Zinc EDDHA

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 zinc ion in the target substance the key value for chemical safety assessment was derived based on a study with zinc sulfate and zinc chloride in rats and mice (Domingo, 1988). Zinc sulfate revealed LD50 values of 1710 and 926 mg/kg bw in rats and mice, respectively. The LD50 values for zinc dichloride were 1100 mg/kg bw and 1260 mg/kg bw in rats and mice, respectively. The majority of deaths for both species were observed within the first 24 hours. No deaths occurred after 3 days. The physical and clinical signs appeared within the first 48 hours. These signs were decreasing or disappearing with time. The principal findings included miosis, conjunctivitis, erythema and necrosis in nose, exophthalmos, and necrosis in tail.

Converted to the target substance under consideration of the maximum zinc concentration of 7.5 % the lowest hazard value found for zinc sulfate in mice of 926 mg/kg bw corresponds to 4500 mg/kg bw.

For more information on the selection of this study 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

Preliminary study:

A preliminary screening with small groups of three animals of each sex was carried out. The LD50 values were then calculated according to the Litchfield and Wilcoxon method.

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 8 060.15 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

95% CL:

>= 4 957.63 - <= 14 712.98

Mortality:

Mostly, deaths occurred during the first 48 h of test compound administration. No deaths occurred after three days.

Clinical signs:

other: other: Conjunctivitis, piloerection, asthenia, decreased food and water consumption and hemorrhages and hematomas in the tail For details see Table 1 in "Remark on results including tables and figures" field.

Gross pathology:

No data

Other findings:

No data

Table 1. Severity of physical and clinical signs in mice after zinc intoxication in a single dose

	Number of days after zinc administration
	1	2-3	4-7	8-14
Mortality rates on oral administration	90%	10%	0%	0%
Conjunctivitis	None	+	+	None
Piloerection	None	+	+	+
Hemorrhages and hematomas in the tail	None	+	+++	+++
Asthenia	++	++	+	None
Decreased food and water consumption, weight loss	None	+	+	None

Mortality rates and physical and observational examination of rats are average for all zinc compounds.

+Light; ++Moderate; +++Severe

Conclusions:

Under the test conditions, the acute oral LD50 of ZnCl2 in mice was calculated to be 1,260 mg/kg (equivalent to 605 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 8060.15 mg/kg.

Executive summary:

A study was conducted to evaluate the acute oral toxicity of the test material in mice according to the OECD Guideline 401 (Acute Oral Toxicity).

Initially a preliminary screening study with small groups of three mice of each sex was carried out and the LD50 values were then calculated according to the Litchfield and Wilcoxon method. The main study was conducted with ten mice. Conjunctivitis, piloerection, asthenia, decreased food and water consumption and severe hemorrhages and hematomas in the tail vein were observed in mice.

Under the test conditions, the acute oral LD50 of ZnCl2 in mice was calculated to be 1,260 mg/kg (equivalent to 605 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 8060.15 mg/kg.

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

Preliminary study:

A preliminary screening with small groups of three animals of each sex was carried out. The LD50 values were then calculated according to the Litchfield and Wilcoxon method.

Sex:

male

Dose descriptor:

LD50

Effect level:

7 036.64 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

95% CL:

>= 4 228.38 - <= 11 706.42

Mortality:

Mortality observed mostly during the first 48 h of test material administration. No deaths occurred after three days.

Clinical signs:

other: other: Miosis, conjunctivitis and hemorrhages and hematomas in the tail. For details see Table 1 in "Remark on results including tables and figures" field

Gross pathology:

No data

Other findings:

No data

Table 1. Severity of physical and clinical signs in rats after zinc intoxication in a single dose

	Number of days after zinc administration
	1	2-3	4-7	8-14
Mortality rates on oral administration	90%	10%	0%	0%
Miosis	+	++	++	+
Conjunctivitis	+	++	+	None
Erythema, necrosis in nose	None	++	++	++
Exophthalmos	None	None	None	None
Decreased food and water consumption, weight loss	None	+	+	None
Hemorrhages and hematomas in the tail	None	++	++	+

Mortality rates and physical and observational examination of rats are average for all zinc compounds.

+Light; ++Moderate

Conclusions:

Under the test conditions, the acute oral LD50 of ZnCl2 in Sprague-Dawley rats was calculated to be 1,100 mg/kg (equivalent to 528 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 7036.64 mg/kg.

Executive summary:

A study was conducted to evaluate the acute oral toxicity of the test material in Sprague-Dawley rats according to the OECD Guideline 401 (Acute Oral Toxicity).

Initially a preliminary screening with small groups of three rats of each kind was carried out and the LD50 values were then calculated according to the Litchfield and Wilcoxon method. The main study was conducted with ten rats.

Miosis, conjunctivitis, decreased consumption of food and water and hemorrhages and hematomas in the tail were observed in the rats.

Under the test conditions, the acute oral LD50 of ZnCl2 in Sprague-Dawley rats was calculated to be 1,100 mg/kg (equivalent to 528 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 7036.64 mg/kg.

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

Preliminary study:

A preliminary screening with small groups of three animals of each sex was carried out. The LD50 values were then calculated according to the Litchfield and Wilcoxon method.

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 4 499.96 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

95% CL:

>= 3 090.68 - <= 6 560.41

Mortality:

Mostly, deaths occurred during the first 48 h of test compound administration. No deaths occurred after three days.

Clinical signs:

other: other: Conjunctivitis, piloerection, asthenia, decreased food and water consumption and hemorrhages and hematomas in the tail For details see Table 1 in "Remark on results including tables and figures" field.

Gross pathology:

No data

Other findings:

No data

Table 1. Severity of physical and clinical signs in mice after zinc intoxication in a single dose

	Number of days after zinc administration
	1	2-3	4-7	8-14
Mortality rates on oral administration	90%	10%	0%	0%
Conjunctivitis	None	+	+	None
Piloerection	None	+	+	+
Hemorrhages and hematomas in the tail	None	+	+++	+++
Asthenia	++	++	+	None
Decreased food and water consumption, weight loss	None	+	+	None

Mortality rates and physical and observational examination of rats are average for all zinc compounds.

+Light; ++Moderate; +++Severe

Conclusions:

Under the test conditions, the acute oral LD50 of ZnSO4 in mice was calculated to be 926 mg/kg (equivalent to 337 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 4499.96 mg/kg.

Executive summary:

A study was conducted to evaluate the acute oral toxicity of the test material in mice according to the OECD Guideline 401 (Acute Oral Toxicity).

Initially a preliminary screening study with small groups of three mice of each sex was carried out and the LD50 values were then calculated according to the Litchfield and Wilcoxon method. The main study was conducted with ten mice. Conjunctivitis, piloerection, asthenia, decreased food and water consumption and severe hemorrhages and hematomas in the tail vein were observed in mice.

Under the test conditions,the acute oral LD50 of ZnSO4 in mice was calculated to be 926 mg/kg (equivalent to 337 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 4499.96 mg/kg.

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

Preliminary study:

A preliminary screening with small groups of three animals of each sex was carried out. The LD50 values were then calculated according to the Litchfield and Wilcoxon method.

Sex:

male

Dose descriptor:

LD50

Effect level:

8 309.85 mg/kg bw

Based on:

test mat.

Remarks:

converted to target substance

95% CL:

>= 6 123.05 - <= 11 177

Mortality:

Mortality observed mostly during the first 48 h of test material administration. No deaths occurred after three days.

Clinical signs:

other: other: Miosis, conjunctivitis and hemorrhages and hematomas in the tail. For details see Table 1 in "Remark on results including tables and figures" field

Gross pathology:

No data

Other findings:

No data

Table 1. Severity of physical and clinical signs in rats after zinc intoxication in a single dose

	Number of days after zinc administration
	1	2-3	4-7	8-14
Mortality rates on oral administration	90%	10%	0%	0%
Miosis	+	++	++	+
Conjunctivitis	+	++	+	None
Erythema, necrosis in nose	None	++	++	++
Exophthalmos	None	None	None	None
Decreased food and water consumption, weight loss	None	+	+	None
Hemorrhages and hematomas in the tail	None	++	++	+

Mortality rates and physical and observational examination of rats are average for all zinc compounds.

+Light; ++Moderate

Conclusions:

Under the test conditions, the acute oral LD50 of ZnSO4 in Sprague-Dawley rats was calculated to be 1,710 mg/kg (equivalent to 623 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 8309.85 mg/kg.

Executive summary:

A study was conducted to evaluate the acute oral toxicity of the test material in Sprague-Dawley rats according to the OECD Guideline 401 (Acute Oral Toxicity).

Initially a preliminary screening with small groups of three rats of each sex was carried out and the LD50 values were then calculated according to the Litchfield and Wilcoxon method. The main study was conducted with ten rats.

Miosis, conjunctivitis, decreased consumption of food and water and hemorrhages and hematomas in the tail were observed in the rats.

Under the test conditions, the acute oral LD50 of ZnSO4 in Sprague-Dawley rats was calculated to be 1,710 mg/kg (equivalent to 623 mg of Zn/kg). Considering the Zn concentration of max. 7.5 % in the target substance, the LD50 corresponds to 8309.85 mg/kg.

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

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 toxicity (oral)

Zinc compounds

To address the hazard of zinc ion, the most conservative value for the source substance zinc sulfate was selected from public reports (EU Risk Assessment Report. ZINC SULFATE CAS No: 7733-02-0, EINECS No: 231-793-3. Final Report, 2008.). The lowest hazard value cited in this report is an LD50 for mice from a publication of Domingo et al. (1988). In this study zinc sulfate and zinc chloride was administered to rats and mice via gavage. The doses were selected based on a preliminary screening. In the main study ten rats and mice were treated with the test item and observed for 14 days. As a result, zinc sulfate revealed LD50 values of 1710 and 926 mg/kg bw in rats and mice, respectively. The LD50 values for zinc dichloride were 1100 mg/kg bw/d and 1260 mg/kg bw/d in rats and mice, respectively. The majority of deaths for both species were observed within the first 24 hours. No deaths occurred after 3 days. The physical and clinical signs appeared within the first 48 hours. These signs were decreasing or disappearing with time. The principal findings included miosis, conjunctivitis, erythema and necrosis in nose, exophthalmos, and necrosis in tail.

Converted to the target substance under consideration of the maximum zinc concentration of 7.5 % the lowest hazard value found for zinc sulfate in mice of 926 mg/kg bw/d corresponds to 4500 mg/kg bw/d.

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 European Regulation (EC) No 1272/2008.