Calcium 1,4-bis(2-ethylhexyl) bis(2-sulphosuccinate)

Endpoint summary

Description of key information

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

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

Reference 1

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.

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Reason / purpose for cross-reference:

reference to same study

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:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

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

Executive summary:

No data concerning acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Acute toxicity testing in 5 male and 5 female rats showed that the LD50 of MARLINAT DF 8 was > 3000mg/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.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1996-03-18 to 1996-04-09

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to GLP and internationally accepted test guidelines, and was considered to be reliable and relevant. When calculated to the active ingredient, the limit dose was however not reached.

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

Method B1 of Commission Directive 92/69/EEC

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, UK
- Age at study initiation: 5-8 weeks
- Weight at study initiation: See Table 1
males: 141-156 g
females: 122-149 g
- Fasting period before study: overnight
- Housing: 1-5 animals by sex in solid-floor polypropylene cages furnished with wood flakes
- Diet : Rat and Mouse Expanded Diet No. 1, Special Diets Services Limited, Witham,
Essex, UK
ad libitum except the overnight fast immediately before dosing and for approximately 2 hours after
dosing
- Water : public supply, ad libitum except the overnight fast immediately before
dosing and for approximately 2 hours after dosing


ENVIRONMENTAL CONDITIONS
- Temperature: 19 – 21°C
- Humidity: 39 – 65 %
- Air changes (per hr): 15 air changes/ hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1996-03-18To: 1996-04-09

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1,89 ml/kg

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Individual bodyweights were recorded prior to dosing on
Day 0 and on Days 7 and 14.
Individual clinical observations and mortality data were recorded 1/2, 1,2,4 hours after dosing and
also 1,2,3,4,5,6,7,8,9,10,11,12,13,and 14 days after dosing.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 320 mg/kg bw

Based on:

act. ingr.

Mortality:

There were no deaths.

Clinical signs:

other: No signs of systemic toxicity were noted during the study.

Gross pathology:

No abnormalities were noted at necroscopy.

Table 1. Individual body weights and weekly body weight changes in the main study

Sex	Animal Number and Sex	Bodyweight (g) at Day			Bodyweight Gain (g) During Week
		0	7	14	1	2
Male         Female	3-0 3-1 3-2 3-3 3-4 4-0 4-1 4-2 4-3 4-4	151 149 156 143 141 149 122 133 135 139	224 211 212 200 185 191 154 190 171 155	300 282 284 270 262 224 189 230 208 188	73 62 56 57 44 42 32 57 36 16	76 71 72 70 77 33 35 40 37 33

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral median lethal dose (LD50) of the test material, SERWET WH 170, in the Sprague-Dawley CD strain rat was>2000 mg/kg bodyweight.

Executive summary:

No data concerning acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

The acute oral median lethal dose (LD50) of the test material, SERWET WH 170, in the Sprague-Dawley CD strain 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.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1984-02-13 to 1984-02-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted in a limited No. of animals; when calculated to the active ingredient, the limit dose was however not reached.

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

limited number of animals

Principles of method if other than guideline:

Only 2 male and 2 female animals were used instead of 5/5.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: TNO Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Not provided (TNO?)
- Weight at study initiation: male animals 169 g, female animals 146g

Route of administration:

oral: unspecified

Vehicle:

other: carboxymethylcellulose + cremophor

Details on oral exposure:

VEHICLE
- 2 % aqueous carboxymethylcellulose solution + 0,5 % cremophor
- Concentration in vehicle: 10 % referred to 70 % active substance

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg

Doses:

2000mg/kg bw

No. of animals per sex per dose:

2 male and 2 female rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, macroscopic pathology

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 400 mg/kg bw

Based on:

act. ingr.

Mortality:

no

Clinical signs:

other: a temporary piloerection and diarrhoea

Gross pathology:

one female animal: hydrometra

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 > 2000 mg/kg bw

Executive summary:

No data concerning acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

In an acute oral toxicity test (Limit-test) in rats, the LD50 of Disponyl SUS IC 8 was > 2000 mg/kg bw for 2 male and 2 female animals, corresponding with >1400 mg active ingredient/kg bw. There was no mortality, but symptoms of a temporarily harsh skin and diarrhoea. The internal organs of the animals were inconspicuous.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1966

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

only male rats

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: CF Nelson albino

Sex:

male

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

Animals were fasted for 24h

Doses:

A 5% aqueous dispersion was dosed in 4 doses: 5.0 g/kg, 2.5 g/kg, 1.25 g/kg and 0.625 g/kg.
At 5 g/kg the dose was administered in 2 separate portions 1/4 hour apart.

No. of animals per sex per dose:

5 male rats in 4 doses

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross autopsy, time of recovery

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 3 080 mg/kg bw

Based on:

test mat.

Mortality:

5/5 at 5.0 g/kg bw
1/5 at 2.5 g/kg bw
0/5 at 1.25 g/kg bw
0/5 at 0.625 g/kg bw

Clinical signs:

other: Depression of varying intensity and diarrhea in all groups, with recovery after 4 days.

Gross pathology:

Survivors: normal.

Table 1. Observations in animals

 

Dosage	Onset of (S) Signs, (D) Death, Hours and Days									Died/ Dosed	Mean Wt.(g)		Time of Recovery, Days
	0-6	6-24	2	3	4	5	6	7	8-14		I	T	1	2	3	4	5	6	7-14
5.0 g/kg		SD5								5/5	119	-
2.5 g/kg		SD1								1/5	127	188				R
1.25 g/kg		S								0/5	136	225				R
0.625 g/kg		S								0/5	143	236				R

Signs of intoxication: Depression of varying intensity, diarrhea.

Gross autopsy: Survivors- normal.

 

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

LD50 = 3.08 g/kg bw

Executive summary:

No data concerning acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

A mortality of 5/5 at 5 g/kg and 1/5 at 2.5 mg/kg bw was taken into account for calculation of the oral LD50, leading to an oral LD50 of 3.08 g/kg bw. Clinical signs of depression with varying intensity and diarrhea were observerd at all doses, but reversible by day 4 after dosing. On the basis of this result, this product is considered to be slightly toxic by ingestion in single doses.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1977

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

males only

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Route of administration:

oral: unspecified

Doses:

25.2mL/kg, 22.4 mL/kg, 17.8 mL/kg and 14.1 mL/kg ; mixed with water to give a 20% solution

No. of animals per sex per dose:

6 males

Control animals:

no

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 4 200 mg/kg bw

Clinical signs:

other: Animals became prostrate and lethargic.

Gross pathology:

Yellow fluid was observed through the gastrointestinal tract of those found dead.

Table1.Single oral dose in male Sprague-Dawley albino Rats

Conditions: fasted overnight ; mixed with water to give a 20% solution.                                                                

Dosage mL/kg	Onset of (S) Signs, (D) Death, Hours and Days									Died/ Dosed	Mean Wt.		Time of( R) Recovery , Days
	0-6	6-24	2	3	4	5	6	7	8-14		I	T	1	2	3	4	5	6	7-14
25.2		4D	1D							5/5	147	-
22.4		3D								3/5	147	218		2R
17.8		1D								1/5	152	229		4R
14.1										0/5	145	232

 

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

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 obsrved through the gastrointestinal tract of those found dead.

Executive summary:

No data concerning the acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

In the current study, 20% dosusate solutions were given of 25.2, 22.4, 17.8 and 14.1 mL/kg bw, corresonding with approximate doses of 5.0, 4.5, 3.5 and 2.8 g/kg bw. 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 obsrved through the gastrointestinal tract of those found dead.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

1974

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: The study was conducted equivalent to international guidelines, but only in few animals, no gross pathology was performed. In addition, test material composition was unknown.

Justification for type of information:

No data are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

less animals

GLP compliance:

no

Test type:

other: exploratory

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Doses:

5050mg/kg, 2525mg/kg, 1263mg/kg, 631mg/kg, 316mg/kg

No. of animals per sex per dose:

2 male rats per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (signs of intoxication), body weight (mean weight)

Sex:

male

Dose descriptor:

approximate LD50

Effect level:

ca. 3 750 mg/kg bw

Based on:

test mat.

Table 1. Single oral dose of DSS in male albino rats

Conditions: Animals fasted for 24 hours were dosed with the product as received

LD₅₀=3570 mg/kg with no range calculable.

Dosage	Onset of (S) Signs, (D) Death, Hours and Days									Died	Mean Wt.		Time of (R) Recovery, Days
	0-6	6-24	2	3	4	5	6	7	8-14	Dosed	I	T	1	2	3	4	5	6	7-14
5050mg/kg				D2						2/2	176	-
2525mg/kg										0/2	180	276
1263mg/kg										0/2	179	263
631mg/kg										0/2	181	264
316mg/kg										0/2	176	269

Signs of intoxication: None observed

Gross autopsy: Survivors = normal Decendents =not performed

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information

Conclusions:

LD50 = 3570 mg/kg

Executive summary:

No data concerning the acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Single doses given were 5050, 2525, 1263, 631 and 316mg/kg bw. This experiment is considered to be "range-finding" (exploratory) in nature and should be used only as indicator of toxicity. LD50 value should be considered as absolute figure since it was not obtained through standard toxicity procedures. The LD50 is 3570 mg/kg ,with no range calculable.

Reference 7

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

disregarded due to major methodological deficiencies

Study period:

1977

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Alltough some materials and methods were available, no details were provided on the test material.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

less animals

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

other: albino ARS/ICR

Sex:

male

Details on test animals or test system and environmental conditions:

Mice of 18-22 g

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Vechile: in 4% acacia

Doses:

2.5-5.0 ml/100 g
Doses of 2340, 2520, 2690, 2880, 3090, 3310, 3550, 3825 mg/kg bw.

No. of animals per sex per dose:

10 male mice per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs (signs of intoxication), body weight (mean weight)

Sex:

male

Dose descriptor:

approximate LD50

Effect level:

ca. 2 643 mg/kg bw

Based on:

test mat.

Mortality:

Dose (mg/kg): mortality
2340: 3/10
2520: 6/10
2690: 4/10
2880: 7/10
3090: 5/10
3310: 7/10
3550: 4/10
3825: 9/10

Clinical signs:

other: The high lethal doses caused mice to be hypoactive.

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

Migrated information

Conclusions:

LD50 = 2643 mg/kg

Executive summary:

No data concerning the acute oral toxicity properties are available for the registered substance, however data are available for the corresponding sodium salt of the substance, docusate sodium (CAS 577-11-7). These data are used for read-across to the registered substance calcium docusate (CAS 128 -49 -4). The presence of either of the counterions sodium or calcium is not considered to have an impact on the toxicity. It is therefore considered justified to use the data of the sodium salt for read across to the calcium salt of docusate.

Single doses given orally by gavage to mice were between 2340 and 3825 mg/kg bw. LD50 was calculated to be 2643 mg/kg bw. Hypoactivity was noted at these high doses.

Endpoint conclusion

Dose descriptor:

LD50

Value:

3 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LC50

Value:

20 000 mg/m³ air

Acute toxicity: via dermal route

Endpoint conclusion

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 > 3000mg/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, which is above the limit dose (ECB, 2000; BUA, 2004). As there were only very few details, the study was 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 of the read-across analogue docusate calcium.

Justification for classification or non-classification

As the LD50 values for docusate sodium were above 2000 mg/kg bw, classification of calcium docusate for acute toxicity is not warranted based on read-across.