Docusate sodium

Endpoint summary

Description of key information

Both oral and dermal acute toxicity were tested in various studies with docusate sodium and formulations, demonstrating that LD50 values were above the limit dose of 2000 mg active ingredient/kg bw. LD50 values are  approximately 3000 mg/kg bw for acute oral toxicity in rats and 2525 mg/kg bw for acute dermal toxicity in rabbits.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988.02.24-1988.03.09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to internationally accepted test guidelines, and was considered to be reliable, adequate and relevant. The limit dose was reached for the active ingredient.

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

dose is higher

Principles of method if other than guideline:

The limit dose is 3000 mg/kg bw instead of 2000 mg/kg bw. Taking into account the purity (70% sodium diisooctylsulfosuccinate), 2100 mg active ingredient/kg was given, which corresponds to the limit dose.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: WISW (SPF TNO)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: F. Winkelmann, 4799 Borchen
- Weight at study initiation: average 147 g (see Table 1)
- Fasting period before study: 16 hours
- Housing: 1-5 animals in Makrolon-cages Type III
- Diet: R10 Alleindiät für Ratten, Ssniff Spezialfutter GmbH, 4770 Soest, ad libitum
- Water: public supply, ad libitum
- Acclimation period: 4 – 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20°C+-1°C
- Humidity (%):60% +- 5%
- Air changes (per hr): 15 air replacements/ hour
- Photoperiod (hrs dark / hrs light):12/12

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: calculated at 2,83 mL /kg
DOSAGE PREPARATION (if unusual): undiluted

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:

Doses:

3000 mg/kg bw

No. of animals per sex per dose:

5 male and 5 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: before administration (fasted), after 24 hours, 1 week and 2 weeks
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: MARLINAT DF 8

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 100 mg/kg bw

Based on:

act. ingr.

Mortality:

No mortality

Clinical signs:

other: All animals showed red brown lips and a slightly harsh skin 20-30 minutes after administration; one animal showed diarrhea 3-7 hours after administration. After 24 hours the skin was very harsh and the animals showed a squatting attitude; 4 animals showed

Gross pathology:

Dissection at the end of testing showed only in 1 animal with a partial bulge of the stomach mucosa.

 Table 1. Mean body weight evolution in g

Dosis mg/kg	Before administration (on an empty stomach) fasted	24 hours after administration	1 week after administration	2 weeks after administration	Increase of weight
3000	147,0	149,8	183,2	205,8	58,8

 

 

 

 

 

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The LD50 of MARLINAT DF 8 was > 3000 mg/kg body weight, corresponding with >2100 mg active ingredient/kg body weight.

Executive summary:

Acute toxicity testing in 5 male and 5 female rats showed that the LD50 of MARLINAT DF 8 was > 3000 mg/kg body weight, corresponding with >2100 mg active ingredient/kg body weight. The body weight evolution was not influenced during the 14-day observation period. All animals showed red brown lips and a slightly harsh skin 20-30 minutes after administration; one animal showed diarrhea 3-7 hours after administration. After 24 hours the skin was very harsh and the animals showed a squatting attitude; 4 animals showed diarrhea and 3 had a dirtily brown skin. After 48 hours, the skin was still slightly harsh and after 72 hours all animals were without poisoning symptoms. Dissection at the end of testing showed only in 1 animal with a partial bulge of the stomach mucosa. All treated animals were free from poisoning symptoms after 72 hours.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

20 000 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted equivlent to international guidelines, but predates GLP conditions. The study was conducted in a renomated laboratory and to the standards possible at the time of testing.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

male animals only

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Type of coverage:

other: covered

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Dermal application to clipped unabraded skin

Duration of exposure:

24 hours

Doses:

10 mL/kg bw; equivalent to 10000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Sex:

male

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Mortality:

no

Clinical signs:

other: Signs of intoxication: none noted. Skin iritation: fissuring, desquamation, coriaceousness was noted. Rabbits noted pulling fur out.

Gross pathology:

No gross pathology was observed

Other findings:

None

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

LD50 >10000 mg/kg, dosed as received.

Executive summary:

Docusate sodium dosed dermally in male rabbits at 10000 mg/kg bw did not lead to mortality. Clinical observations included some skin iritation (fissuring, desquamation, coriaceousness, pulling fur out), however no signs of intoxication or gross pathological findings were noted .

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 525 mg/kg bw

Additional information

A key study for acute oral toxicity was performed in rats with a 70% docusate sodium formulation (Elementis, Mürmann 1988a); the study was conducted according to OECD 401, and was considered to be reliable, adequate and relevant. The limit dose was reached for the active ingredient. LD50 was > 3000 mg/kg body weight, corresponding with >2100 mg active ingredient/kg bw. The body weight evolution was not influenced during the 14-day observation period. All animals showed red brown lips and a slightly harsh skin 20-30 minutes after administration; one animal showed diarrhoea 3-7 hours after administration. After 24 hours the skin was very harsh and the animals showed a squatting attitude; 4 animals showed diarrhoea and 3 had a dirtily brown skin. After 48 hours, the skin was still slightly harsh and after 72 hours all animals were without poisoning symptoms. Dissection at the end of testing showed only 1 animal with a partial bulge of the stomach mucosa. All treated animals were free from poisoning symptoms after 72 hours.

Supporting acute oral toxicity studies with lower reliability levels (2-4) were collected with different formulations. In the various rat acute toxicity studies, LD50 values were either above tested doses, or fell between 3.0 and 4.5 g/kg bw, therefore exceeding the limit dose.

·        The LD50 of a 66% docusate formulation in the rat was >2000 mg/kg bodyweight, corresponding to > 1320 mg active ingredient/kg bw. There were no clinical observations, effects on body weight and macroscopic findings (Elementis, Discroll 1966). 

·        The LD50 of a 70% docusate formulation was > 2000 mg/kg bw, corresponding with >1400 mg active ingredient/kg bw (Cognis, Potokar 1984). There was no mortality, but symptoms of a temporarily harsh skin and diarrhoea appeared. The internal organs of the animals were inconspicuous.

·        In a study with a 100% formulation, doses given were 5, 2.5, 1.25 and 0.625 g/kg bw (Cytec, American Cyanamid 1966). A mortality of 5/5 at 5 g/kg and 1/5 at 2.5 mg/kg bw resulted in an oral LD50 of 3.08 g/kg bw. Clinical signs of depression with varying intensity and diarrhoea were observed at all doses, but reversible by day 4 after dosing.

·        In a study with a product formulation of 20% docusate solutions were given at 25.2, 22.4, 17.8 and 14.1 mL/kg bw, corresponding doses were approximately 5.0, 4.5, 3.5 and 2.8 g/kg bw (Cytec, McGinty 1976a). A mortality of 5/5 at 5.0 g/kg bw, 3/5 at 4.5 mg/kg bw and 1/5 at 3.5 g/kg bw (and 0/5 at 2.8 g/kg bw) resulted in an oral LD50 of 4.2 g/kg bw. Animals became prostrate and lethargic; at necropsy,yellow fluid was observed through the gastrointestinal tract of those found dead.

·        Finally, there were 2 other disregarded studies, one in rats (Dow, Rohm-Haas 1974) and one in mice (Literature, Case et al. 1977); they had a lower reliability and did not reveal new information.

In a key study for acute dermal toxicity, rabbits were dosed at 10000 mg/kg bw on a 10% body surface area (Cytec, McGinty 1977). Clinical observations included signs of skin irritation (fissuring, desquamation, coriaceousness, pulling fur out), however no signs of intoxication or gross pathological findings were noted ; there was no mortality (LD50 >10000 mg/kg bw). In another study, dermal dosing with a test formulation in male rabbits at 1263, 2525 and 5050 mg/kg bw resulted in mortality at 2525 (1/2) and 5050 (2/2) mg/kg bw; the LD50 was therefore 2525 mg/kg bw. Clinical observations included severe edema, moderate erythema with subsequent eschar formation. No gross pathological examination was performed. The study was of lower reliability and disregarded, but confirmed that LD50 was higher than the limit dose (Dow, Rohm-Haas 1974).

Intoxication due to acute inhalation exposure of industrial workers or even the acute inhalation exposure as such is very unlikely for sulphosuccinates due to their substance properties and the risk management measures that are already implemented. Additional acute inhalation toxicity tests would therefore neither lead to a better risk assessment, nor improve the safety of applications. Data were found in literature with an LC50 of 20 mg/L in rats, which is above the limit dose (ECB, 2000; BUA, 2004). In another study, rats were subjected to inhalation of increasing doses of 100 mg to 500 mg aerosol. Administration of 500 mg resulted in peribronchial and focal alveolar oedema in 3 out of 5 animals. As there were only very few details, the studies were not taken into account. On the basis of the argumentation summarized above, further acute inhalation toxicity testing is waived.

In summary, both oral and dermal acute toxicity were tested in various studies with docusate sodium and formulations, demonstrating that LD50 values were above the limit dose of 2000 mg active ingredient/kg bw. Therefore, there is no need for classification and labeling.

Justification for classification or non-classification

As the LD50 values were above 2000 mg/kg bw, classification for acute toxicity is not warranted.