	Standard Error of Mean, g
0.25	10	436.0	± 15.5
0.5	10	441.3	± 14.5
1	10	395.8	± 11.6 p<0.001
Control: 0	11	471.9	± 13.2

 

Conclusions:

Effects on growth and mortality: no effects on mortality, there was a highly significant (p<0.001) difference in body weight gain between the control group and the 1% dose group .
Pathology: there were no changes whatever attributable to treatment.

Executive summary:

The 1,2-dimethylhydrazine (DMH) rodent model for colorectal carcinogenesis was used to explore the effect of dietary Docusate sodium on carcinogenesis. Inbred male F344 rats were divided into two groups of 84 each and fed the following diets: ground chow and 5% corn oil (control group) and ground chow, 5% corn oil, and 1% DSS (experimental group). All rats received high-dose DMH base, 20 mg/kg/week sc for 20 weeks. Twenty rats per group were killed after 3, 4, 5, and 6 months. Duodenum, small intestine, colon, and rectum were dissected out. Each tumor was measured for size and location and evaluated histologically. The percentage of rats bearing tumors in the control and experimental groups did not differ significantly. In each rat there were fewer gastrointestinal tumors in the DSS-fed group of all histologic types combined, at all organ sites, at 5 and 6 months. This difference between the control and DSS-fed rats reached the level of statistical significance for tumors of the duodenum, colon, and rectum and for total gastrointestinal tumors at the 5th month.

Endpoint conclusion

Dose descriptor:

NOAEL

500 mg/kg bw/day

Justification for classification or non-classification

As there were no tumours observed, classification is not warranted.

Additional information

A literature study was available, where Docusate sodium was tested for 2 years in rats at concentrations of 0.25, 0.5 and 1% in the diet (Literature: Fitzhugh and Nelson, 1948). At 1%, there were no effects on mortality, but there was a significant (p<0.001) difference in body weight gain between the control group and the 1% dose group. No effects were observed at the 0.5% dose level, corresponding with 250 mg/kg bw/day. There were no dose related changes in tumour incidences up to 1%, corresponding with at least 500 mg/kg bw/day.

 

Secondly, a review also mentioned a study of Docusate sodium (DSS) in the 1,2-dimethylhydrazine (DMH) rodent model for colorectal carcinogenesis to explore the effect of on carcinogenesis. Inbred male F344 rats were divided into two groups of 84 each and fed the following diets: ground chow and 5% corn oil (control group) and ground chow, 5% corn oil, and 1% DSS (experimental group). All rats received high-dose DMH base, 20 mg/kg/week sc for 20 weeks. Twenty rats per group were killed after 3, 4, 5, and 6 months. Duodenum, small intestine, colon, and rectum were dissected out. Each tumor was measured for size and location and evaluated histologically. The percentage of rats bearing tumors in the control and experimental groups did not differ significantly. In each rat there were fewer gastrointestinal tumors in the DSS-fed group of all histologic types combined, at all organ sites, at 5 and 6 months. This difference between the control and DSS-fed rats reached the level of statistical significance for tumors of the duodenum, colon, and rectum and for total gastrointestinal tumors at the 5th month.

 

In summary, Docusate sodium was tested up to 1% dietary concentrations in standard rats for 2 years and in a special rat model for colorectal carcinogenesis for 20 weeks. Both models did not result in increased tumor findings up to at a slight toxic dose level of 1% showing decreased body weight. NOAEL for toxicity was 0.5% dietary concentration (250 mg/kg bw/day) and NOAEL for tumorigenicity was 1% in the diet (500 mg/kg bw/day). The absence of tumorigenicity confirmed the negative genetic toxicity potential of Docusate sodium described in section 7.6.