OligoActiv EDDHA-Mn

Endpoint summary

Description of key information

Acute oral toxicity

Acute oral toxicity was experimentally determined for Fe(Na)EDDHA in rats according to OECD TG 401 . The LD50 values derived from the acute oral toxicity studies with the source substance Fe(Na)EDDHA were > 2000 mg/kg bw (Ciba-Geigy, 1993, Hempstock, 1996).

To address the acute oral toxicity of the manganese ion in the target substance the key value for chemical safety assessment was set to an oral LD50 value of 4946 mg/kg bw.

This value was calculated from a LD50 derived in a study with MnCl₂ on female rats after oral application (by stomach tube) (Kostial et al., 1978). For the whole evaluation of the availbale data on manganese compounds please refer to 'Additional information'.

Acute dermal toxicity

Acute dermal toxicity was experimentally determined for Fe(Na)EDDHA in rats according to OECD TG 402. The LD50 values derived from the acute dermal toxicity studies with the source substance Fe(Na)EDDHA were > 2000 mg/kg bw (Ciba-Geigy, 1993, Hempstock, 1996).

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:

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

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities occured in this study.

Clinical signs:

other: other: Piloerection, hunched posture, and dyspnea were seen, being common symptoms in acute tests. Additionally, diarrhea was observed in all animals. The animals recovered within 5 to 6 days.

Gross pathology:

At necropsy no deviations from normal morphology were found in all animals.

Other findings:

No other findings were noted

No other information

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

The acute oral median LD50 of the source substance Fe(Na)EDDHA in albino rats was found to be greater than 2000 mg/kg bodyweight. The same result is expected for the organic constituents of target substance since it has the same composition as the source substance.

Executive summary:

The acute oral toxicity of the source substance FeNaEDDHA in albino rats was determined acoording to the OECD Guideline 401 (Acute Oral Toxicity) and the EU Method B.1 (Acute Toxicity Oral). Upon an acute oral administration and a 14 day post-treatment observation period, the LD50 of the test material in albino rats was found to be greater than 2000 mg/kg bw. No mortalities occurred in this study. At necropsy no deviations from normal morphology were found in all animals. Piloerection, hunched posture, and dyspnea were seen, being common symptoms in acute tests. Additionally, diarrhea was observed in all animals. The animals recovered within 5 to 6 days.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

no deaths

Clinical signs:

other: other: no signs of systemic toxicity

Gross pathology:

no abnormalities were noted at necropsy

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

The acute oral median LD50 of the test material in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg bodyweight. The same result is expected for the organic constituents of target substance since it has the same composition as the source substance.

Executive summary:

The acute oral toxicity of the source substance FeNaEDDHA in Sprague Dawley rats was determined according to the OECD Guideline 401 (Acute Oral Toxicity). Upon an acute oral administration, the LD50 of the test material in rats was found to be greater than 2000 mg/kg bw. No mortalities and signs of systemic toxicity occurred in this study. The animals gained in body weight. At necropsy no abnormalities were noted in all animals.

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male

Dose descriptor:

LD50

Effect level:

5 493 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

Calculation of the LD50 for the manganese moiety in the target substance:

EC(Mn) in source substance

Source substance MnCl2* 4 H2O

MW (MnCl2* 4 H2O) = 197.91 g/mol

MW (Mn) = 109.8 g/mol

Mn in MnCl2* 4H2O = 54.9 / 197.91 = 0.28

EC (Mn) = EC(MnCl2) x 0.44 = 1484.33 mg/kg bw x 0.28 = 412 mg/kg bw

 

EC of target substance MnEDDHA

concentration of Mn in target substance: 7.5 %

ED of target substance = 412 mg/kg bw / 0.075 = 5493 mg/kg bw.

Conclusions:

The LD50 for manganese chloride tetrahydrate converted to the manganese moiety of the target substance is 5493 mg/kg bw.

Executive summary:

The data on manganese chloride tetrahydrate allows estimating a corresponding LD50 for the manganese moiety of the target substance. 

 

The LD50 for manganese chloride tetrahydrate is reported to be 7.5 mmol/kg bw which corresponds to 1484.33 mg/kg bw. The corrected LD50 value for the manganese moiety is 5493 mg/kg bw.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 678 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 2 weeks old sucklings

Remarks:

converted to target substance

Sex:

female

Dose descriptor:

LD50

Effect level:

10 823 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 3 weeks old rats

Remarks:

converted to target substance

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

9 962 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 6 weeks old rats

Remarks:

converted to target substance

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

4 946 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 18 weeks old rats

Remarks:

converted to target substance

Sex:

female

Dose descriptor:

LD50

Effect level:

3 602 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 54 weeks old rats

Remarks:

converted to target substance

The highest oral toxicity was found in the youngest group of rats (two week-old sucklings) as indicated by the lowest LD50 values for manganese dichloride. In three and six week-old animals a sharp decrease in toxicity was noted and in comparison to sucklings LD50 values increased by a factor of 2. In adult rats the toxicity increased again and reached in the oldest animals values which were similar to sucklings. The increase in the toxicity of metals in sucklings was not as high as expected on the basis of the very high intestinal absorption at this age. The lower sensitivity to toxic metals might result from a different binding of metals to ligands and a lower level of "free metal" in sucklings. Older rats might be more susceptible to metal toxicity because of a general decrease in adaptive responsiveness which is characteristic of the process of aging.

Conclusions:

The LD50 value of MnCl2 on female rats after oral application (by stomach tube) converted to the manganese moiety in the target substance is 9962 and 4946 mg/kg bw for 6 and 18 week-old rats, respectively.

Executive summary:

The data on manganese chloride allows estimating a corresponding LD50 for the manganese moiety of the target substance.

The LD50 value of MnCl2 on female rats after oral application (by stomach tube) converted to the manganese moiety in the target substance is 9962 and 4946 mg/kg bw for 6 and 18 week-old rats, respectively.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male

Dose descriptor:

LD50

Remarks:

mice

Effect level:

7 739 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

Sex:

male/female

Dose descriptor:

LD50

Remarks:

rats

Effect level:

8 554 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

Calculation of the LC50 value for target substance:

 

MW of source substance MnCl2 = 125.8

MW of Mn = 54.9

concentration of Mn in target substance: 7.5 %

 

LC50 for manganese dichloride = 1330 mg/kg bw

LC50 for manganese = 1330 mg/kg bw * (54.9/125.8) = 1330 mg/kg bw * 0.44 = 580 mg/kg bw

 

LC50 of target substance = 580 mg/kg bw / 0.075 = 7739 mg/kg bw.

 

The other values were calculated accordingly.

Conclusions:

The LD50 value of MnCl2 for male mice and male/female rats after oral application converted to the manganese moiety in the target substance is 7739 and 8554 mg/kg bw, respectively.

Executive summary:

The data on manganese chloride allows estimating a corresponding LD50 for the manganese moiety of the target substance.

The LD50 value of MnCl2 for male mice and male/female rats after oral application converted to the manganese moiety in the target substance is 7739 and 8554 mg/kg bw, respectively.

Reference 6

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male

Dose descriptor:

LD50

Remarks:

mice

Effect level:

11 295 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

Sex:

male/female

Dose descriptor:

LD50

Remarks:

rats

Effect level:

10 423 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

Calculation of the LC50 value for target substance:

 

MW of source substance MnSO4 = 151

MW of Mn = 54.9

concentration of Mn in target substance: 7.5 %

 

LC50 for manganese sulfate = 2330 mg/kg bw

LC50 for manganese = 2330 mg/kg bw * (54.9/151) = 2330 mg/kg bw * 0.36 = 847 mg/kg bw

 

LC50 of target substance = 847 mg/kg bw / 0.075 = 11295 mg/kg bw.

 

The other values were calculated accordingly.

Conclusions:

The LD50 value of MnSO4 for male mice and male/female rats after oral application converted to the manganese moiety in the target substance is 11295 and 10423 mg/kg bw, respectively.

Executive summary:

The data on manganese sulfate allows estimating a corresponding LD50 for the manganese moiety of the target substance. 

The LD50 value of MnSO4 for male mice and male/female rats after oral application converted to the manganese moiety in the target substance is 11295 and 10423 mg/kg bw, respectively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

Good overall quality, studies well documented and meet generally accepted scientific principles.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortalities occured in this study.

Clinical signs:

other: other: Piloerection and hunched posture were seen, being common symptoms in acute dermal tests.

Gross pathology:

At necropsy no deviations from normal morphology were found.

Other findings:

No other findings were noted.

No other information

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

The LD50 is greater than 2000 mg/kg body weight.The same level of toxicity is expected for the target substance since it acts via the same mechanism as the source substance. The same result is expected for the organic constituents of target substance since it has the same composition as the source substance.

Executive summary:

The toxic effects of the source substance Fe(Na)EDDHA in the albino rats were investigated according to the OECD Guideline 402 on Acute Dermal Toxicity. Ten healthy albino rats were dosed dermally in a limit test with a single concentration of test material at a dose level of 2000 mg/kg body weight.

Approx. 24 hours before treatment an area on the back of the rat of at least 10% of the body surface was shaved with an electric clipper.The test substance was evenly dispersed on the skin. It was covered with a gauze-lined semiocclusive dressing fastened around the trunk with an adhesive elastic bandage. After 24 hours the dressing was removed and the skin was cleaned with lukewarm water.

The animals were observed daily for signs of mortality, toxicity and pharmacological effects. Bodyweights were recorded immediately before application and on days 7 and 14. All animals were examined for gross pathology.

All animals survived the 2000 mg/kg bw dermal application. Piloerection and hunched posture were seen in the study, being common symptoms in acute dermal tests. Body weight changes were normal. The animals recovered within 1 day. At necropsy, no deviations from normal morphology were found. The LD50 is greater than 2000 mg/kg body weight.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths

Clinical signs:

other: other: No signs of systemic toxicity

Gross pathology:

No abnormalities

Other findings:

Signs of skin irritation: slight to well defined erythema, very slight to slight oedema

Interpretation of results:

GHS criteria not met

Remarks:

according to EU GHS

Conclusions:

The acute dermal LD50 was found to be greater than 2000 mg/kg bodyweight. The same result is expected for the organic constituents of target substance since it has the same composition as the source substance.

Executive summary:

The toxic effects of the source substance Fe(Na)EDDHA in Sprague Dawley rats were investigated according to the OECD Guideline 402 on Acute Dermal Toxicity. The animals were dosed dermally in a limit test with a single concentration of test material at a dose level of 2000 mg/kg body weight. The test material was applied to skin of test animals and left for 24 hours in semiocclusive contact.

All animals survived the 2000 mg/kg bw dermal application. No signs of systemic toxicity were noted in treated animals. Signs of skin irritation: slight to well defined erythema and very slight to slight oedema were observed. All animals showed expected bodyweight gain during the study. At necropsy, no deviations from normal morphology were found. The LD50 is greater than 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Quality of whole database:

Good overall quality, studies well documented and meet generally accepted scientific principles.

Additional information

Acute oral toxicity

Manganese compounds

The effect concentrations of manganese compounds were converted to the manganese moiety of the target substance under consideration of the molecular weight purity.

The toxicity of manganese chloride was determined in animals of five different age groups (2, 3, 6, 20, and 54 weeks) (Kostial et al., 1978). Manganese chloride was administered by stomach tube in a volume of 1 mL/200 g of body weight. Six dose levels were used in each age group. Each dose level was tested on six animals. This study was evaluated with Klimisch 2 (reliable with restrictions). The LD50 value of MnCl₂ on female rats after oral application (by stomach tube) converted to the manganese moiety of the target substance is 9962 and 4946 mg/kg bw for 6 and 18 week-old rats, respectively. According to OECD guidelines on acute toxicity testing (OECD TG 420, 423 and 425), rats aged 8 to 12 weeks are recommended. Therefore, data of 6 and 18 week-old rats are taken into account. As a worst-case value 4946 mg/kg bw is selected here for hazard assessment.

 

In an acute oral toxicity study (Holbrook et al., 1975), groups of 4-5 weeks old male Sprague-Dawley rats were given a single oral dose of Manganese chloride and were observed for 14 days. This study was evaluated with Klimisch 2 (reliable with restrictions). The LD50 for manganese chloride tetrahydrate is reported to be 7.5 mmol/kg bw which corresponds to 1484.33 mg/kg bw. The corrected LD50 value for the manganese moiety of the target substance is 5493 mg/kg bw.

 

In an acute oral toxicity study (Singh et al. 1991), groups of male and female Wistar albino rats and male Swiss albino mice (five animals / dose) were given a single oral dose by gavage of Manganese chloride and Manganese sulphate and were observed for 14 days. This study was evaluated with Klimisch 2 (reliable with restrictions). The LD50 for manganese sulfate is reported to be 2330 and 2150 mg/kg bw for male mice and male/female rats, respectively. Those values correspond to a LD50 of 11295 mg/kg bw for male mice and to a LD50 of 10423 mg/kg bw for male/female rats for the manganese moiety of the target substance. The LD50 for manganese chloride is reported to be 1330 and 1470 mg/kg bw for male mice and male/female rats, respectively. Those values correspond to a LD50 of 7126 mg/kg bw for male mice and to a LD50 of 7739 mg/kg bw for male/female rats for the manganese moiety of the target substance.

Justification for classification or non-classification

Based on the available data the substance does not meet the criteria for classification and labelling for acute toxicity in accordance with Regulation (EC) No 1272/2008.