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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
19-06-1996 till 04-07-1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The underlying hypothesis for the read-across is that chelates have the same mode of action based on their ability to chelate, remove or add metal cations to body causing perturbation of body’s micronutrients balance.
The source substance is a chelating agent in a target substance. The only difference between the target and the main source substance is presence of magnessium (Mg) cation instead two Na+ cations. As magnessium is an essential micro element required by all forms of life, is considered not to influence the toxicological activity.
Detailed information about the substances purity and data matric are available in RA Statement (IUCLID 13.2)
Cross-referenceopen allclose all
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2006-12-20 to 2007-01-29
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Justification for type of information:
A substantial body of evidence exists that the toxicity profiles of chelates depends mainly on metal ion, its affinity to this metal, and their ability to supply or to sequester it from the body/environment. The source substance has the same chelating agent as in a target substance (MgNa2IDHA). The only difference between the target and the source substance is presence of magnessium (Mg) cation instead Cu2+ cations. As magnesium is an essential micro element required by all forms of life, is considered not to influence the toxicological activity.
Detailed information about the substances purity and data matric are available in RA Statement (IUCLID 13.2)
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Statement of GLP Compliance No. G 024 (Slovak National Accreditation Service); Statement of GLP Compliance No. 4/2006/DPL.
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute of Occupational Medicine in Łódź, Poland
- Age at study initiation: Pilot study: 9 week (dose of 2,000 mg/kg bw); 11 week (dose of 300 mg/kg bw). Main experiment: 11 weeks (average body weight of 179 g).
- Weight at study initiation: Pilot study: 168 g (dose of 2,000 mg/kg bw); 198 g (female; dose of 300 mg/kg bw). Main experiment: average body weight of 179 g.
- Fasting period before study: yes. The day before the experiment was due to commence, some 18 hours before administration of the analysed material, the animals were deprived of feed, being left with only water. Feed was made available again 3 hours after administration of the analysed substance.
- Housing: The animals were kept in plastic cages with metal wire covers, with the following dimensions (length x width x height): 58 x 37 x 21 cm.
During the experiment, the animals were kept in cages individually (initial study) and in groups of four (main study).
- Diet (e.g. ad libitum): ad libitum (standard granulated "Murigran" laboratory feed, manufactured by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL of Motycz
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-71
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
The analysed substance was administered to the rats on the following days: 20.12.2006. (1 female – initial experiment, dose of 2,000 mg/kg of body mass), 04.01.2007. (1 female – initial experiment, dose of 300 mg/kg of body mass), 09.01.2007. (4 females – experiment proper, dose of 300 mg/kg of body mass). The experiment was terminated on the following days: 20.12.2006. (female that died during the initial experiment, dose of 2,000 mg/kg of body mass), 18.01.2007. (female – initial experiment, dose of 300 mg/kg of body mass), 19.01.2007 (female that died during the experiment proper, dose of 300 mg/kg of body mass), 23.01.2007. (3 females – experiment proper, dose of 300 mg/kg of body mass), respectively.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1 ml of the water solution of the analysed substance contained: 400 mg of the substance (dose of 2,000 mg/kg of body mass); 60 mg of the substance (dose of 300 mg/kg of body mass).
- Amount of vehicle (if gavage): 0.5 mL per 100 g of the body weight.

- Rationale for the selection of the starting dose: During the initial experiment, one female received a dose of 2,000 mg/kg of body mass of the analysed substance. Since this female died, the analysed substance was then administered to another female, in a dose of 300 mg/kg of body mass. On the basis of the initial experiment, during the experiment proper the analysed substance was administered to four successive females in a dose of 300 mg/kg of body mass.
Doses:
Initial experiment: 2000 mg/kg bw, 300 mg/kg bw;
Main strudy: 300 mg/kg bw
No. of animals per sex per dose:
Initial experiment: 2000 mg/kg bw (one animal), 300 mg/kg bw (one animal);
Main strudy: four animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: An assessment of the general condition of the animals, i.e. observation of all animals in terms of incidence and mortality, was performed twice daily throughout the 14-day duration of the experiment. Detailed clinical observations were performed on the day of administration of the analysed substance (day 0), 10, 30 and 60 minutes after administration, and subsequently every hour over a period of 5 hours from the time of administration. On successive days of the 14-day period of the experiment – once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Preliminary study:
Following the single administration of the analysed substance at the dose of 2,000 mg/kg of body weight to one female (initial experiment), on the same day there were observed changes in posture, the way of walking, kinetic activity and reactivity. The female died within the second hour of administration.
Following the administration of the analysed substance at the dose of 300 mg/kg of body weight to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. The animal survived the 14-day period of observation.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on mortality, clinical signs and findings at necropsy at 2000 mg/kg bw
Mortality:
One female died between the ninth and tenth day of observation. The remaining females survived the 14-day observation period.
Clinical signs:
Following the single administration of the analysed substance at the dose of 300 mg/kg bw to four successive females (main experiment), no symptoms of toxicity were observed during the 14-day period of observation for three of the animals. On day seven and eight, one female displayed changes in posture, the way of walking, kinetic activity, which were accompanied by horripilation, quickened breathing, and a mucoid secretion from the nostrils. On the ninth day of observation, the female additionally displayed changes in reactivity, respiratory murmurs, and blood-coloured secretion from the nostrils. In all probability, these changes were not connected with the analysed material. The female died between the ninth and tenth day of observation. The remaining females survived the 14-day observation period.
Body weight:
No body weight increase disorders were observed. The exception was one female, which body weight decreased during the first week of the experiment.
Gross pathology:
The females that died (initial and main studies) and the remaining females that survived following the 14-day period of observation underwent autopsies and macroscopic studies. The macroscopic study of the female that died having received a dose of 2,000 mg/kg bw disclosed hepatic hyperaemia, as well as pale and enlarged lungs. No changes were found during the macroscopic study in the female that died having received a dose of 300 mg/kg bw (the animal was devoured by the other animals present in the cage). Macroscopic studies did not find any pathological changes in the remaining animals.

Table 1. Clinical signs.

Dose(mg/kg of body mass)

Day following administration

Number of live animals

Rat no.

1*

2

3

4

5

2,000

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

OK, P

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

300

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

5

5

5

5

5

5

5

5

5

5

4

4

4

4

4

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

OK

OK

OK

P

-

-

-

-

* females from the initial experiment

BZ = without change

OK = clinical symptoms observed

P = died

Table 2. Body weights

Dose

mg/kg of body mass

Rat no.

Day of experiment

Difference

14 – 0

0

7

14

2,000

1*

168

-

-

-

300

1*

2

3

4

5

198

179

174

189

174

233

206

189

219

155

241

197

196

221

-

43

18

22

32

-

* females from the initial experiment

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the mortality, clinical signs and findings at necropsy in one animal dosed by 2000 mg/kg bw, LD50 is considered to be between 300 - 2000 mg/kg bw that corresponds to Cat. 4 in accordance with the ECHA guidance on the Application of the CLP Criteria (2013).
Executive summary:

A study was conducted to test oral toxicity potential of Cu (II) IDHA in rats. Following the single administration of the analysed substance at dose level of 2000 mg/kg bw to a single female Wistar rat symptoms of toxicity were observed within the first hour of administration. The female died within the second hour of administration of the analysed material. Following the single administration of the analysed substance at dose level of 300 mg/kg bw to a single female, no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation. Based on this result, the test substance at the dose level of 300 mg/kg bw was administered to four successive females. No symptoms of toxicity were observed during the 14-day period of observation for three of the animals. In one animal, symptoms of toxicity were observed from the seventh day of observation. In all probability, these changes were not connected with the analysed material. The female died on the tenth day of observation. The remaining females survived the 14-day observation period.

The females that died (initial and main studies) and the remaining females that survived the 14-day period of observation underwent autopsies and macroscopic studies.

The macroscopic study of the female that died having received the dose of 2000 mg/kg bw disclosed hepatic hyperaemia, as well as pale and enlarged lungs. No changes were found during the macroscopic study in the female that died having received the dose of 300 mg/kg bw (the animal was devoured by the other animals present in the cage). Macroscopic studies did not find any pathological changes in the remaining animals.

Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2006-12-20 to 2007-01-23
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Justification for type of information:
A substantial body of evidence exists that the toxicity profiles of chelates depends mainly on metal ion, its affinity to this metal, and their ability to supply or to sequester it from the body/environment. The source substance has the same chelating agent as in a target substance (MgNa2IDHA). The only difference between the target and the source substance is presence of magnessium (Mg) cation instead Fe3+ cations. As magnessium is an essential micro element required by all forms of life, is considered not to influence the toxicological activity.
Detailed information about the substances purity and data matric are available in RA Statement (IUCLID 13.2)
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Statement of GLP Compliance No. G 024 (Slovak National Accreditation Service); Statement of GLP Compliance No. 4/2006/DPL
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Institute of Occupational Medicine in Łódź, Poland
- Age and weight at study initiation: Pilot study: 10 week (dose of 2,000 mg/kg bw). Main experiment: 11 weeks (average body weight of 188.5 g).
- Fasting period before study: yes. The day before the experiment was due to commence, some 18 hours before administration of the analysed material, the animals were deprived of feed, being left with only water. Feed was made available again 3 hours after administration of the analysed substance.
- Housing: The animals were kept in plastic cages with metal wire covers, with the following dimensions (length x width x height): 58 x 37 x 21 cm.
During the experiment, the animals were kept in cages individually (initial study) and in groups of four (main study).
- Diet (e.g. ad libitum): ad libitum (standard granulated "Murigran" laboratory feed, manufactured by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL of Motycz
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-71
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
The analysed substance was administered to the rats on the following days: 20.12.2006. (1 female – initial experiment, dose of 2,000 mg/kg of body mass), 04.01.2007 (4 females – experiment proper, dose of 2000 mg/kg of body mass). The experiment was terminated on the following days: 03.01.2007. (1 female – initial experiment, dose of 2000 mg/kg of body mass), 23.01.2007. (4 females – experiment proper, dose of 2000 mg/kg of body mass), respectively.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1 ml of the water solution of the analysed substance contained: 400 mg of the substance (dose of 2,000 mg/kg of body mass).
- Amount of vehicle (if gavage): 0.5 mL per 100 g of the body weight.

- Rationale for the selection of the starting dose: During the initial experiment, one female received a dose of 2,000 mg/kg of body mass of the analysed substance. During the 14 day observation period were not observed the symptoms of toxicity. The female survived the 14-day observation period.
On the basis of the initial experiment, during the experiment proper the analysed substance was administered to four successive females in a dose of 2000 mg/kg of body mass.
Doses:
Initial experiment: 2000 mg/kg bw;
Main strudy: 2000 mg/kg bw
No. of animals per sex per dose:
Initial experiment: 2000 mg/kg bw - one animal;
Main strudy: 2000 mg/kg bw - four animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: An assessment of the general condition of the animals, i.e. observation of all animals in terms of incidence and mortality, was performed twice daily throughout the 14-day duration of the experiment. Detailed clinical observations were performed on the day of administration of the analysed substance (day 0), 10, 30 and 60 minutes after administration, and subsequently every hour over a period of 5 hours from the time of administration. On successive days of the 14-day period of the experiment – once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Preliminary study:
Following the single administration of the analysed substance at the dose of 2,000 mg/kg of body weight to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. The animal survived the 14-day period of observation.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on mortality, clinical signs and findings at necropsy at 2000 mg/kg bw
Mortality:
No mortality occured during the 14-day observation period.
Clinical signs:
After a single administration of test substance to one female at a dose of 2000 mg / kg b.w. (preliminary experience), during the 14-day period of observation there was no diagnosed with symptoms of toxicity. The female survived the 14-day observation period.
After a single administration of a test substance following four females at a dose of of 2000 mg / kg b.w. (Experience appropriate), during the 14-day observation period also there were no signs of toxicity. Females survived the 14-day period observation.
Body weight:
No body weight increase disorders were observed.
Gross pathology:
Macroscopic studies did not find any pathological changes in the test animals.





Table 1. Clinical signs.

Dose

(mg/kg bw)

Day following administra

tion

Number of live animals

 

 

Rat No

 

 

 

 

 

 

 

 

 

1 *

2

3

4

5

 

 

 

 

 

 

 

 

 

0

5

BZ

BZ

BZ

BZ

BZ

 

 

1

5

BZ

BZ

BZ

BZ

BZ

 

 

2

5

BZ

BZ

BZ

BZ

BZ

 

 

3

5

BZ

BZ

BZ

BZ

BZ

 

2000

4

5

BZ

BZ

BZ

BZ

BZ

 

5

5

BZ

BZ

BZ

BZ

BZ

 

 

6

5

BZ

BZ

BZ

BZ

BZ

 

 

7

5

BZ

BZ

BZ

BZ

BZ

 

 

8

5

BZ

BZ

BZ

BZ

BZ

 

 

9

5

BZ

BZ

BZ

BZ

BZ

 

 

10

5

BZ

BZ

BZ

BZ

BZ

 

 

11

5

BZ

BZ

BZ

BZ

BZ

 

 

12

5

BZ

BZ

BZ

BZ

BZ

 

 

13

5

BZ

BZ

BZ

BZ

BZ

 

 

14

5

BZ

BZ

BZ

BZ

BZ

 

 

 

 

 

 

 

 

 

 

* females from the initial experiment

BZ = without change

Table 2. Body weights

Dose

mg/kg of body mass

Rat no.

Day of experiment

Difference

14 – 0

0

7

14

2000

1*

2

3

4

5

198

179

174

189

174

233

206

225

211

222

241

225

232

216

232

52

35

42

33

41

* females from the initial experiment

Interpretation of results:
Toxicity Category V
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the mortality, clinical signs and findings at necropsy in five animal dosed by 2000 mg/kg bw, LD50 is considered to be over 2000 mg/kg bw that corresponds to Cat. 5 (not clasified) in accordance with the ECHA guidance on the Application of the CLP Criteria (2013).
Executive summary:

A study was conducted to test oral toxicity potential of Fe(III)IDHA in rats. Following the single administration of the analysed substance in a dose of 2,000 mg/kg b.w. to a single female, no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation. Following the single administration of the analysed substance in a dose of 2,000 mg/kg bw to four successive females, no symptoms of toxicity were observed during the 14-day period of observation. The females survived the 14-day observation period. All the animals were put down following the 14-day period of observation and subsequently underwent autopsies and macroscopic studies. No pathological changes were found during the macroscopic study in the studied animals.

Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2006-12-20 to 2007-01-18
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Justification for type of information:
A substantial body of evidence exists that the toxicity profiles of chelates depends mainly on metal ion, its affinity to this metal, and their ability to supply or to sequester it from the body/environment. The source substance has the same chelating agent as in a target substance (MgNa2IDHA). The only difference between the target and the source substance is presence of magnessium (Mg) cation instead Mn2+ cations. As magnessium is an essential micro element required by all forms of life, is considered not to influence the toxicological activity.
Detailed information about the substances purity and data matric are available in RA Statement (IUCLID 13.2)
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Statement of GLP Compliance No. G 024 (Slovak National Accreditation Service); Statement of GLP Compliance No. 4/2006/DPL.
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: conventional farm of laboratory animals run by the Institute of Occupational Medicine in Łódź, Poland.
- Age at study initiation: Pilot study: 9 week; Main experiment: 11 weeks
- Weight at study initiation: Pilot study: 166 g; Main experiment: average body weight of 190.5 g.
- Fasting period before study: yes. The day before the experiment was due to commence, some 18 hours before administration of the analysed material, the animals were deprived of feed, being left with only water. Feed was made available again 3 hours after administration of the analysed substance.
- Housing: plastic cages with metal wire covers, with the following dimensions (length x width x height): 58 x 37 x 21 cm.
During the experiment, the animals were kept in cages individually (initial study) and in groups of four (study proper). The litter comprised dedusted wood shavings, sterilised with ultraviolet radiation. Each cage was fitted with a signboard containing the study code, the dose applied, the date of commencement and planned termination of the experiment, as well as the sex and individual numbers of animals.
- Diet (e.g. ad libitum): ad libitum (standard granulated "Murigran" laboratory feed, manufactured by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL of Motycz)
- Water (e.g. ad libitum): ad libitum (tap water)
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 45-71
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
The analysed substance was administered to the rats on the following days: 20.12.2006. (1 female – initial experiment, dose of 2,000 mg/kg of body mass) and 04.01.2007. (4 females – experiment proper, dose of 2,000 mg/kg of body mass). The experiment was terminated on the following days: 03.01.2007 (1 female – initial experiment, dose of 2,000 mg/kg of body mass) and 18.01.2007 (4 females – experiment proper, dose of 2,000 mg/kg of body mass), respectively.
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1 mL of the water solution of the analysed substance contained: 400 mg of the substance (dose of 2,000 mg/kg b.w.);
- Amount of vehicle (if gavage): 0.5 mL per 100 g of the body weight.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
Initial experiment: one animal
Main strudy: four animals
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: An assessment of the general condition of the animals, i.e. observation of all animals in terms of incidence and mortality, was performed twice daily throughout the 14-day duration of the experiment. Detailed clinical observations were performed on the day of administration of the analysed substance (day 0), 10, 30 and 60 minutes after administration, and subsequently every hour over a period of 5 hours from the time of administration. On successive days of the 14-day period of the experiment – once daily.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Preliminary study:
Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation.
Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to four successive females (experiment proper), no symptoms of toxicity were observed during the 14-day period of observation for three of the animals. The females survived the 14-day observation period.
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: based on mortality, clinical signs and findings at necropsy at 2000 mg/kg bw
Mortality:
All females survived the 14-day observation period.
Clinical signs:
Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to one female (initial experiment), no symptoms of toxicity were observed during the 14-day period of observation. Following the single administration of the analysed substance, this in a dose of 2,000 mg/kg of body mass, to four successive females (main experiment), no symptoms of toxicity were observed during the 14-day period of observation for three of the animals.
Body weight:
No body mass increase disorders were observed.
Gross pathology:
No pathological changes were found during the macroscopic study in the analysed animals.

Table 1. Mn (II) IDHA Acute oral toxicity study conducted on rats – clinical symptoms – summary breakdown 

Dose(mg/kg b.w.)

Day following administration

Number of live animals

Rat no.

1*

2

3

4

5

2,000

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

5

5

5

5

5

5

5

5

5

5

5

5

5

5

5

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

BZ

* female from the initial experiment

BZ = without change

Table 2. Mn (II) IDHA Acute oral toxicity study conducted on rats - animal body mass (g)

Dose

mg/kg b.w.

Rat no.

Day of experiment

Difference

14 – 0

0

7

14

2,000

1*

2

3

4

5

166

183

198

188

193

215

210

227

206

228

236

219

229

216

232

70

36

31

28

39

* females from the initial experiment

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
On the grounds of the study, it may be stated that the median lethal dose (LD50) of Mn (II) IDHA is greater than 2000 mg/kg b.w.
Executive summary:

A study was conducted to test oral toxicity potential of Mn (II) IDHA in rats. Following the single administration of the analysed substance in a dose of 2,000 mg/kg b.w. to a single female, no symptoms of toxicity were observed during the 14-day period of observation. The female survived the 14-day period of observation. Following the single administration of the analysed substance in a dose of 2,000 mg/kg bw to four successive females, no symptoms of toxicity were observed during the 14-day period of observation. The females survived the 14-day observation period. All the animals were put down following the 14-day period of observation and subsequently underwent autopsies and macroscopic studies. No pathological changes were found during the macroscopic study in the studied animals.

Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
20-12-2006 till 18-01-2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
A substantial body of evidence exists that the toxicity profiles of chelates depends mainly on metal ion, its affinity to this metal, and their ability to supply or to sequester it from the body/environment. The source substance has the same chelating agent as in a target substance (MgNa2IDHA). The only difference between the target and the source substance is presence of magnessium (Mg) cation instead Zn2+ cations. As magnessium is an essential micro element required by all forms of life, is considered not to influence the toxicological activity.
Detailed information about the substances purity and data matric are available in RA Statement (IUCLID 13.2)
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Deviations:
no
GLP compliance:
yes
Remarks:
G024
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: W doswiadczeniu użyto szczurów o symbolu Imp: WIST (stado outbred), pochodzacych z hodowli zwierzat laboratoryjnych Instytutu Medycyny Pracy w Łodzi, utrzymanej w typie konwencjonalnym.
Sex:
female
Details on test animals and environmental conditions:
Zwierzęta.

W doświadczeniu użyto szczurów o symbolu Imp: WIST (stado outbred), pochodzących
z hodowli zwierząt laboratoryjnych Instytutu Medycyny Pracy w Łodzi, utrzymanej w
typie konwencjonalnym.
IPO Oddział w Pszczynie Kod badania: OS-47/06
Zakład Badań Toksykologicznych
7/23
Szczury przeszły co najmniej 5-dniowa kwarantannie, w czasie której były codziennie
obserwowane.
Zwierzęta były indywidualnie oznaczone.
W doświadczeniu wstępnym użyto jednej 9-tygodniowej samicy, ważącej 168 g (dawka
2000 mg/kg m.c.) W doświadczeniu właściwym (dawka 2000 mg/kg m.c.) użyto czterech
10-tygodniowych samic o średniej masie ciała 189,3 g.

Warunki przetrzymywania zwierząt.

W czasie kwarantanny i doświadczenia zwierzęta przebywały w klimatyzowanych
pomieszczeniach o następujących parametrach:
- temperatura 19 – 21 °C
- wilgotność względna powietrza 45 – 71 %
- oświetlenie sztuczne, jarzeniowe; cykl oświetlenia: 12 godzin jasno - 12 godzin
ciemno.
Zwierzęta przetrzymywano w plastykowych klatkach z pokrywa z metalowych drutów, o
wymiarach (długość × szerokość × wysokość): 58×37×21 cm.
W doświadczeniu zwierzęta przetrzymywano w klatkach pojedynczo (badanie wstępne)
oraz po cztery (badanie właściwe).
Jako ściółki używano odpylonych wiórów drzewnych, sterylizowanych promieniami UV.
Każda klatka była wyposażona w wywieszkę zawierającą kod badania, stosowana
dawkę, date założenia i planowanej likwidacji doświadczenia, pleć i numery zwierząt.

Pasza i woda.

Zwierzętom podawano bez ograniczeń granulowana standardowa pasze laboratoryjna
„Murigran”, produkowana przez Wytwórnie Koncentratów i Mieszanek Paszowych
AGROPOL z Motycza oraz wodne wodociągową.
Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
W doświadczeniu wstępnym jednej samicy podano badaną substancję w dawce 2000
mg/kg m.c. Na podstawie doświadczenia wstępnego, w doświadczeniu właściwym
badaną substancję podano kolejnym czterem samicom w dawce 2000 mg/kg m.c.
Roztwór wodny badanej substancji podawano samicom jednorazowo, za pomocą sondy
metalowej do żołądka, w objętości 0,5 ml cieczy na 100 g masy ciała szczura. 1 ml
wodnego roztworu badanej substancji zawierał 400 mg substancji.
No. of animals per sex per dose:
W doświadczeniu wstępnym użyto jednej 9-tygodniowej samicy, ważącej 168 g (dawka
2000 mg/kg m.c.) W doświadczeniu właściwym (dawka 2000 mg/kg m.c.) użyto czterech
10-tygodniowych samic o średniej masie ciała 189,3 g.
Control animals:
not specified
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Wszystkie zwierzęta przeżyły 14 dniowy okres badań.
Clinical signs:
Po jednorazowym podaniu badanej substancji jednej samicy w dawce 2000 mg/kg m.c.
(doświadczenie wstępne), w dniu podania u samicy obserwowano zmiany w postawie
ciała, sposobie chodzenia, aktywności ruchowej i reaktywności. Od pierwszego do
czternastego dnia po podaniu badanej substancji u samicy nie stwierdzono już objawów
toksyczności. Zwierzę przeżyło 14-dniowy okres obserwacji.
Body weight:
Bez zmian w trakcje badań
Gross pathology:
W badaniu makroskopowym u badanych zwierząt zmian patologicznych nie
stwierdzono.

Objawy kliniczne.

Po jednorazowym podaniu badanej substancji jednej samicy w dawce 2000 mg/kg m.c. (doświadczenie wstępne), w dniu podania u samicy obserwowano zmiany w postawie ciała, sposobie chodzenia, aktywności ruchowej i reaktywności. Od pierwszego do czternastego dnia po podaniu badanej substancji u samicy nie stwierdzono już objawów toksyczności. Zwierzę przeżyło 14-dniowy okres obserwacji. Po jednorazowym podaniu badanej substancji kolejnym czterem samicom w dawce 2000 mg/kg m.c. (doświadczenie właściwe), w trakcie 14-dniowego okresu obserwacji również nie obserwowano objawów toksyczności. Samice przeżyły 14-dniowy okres obserwacji. Zestawienie zbiorcze wyników obserwacji klinicznych u zwierząt zawarto w Tabeli 1, a wyniki obserwacji klinicznych u poszczególnych zwierząt przedstawiono w indywidualnych kartach badania, dołączonych do sprawozdania (strony 14 – 23).

Masa ciała zwierząt.

Indywidualne wyniki przyrostu masy ciała zwierząt zestawiono w Tabeli 2 oraz w indywidualnych kartach badania, dołączonych do sprawozdania (strony 14 – 23). Nie stwierdzono zaburzeń w przyroście masy ciała.

Patologia.

W badaniu makroskopowym u badanych zwierząt zmian patologicznych nie stwierdzono. Wyniki badań makroskopowych u poszczególnych zwierząt przedstawiono w indywidualnych kartach badania, dołączonych do sprawozdania (strony 14 – 23).

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
LD50 > 2000 mg/kg bw
Executive summary:

Na podstawie przeprowadzonego badania, Zn (II) IDHA można zaliczyć do:

– Kategorii 5 - zgodnie z zasadami Światowego Ujednoliconego Systemu (GHS)

– Kategorii U - zgodnie ze schematem UE na okres przejściowy do pełnego wdrożenia Światowego Ujednoliconego Systemu (GHS)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
The study was conducted according to the Acute Toxic Class Method in the version of28th April 1995 (ENV/MC/CHEM(95)5. This method is to a great extent in reference to methods of Annex V, Part B. l. (acute toxicity (oral)), to Directive 67/548/EEC of the Council of the European 0
Communities of June 27, 1967 (Official Journal of the European Communities L196/1 of A4Pst 16, 1967) in the current version as amended for the seventeenth time by Directive 92/69/EEC of the Commission ofthe European Communities ofJuly 31, 1992 (Official Journal ofł&uropean Communities L 383 A ofDecember 29, 1992).
GLP compliance:
yes
Test type:
acute toxic class method

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
The acute toxicity experiment was caried out with young-adult, SPF-bred Wistar rats (strain Hsd Cpb:WU, bred by Harlan Winkelmann, Borchen, Germany).
At time of receipt (on June 14, 1996) males were 6 - 7 and females 8 - 9 weeks old. At the art of the study the mean initial weight ofmales was 183 g and offemales 159 g. The mean deviation in animal weights was less than 20 %. Females were nulliparous and not pregnant.z -condition of the animals' health was checked before the start of experiment. Only healthy m'als, without any clinical signs, were included in the study. Prior to application the animals were acclimated for at least 5 days. Three rats were used per sex.

Housing conditions
The rats were housed in groups of 3 animals, under conv tional conditions, in Makrolon® Type­ III cages on low-dust wood granules (supplier: ssruą: Soest/Westphalia), at a room temperature of22 ± 2° C, with a 12-hour light/dark cycle (ańi{icial light from 6 a.m. to 6 p.m. CET), a relative
humidity ofabout 55 ± 5% and approximatelyl5 to 20 air exchanges per hour.
All animals of this experiment were kep one animal room. For reasons of capacity, animals from other toxicological experiments were temporarily housed in the same room. Confusion of the animal numbers or influence by one another were avoided by appropriate organization of operations.

Cleaning, Disinfection, Pest Control
The anima! room was disinfected once a week (Tegol®2000). Continuous pest control was carried out in which 2 to 3 sticky traps ofKillgerm Co., were placed in the animal room. The effect of the pesticide-free sticky traps is based on pheromone lures.
The cage shelves were cleaned at regular intervals. Water bottles and cage lids were also c ged regularly. All cage equipment was cleaned with hot water.

Nutrition
The animals received fixed-fonnula standard diet Altromin® 1324 pellets :oducer: Altromin GmbH, Lage) and tap water ad libitum. There were feeding troughs fitted in the cage lids as feed containers. Water was offered in polycarbonate bottles holding approximately 700 ml (as described by SPIEGEL A. and GONNERT, R. Zschr. Vers[c'i\stierkunde l, 38 (1961)).
The nutritional composition and the contaminant c ient of the standard diet were routinely spot­ checked and analyzed. The tap water was of drirfijng quality (in accordance with the Drinking Water Statute of Dec. 05, 1990, Federat Lawl3azette No. 66, issued on Dec. 12, 1990, pages 2612-2629). The results of the feed and rtte-r analyses have been filed. Available data provided no evidence of any influence on the study objective.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
From approx. 16 hours prior to until 4 hours aftm(Jlpplication feed was withdrawn; all the other time it was available ad libitum. Tap water was\vailable ad libitum during the entire study period. The test substance was formulated unde tirring on a magnetic stirrer in water at room temperature and intragastrically applied by gavage to 3 males and 3 females per group at a constant application volume of 20 ml/kg body weight. The test substance was formulated in the application vehicle immediately prior to treatment.
First of all, only females received the intended dosage. As there was no indication for an increased lethality 3 małe ais were treated in order to detect possible difference between the sexes
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
3 female and 3 male
Control animals:
yes
Details on study design:
The animals were inspected severa} times on the day of administration (day 1), and twice daily during the following 14-day observation period (once on weekends and bank holidays). During inspections, the type, onset, duration, and intensity of clinical signs were recorded and dead animals were removed if necessary.

The animals were individually weighed directly before administration (day 1), after one week- (only females) and at the end of the 14-day observation period. The application volume for e' ach individual animal was based on its body weight just before application.

Gross pathological examinations were done on all animals sacrificed under de"ęp diethyl ether anesthesia at the end of study. Necropsy records were prepMed for all aniiflAfs.

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred.
Clinical signs:
No signs of intoxication occurred during the observation time.
Body weight:
Growth ofmale and female rats was not affected.
Gross pathology:
None of the animals sacrificed at the end of the 14-day observation peńod showed any noticeable gross pathological findings.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The Ld50 value is > 2000 mg/kg bw. Based on the present investigations, the test substance is therefore to be regarded as relatively non-toxic and not to be classified according to Regulation No. 1272/2008.
Executive summary:

Acute toxicological investigations of male and female Wistar rats were conducted after single oral administration of,Jminodisuccinat-tetra-Na-Salz".The LD50 for male and female rats was greater than 2000 mg/kg and was not exactly  determined. No clinical signs were observed after administration of2000 mg/kg body weight. Body weight development of male and female rats was not affected.  No deaths occurred. None of the animals sacrificed at the end of study showed any noticeable gross pathological findings.

Based on the present investigations, the test substance is therefore to be regarded as relatively non-toxic and not to be classified according to Regulation No. 1272/2008.