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Diss Factsheets

Toxicological information

Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
from 19-02-1997 till 12-03-1997
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 calcium (Ca) cation instead two Na+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
from 2010-11-10 to 2010-11-24
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented 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 (CaNa2IDHA). The only difference between the target and the source substance is presence of calcium (Ca) cation instead Cu2+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: SOP/T/21: „Acute dermal toxicity study”
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Slovak National Accreditation Service (No. G-024)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: conventional husbandry of laboratory animals of Institute of Occupational Medicine, Łódź
- Age at study initiation: 10 weeks old
- Weight at study initiation: 295.8 g (males) and 218.2 g (females)
- Fasting period before study: none
- Housing: in cages with dimensions (length x width x height): 58 x 37 x 21 cm; with plastic bottom and wired lid. After application of the test item each animal was kept individually in cage. After removal of test item from animals’ skin during the following days of experiment, the rats were kept five per cage, each separately. UV-sterilized wooden shavings were used as a bedding.
- Diet (e.g. ad libitum): ad libitum standard granulated "Murigran" fodder produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23 °C;
- Humidity (%): 47 – 63 %
- Air changes (per hr): about 16 times/hour
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: ca. 41 cm² (males) ca. 31 cm² (females)
- Type of wrap if used: gauze patches were covered with PCV foil and elastic bandage was used to make circular protecting band

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
- Time after start of exposure: 24 hours after application of chemical and immediately after removal of the gauze patch

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Constant volume or concentration used:no
- For solids, paste formed: no (The test item was applied to gauze patches, moistened with few drops of water and then laid on prepared skin.)

VEHICLE
- Amount(s) applied (volume or weight with unit): a few drops of water were applied to the powdered amount of chemical on the gauze patch
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: General and detailed clinical observations were performed in all animals daily during the entire experiment. Body weight of animals was individually determined for each animal: on day 0 (directly before administration of test item) and on 7th and 14th day.
- Necropsy of survivors performed: yes (All animals were sacrificed after 14-day observation period, dissected and subjected to detailed gross necropsy. )
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortality occurred
Clinical signs:
other: no general signs of toxicity were stated in the animals. Changes in form of erythema, dryness of epidermis, desquamation of epidermis and scabs were stated on the skin in the site of test item application. Dryness of epidermis and scabs were stated in fiv
Gross pathology:
No pathological changes were stated in animals at gross necropsy.
Other findings:
no other findings reported

Following single application of test item no general signs of toxicity were stated in animals. Changes in form of erythema, dryness of epidermis, desquamation of epidermis and scabs were stated on skin in the site of test item application. Dryness of epidermis and scabs were stated in five males whereas desquamation of epidermis – in one male. Erythema and scabs were stated in four females, dryness of epidermis – in five females, desquamation of epidermis – in two females. These were transient changes except dryness of epidermis in three females which was observed till the end of experiment. All animals survived period of experiment. Slight body weight loss was stated in one female No 2 (6g) and three males No 1 (3g), No 4 (6g) and No 5 (8g) during 1st week of experiment. Body weight gains were stated in all animals after 14-day period of experiment. No pathological changes were stated in animals at gross necropsy.

Table 1: Summary of findings

Cu (II) IDHA: acute dermal toxicity study on rats
Administered dose of test item(mg/kg b.w.) 2000
Sex males females
Mortality of animals 0/5 0/5
Clinical signs no general clinical signs; no general clinical signs;
on treated skin: dryness of epidermis and scabs (in 5 males)  on treated skin: erythema and scabs (in 4 females)
on treated skin: desquamation of epidermis (in 1 male) on treated skin: dryness of epidermis (in 5 females)
  on treated skin: desquamation of epidermis (in 2 females)

Clinical signs

Following single application of test item no general signs of toxicity were stated in animals. Changes in form of dryness of epidermis from 2nd – 10th to 5th – 13th day and scabs from 2nd to 5th – 9th day after administration were stated in five males on skin in the site of test item application. Furthermore, desquamation of epidermis on 2nd day after administration was stated in one male (No 1). Changes in form of erythema on 2nd day and scabs from 2nd to 9th – 14th day after administration were stated in four females (No 1, No 2, No 3 and No 5). Changes in form of dryness of epidermis from 2nd – 3rd to 4th – 5th day after administration were stated in five females. Furthermore, dryness of epidermis formed in place of scabs was observed in four females (No 1, No 2, No 3 and No 5) from 8th – 9th to 11th – 14th day after administration. Desquamation of epidermis on 2nd day after administration was stated in two females (No 1 and No 4). All animals survived period of experiment. The overall list of results of clinical observations is presented in Table 2.

Table 2 - Clinical signs - overall list
Cu (II) IDHA: acute dermal toxicity study on rats
Dose (mg/kg b.w.) Sex Day after administration Number of alive animals Rat No
1 2 3 4 5
2000 males 0 5 NC NC NC NC NC
1 5 NC NC NC NC NC
2 5 SIGNS SIGNS SIGNS SIGNS SIGNS
3 5 SIGNS SIGNS SIGNS SIGNS SIGNS
4 5 SIGNS SIGNS SIGNS SIGNS SIGNS
5 5 SIGNS SIGNS SIGNS SIGNS SIGNS
6 5 NC SIGNS SIGNS SIGNS SIGNS
7 5 NC SIGNS SIGNS SIGNS SIGNS
8 5 NC SIGNS SIGNS SIGNS SIGNS
9 5 NC SIGNS SIGNS NC SIGNS
10 5 NC SIGNS SIGNS NC SIGNS
11 5 NC SIGNS SIGNS NC SIGNS
12 5 NC SIGNS SIGNS NC SIGNS
13 5 NC NC SIGNS NC SIGNS
14 5 NC NC NC NC NC
females 0 5 NC NC NC NC NC
1 5 NC NC NC NC NC
2 5 SIGNS SIGNS SIGNS SIGNS SIGNS
3 5 SIGNS SIGNS SIGNS SIGNS SIGNS
4 5 SIGNS SIGNS SIGNS SIGNS SIGNS
5 5 SIGNS SIGNS SIGNS SIGNS SIGNS
6 5 SIGNS SIGNS SIGNS NC SIGNS
7 5 SIGNS SIGNS SIGNS NC SIGNS
8 5 SIGNS SIGNS SIGNS NC SIGNS
9 5 SIGNS SIGNS SIGNS NC SIGNS
10 5 SIGNS SIGNS SIGNS NC SIGNS
11 5 SIGNS SIGNS SIGNS NC SIGNS
12 5 SIGNS SIGNS SIGNS NC NC
13 5 SIGNS SIGNS SIGNS NC NC
14 5 SIGNS SIGNS SIGNS NC NC
NC - no changes
SIGNS - clinical signs

Body weight of animals

Slight body weight loss was stated in one female No 2 (6g) and three males No 1 (3g), No 4 (6g) and No 5 (8g) during 1st week of experiment. Body weight gains were stated in all animals after 14-day period of experiment.

Table 2- Bodyweight of animals (g)-overall list
Cu(II)IDHA:acute dermal toxicity study on rats
Dose(mg/kgb.w.) Sex Rat No Day of experiment/Body weight(g) Body weight gain(g)(0-14)
0 7 14
2000 males 1 308 305 310 2
2 292 295 312 20
3 299 302 322 23
4 287 281 296 9
5 293 285 306 13
females 1 218 220 237 19
2 216 210 230 14
3 219 220 233 14
4 223 231 235 12
5 215 228 232 17

Gross examination

At necropsy no pathological changes were stated in males and females sacrificed after 14-day experiment period.

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

A study was conducted to test the dermal toxicity potential of Cu (II) IDHA in rats (Kropidlo, A., 2010). Following the single administration of the analysed substance at dose level of 2000 mg/kg bw (semi-occlusive application to the shaved skin for 24 hours) to 5 female and 5 male Wistar rats, no symptoms of general toxicity were observed within the 14 day observation period. No mortality was observed. Changes in form of erythema, dryness of epidermis, desquamation of epidermis and scabs were stated on skin in the site of test item application. Dryness of epidermis and scabs were stated in five males whereas desquamation of epidermis – in one male. Erythema and scabs were stated in four females, dryness of epidermis – in five females, desquamation of epidermis – in two females. These were transient changes except dryness of epidermis in three females which was observed till the end of experiment. Slight body weight loss was stated in one female No 2 (6g) and three males No 1 (3g), No 4 (6g) and No 5 (8g) during 1st week of experiment. Body weight gains were stated in all animals after 14-day period of experiment. No pathological changes were stated in animals at gross necropsy. On the ground of the study, one may state that the median dermal lethal dose (LD50) for Cu (II) IDHA is greater than 2000 mg/kg b.w.

Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
May, 29 - June, 12, 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented 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 (CaNa2IDHA). The only difference between the target and the source substance is presence of calcium (Ca) cation instead Fe3+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. QA statement)
Remarks:
Statement of GLP Compliance No G-024 issued by Slovac National Accreditation Service; Statement of GLP Compliance No 4/2006/DPL issued by Bureau for Chemical Substances and Preparations
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Institute of Occupational Medicine in Łódz kept in conventional type.
- Age at study initiation: 10-week-old male rats and 11-weekold females
- Weight at study initiation: male rats with the average body weight of 287 g and females with the average body weight of 194 g
- Fasting period before study: no
- Housing:
- Diet (e.g. ad libitum): standard granulated "Murigran" fodder produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz
- Water (e.g. ad libitum): tap water
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23 °C;
- Humidity (%): 48 - 80
- Photoperiod (hrs dark / hrs light): artificial, fluorescent lighting: 12 hours light / 12 hours darkness

The animals were kept in cages with plastic bottom and wired lid, with dimensions: (length x width x height) 58 x 37 x 21 cm. Following administration of the test material on animals skin, each one was kept individually per cage. After removal of the test material from animals skin, during the following days of experiment the rats were kept five per cage, each sex separately.

Wooden UV-sterilized shavings were used as a litter. Each cage was equipped with label containing information on name of test material, study code, used dose, start date and planned ending date of the experiment, animal sex and animal numbers.

IN-LIFE DATES: From: To:
The experiment was started on May 29th, 2007 (males and females) and ended on June 12th, 2007.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
The day before the test back and sides of animals were shaved with electric razor on skin surface area of about 4 x 6 cm. Only those animals that showed no macroscopically visible irritation or damages of skin were used for the experiments. The animals were not starved prior to the experiment.

The undiluted test material was applied to the dorsal skin of 10 rats (5 males and 5 females) in dose of 2000 mg/kg b.w. The area of skin treated with the test material was about 6 cm2. The test material was applied to gauze patches and then laid on the prepared skin. The gauze patches were covered with PCV foil and elastic bandage was used to make circular protecting band. After 24 hours the band and gauze patches were taken off and the residual test material was removed using water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg b.w.
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: Evaluation of general condition of animals, i.e. observation of all animals in regards to mortality and morbidity was conducted twice a day during 14-day observation period. Following administration of the test material, detailed clinical observations were performed in hour intervals during the day of administration (day 0). Since the first till the 14th day of observation period detailed clinical observations were performed once a day.
Body weight of animals was determined individually for each animal directly before administration of the test material (day 0) and then on seventh andfourteenth day - before the finishing of the experiment.
- Necropsy of survivors performed: yes
- Other examinations performed: After opening of thorax and abdomen macroscopic examination of internal organs was performed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All rats survived the 14-day observation period.
Clinical signs:
other: During 14-day experiment period no changes on skin or in behavior of test animals were stated.
Gross pathology:
No pathological changes were stated in animals during macroscopic examination.

Chelate with name: Fe (III) IDHA Acute dermal toxicity study for rats – clinical signs – overall list

Dose

(mg/kg

b.w.)

Sex

Day after

administration

No of

alive

animals

Rat No

 

1

2

3

4

5

 

 

 

2000

Males

0

5

NC

NC

NC

NC

NC

 

1

5

NC

NC

NC

NC

NC

 

2

5

NC

NC

NC

NC

NC

 

3

5

NC

NC

NC

NC

NC

 

4

5

NC

NC

NC

NC

NC

 

5

5

NC

NC

NC

NC

NC

 

6

5

NC

NC

NC

NC

NC

 

7

5

NC

NC

NC

NC

NC

 

8

5

NC

NC

NC

NC

NC

 

9

5

NC

NC

NC

NC

NC

 

10

5

NC

NC

NC

NC

NC

 

11

5

NC

NC

NC

NC

NC

 

12

5

NC

NC

NC

NC

NC

 

13

5

NC

NC

NC

NC

NC

 

14

5

NC

NC

NC

NC

NC

 

Females

0

5

NC

NC

NC

NC

NC

 

 

1

5

NC

NC

NC

NC

NC

 

2

5

NC

NC

NC

NC

NC

 

3

5

NC

NC

NC

NC

NC

 

4

5

NC

NC

NC

NC

NC

 

5

5

NC

NC

NC

NC

NC

 

6

5

NC

NC

NC

NC

NC

 

7

5

NC

NC

NC

NC

NC

 

8

5

NC

NC

NC

NC

NC

 

9

5

NC

NC

NC

NC

NC

 

10

5

NC

NC

NC

NC

NC

 

11

5

NC

NC

NC

NC

NC

 

12

5

NC

NC

NC

NC

NC

 

13

5

NC

NC

NC

NC

NC

 

14

5

NC

NC

NC

NC

NC

 

NC – no changes

Chelate with name: Fe (III) IDHA Acute dermal toxicity study for rats – body weight of animals (g)

Dose

(mg/kg

b.w.)

Sex

Rat No

Day

Difference

 

 

0

7

14

14 - 0

 

 

 

 

 

 

2000

Males

1

260

281

302

42

 

2

299

308

326

27

 

3

285

293

315

30

 

4

300

316

345

45

 

5

293

309

332

39

 

 

 

 

 

 

 

 

 

1

191

206

209

18

 

Females

 

2

191

203

215

24

 

3

194

203

211

17

 

4

198

207

216

18

 

5

195

199

218

23

 

 

 

 

 

 

 

 

 
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Taking into account the obtained results one may state that the median dermal acute dose (LD50) for Chelate with name: Fe (III) IDHA is higher than 2000 mg/kg b.w.
Executive summary:

Acute dermal toxicity study of Chelate with name: Fe (III) IDHA for rats was performed according to the OECD Guideline for Testing of Chemicals No 402/ Method B.3 as well as Principles of Good Laboratory Practice (GLP - OECD, 1997). The test material was given to 10 rats (5 males and 5 females) to shaved dorsal skin in single dose of 2000 mg/kg b.w. for 24 hours. During 14-day observation period no changes on skin or in behavior were stated in test animals. All animals survived 14- day experiment period. All animals which were euthanized after 14-day observation period were dissected and studied macroscopically. Macroscopic examination showed no pathological changes in test animals. Taking into account the obtained results one may state that median dermal acute dose (LD50) for Chelate with name: Fe (III) IDHA is higher than 2000 mg/kg b.w.

Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
from 2013-10-01 to 2013-10-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well documented 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 (CaNa2IDHA). The only difference between the target and the source substance is presence of calcium (Ca) cation instead Mn2+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: SOP/T/21: „Acute dermal toxicity study”
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Bureau of Chemical Substances
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: husbandry of laboratory animals of the Experimental Medicine Centre at the Medical University in Białystok kept behind the breeding barrier (number in the register of units entitled to the husbandry of laboratory animals: 0043).
- Age at study initiation: 8 weeks old
- Weight at study initiation: 282.8 g (males) and 211.4 g (females)
- Fasting period before study: none
- Housing: in plastic cages covered with wi re bar lids. The dimensions of the cages were 58 x 37 x 21 cm (length x width x height). After the application of the test item, each animal was housed individually. After the removal of the test item from the animals’ skin, there were five rats per cage. Each sex was kept separately. UV-sterilized wood shavings were used as bedding. Each cage was equipped with a label containing the study code, the dose, the dates of the commencement and the expected termination of the experiment, and the animals’ sex and numbers
- Diet (e.g. ad libitum): ad libitum to “Murigran” standard granulated fodder produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23 °C;
- Humidity (%): 35 – 58 %
- Air changes (per hr): about 16 times/hour
- Photoperiod (hrs dark / hrs light): 12 / 12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: ca. 41 cm² (males) ca. 31 cm² (females)
- Type of wrap if used: gauze patches were covered with PCV foil and elastic bandage was used to make circular protecting band

REMOVAL OF TEST SUBSTANCE
- Washing (if done): water
- Time after start of exposure: 24 hours after application of chemical and immediately after removal of the gauze patch

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
- Constant volume or concentration used:no
- For solids, paste formed: no (The test item was ground, applied to gauze patches, and moistened with a few drops of water. Then, the patches were laid on the prepared skin.)

VEHICLE
- Amount(s) applied (volume or weight with unit): a few drops of water were applied to the ground test item, which was applied to gauze patches
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: General and detailed clinical observations of all animals were performed daily during the entire experiment. Body weights of the animals were determined on days 0 (di rectly before the application of the test item), 7, and 14. After the 14-day observation period, the animals were euthanized, dissected, and subjected to detailed gross examinations.
- Other examinations performed: clinical signs, body weight, gross necropsy
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived the experiment.
Clinical signs:
other: no general signs of toxicity were stated in the animals. No pathological skin changes in the site of the test item application were noticed in all males and three females (no. 2, 4, and 5). Skin dryness was stated in two females (no.1 and 3).Moreover, sca
Gross pathology:
Gross examinations did not reveal any pathological changes in the examined animals.
Other findings:
no other findings reported

Following single application of the test item, the animals did not exhibit any general clinical signs. No pathological skin changes in the site of the test item application were noticed in all males and three females (no. 2, 4, and 5). Skin dryness was stated in two females (no. 1 and 3). Moreover, scabs were stated in one female (no. 3). All animals survived the experiment. During the 14-day experiment, body weight gain was stated in all animals. Gross examinations did not reveal any pathological changes in the examined animals.

Table 1: Summary of results

Mn (II) IDHA: acute dermal toxicity study on rats
Dose of test item(mg/kg b.w.) 2000
Sex males females
Mortality 0/5 0/5
Clinical signs no changes no changes were stated (no 2, 4, and 5)
 skin dryness was stated (no 1 and 3)
 scabs were stated (no. 3)
 

Clinical signs

Following single application of the test item, the animals did not exhibit any general clinical signs. No pathological skin changes in the site of the test item application were noticed in all males and three females (no. 2, 4, and 5). Skin dryness was stated in two females (no. 1 and 3) between the 2nd and the 3rd day after the application. Moreover, scabs were stated in one female (no. 3) between the 2nd and the 3rd day after the application. All animals survived the experiment. An overall list of the results of the clinical observations is presented in Table 2.

Table 2 - Clinical signs - overall list
Mn (II) IDHA: acute dermal toxicity study on rats
Dose (mg/kg b.w.) Sex Day after application Number of living animals Rat number
1 2 3 4 5
2000 males 0 5 NC NC NC NC NC
1 5 NC NC NC NC NC
2 5 NC NC NC NC NC
3 5 NC NC NC NC NC
4 5 NC NC NC NC NC
5 5 NC NC NC NC NC
6 5 NC NC NC NC NC
7 5 NC NC NC NC NC
8 5 NC NC NC NC NC
9 5 NC NC NC NC NC
10 5 NC NC NC NC NC
11 5 NC NC NC NC NC
12 5 NC NC NC NC NC
13 5 NC NC NC NC NC
14 5 NC NC NC NC NC
females 0 5 NC NC NC NC NC
1 5 NC NC NC NC NC
2 5 SIGNS NC SIGNS NC NC
3 5 SIGNS NC SIGNS NC NC
4 5 NC NC NC NC NC
5 5 NC NC NC NC NC
6 5 NC NC NC NC NC
7 5 NC NC NC NC NC
8 5 NC NC NC NC NC
9 5 NC NC NC NC NC
10 5 NC NC NC NC NC
11 5 NC NC NC NC NC
12 5 NC NC NC NC NC
13 5 NC NC NC NC NC
14 5 NC NC NC NC NC
NC - no changes
SIGNS - clinical signs

Body weights of the animals

During the 14-day experiment, body weight gain was stated in all animals. The individual results of body weight measurements are presented in Table 3

Table 3- Bodyweight of animals (g)-overall list
Mn(II)IDHA:acute dermal toxicity study on rats
Dose(mg/kgb.w.) Sex Rat No Day of experiment/Body weight(g) Body weight gain(g)(0-14)
0 7 14
2000 males 1 298 330 362 64
2 285 305 326 41
3 300 325 361 61
4 243 262 280 37
5 288 301 322 34
females 1 203 220 230 27
2 215 229 245 30
3 208 223 231 23
4 211 223 233 22
5 220 237 252 32

Gross examinations

The gross examinations did not reveal any pathological changes in the examined animals.

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 the dermal toxicity potential of Mn (II) IDHA in rats (Kropidlo, A., 2013). Following single application of the test item, the animals did not exhibit any general clinical signs. No pathological skin changes on the site of the test item application were noticed in all males and three females (no. 2, 4, and 5). Skin dryness was stated in two females (no. 1 and 3). Moreover, scabs were stated in one female (no. 3). All animals survived the experiment. During the 14-day experiment, body weight gain was stated in all animals. Gross examinations did not reveal any pathological changes in the examined animals. 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.

Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2008
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 (CaNa2IDHA). The only difference between the target and the source substance is presence of calcium (Ca) cation instead Zn2+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: wg. Wytycznej OECD nr 404 / Metody B.4.
Deviations:
yes
Remarks:
: W trakcie badania wilgotność względna powietrza kilkakrotnie przekroczyła wartość 70 %. Nie miało to wpływu na przebieg i wyniki badania. Nie stwierdzono innych odchyleń od wytycznej / metody.
GLP compliance:
yes (incl. QA statement)
Remarks:
G-024
Test type:
standard acute method
Species:
rabbit
Strain:
New Zealand White
Sex:
male
Details on test animals or test system and environmental conditions:

Zwierzęta.

W doświadczeniu użyto trzech królików białych rasy nowozelandzkiej pochodzących z Instytutu Zootechniki w Balicach. Króliki przeszły minimum 5-dniowy okres kwarantanny, w czasie którego były pod stałą obserwacją [SPR/T/6]. W dniu przyjęcia zwierząt do kwarantanny wykonano ogólne badanie lekarsko-weterynaryjne, a przed wprowadzeniem do doświadczenia u zwierząt wykonano szczegółowe badanie lekarsko-weterynaryjne [SPR/T/46]. Do doświadczenia wprowadzono zwierzęta nie wykazujące żadnych objawów klinicznych. Wszystkie zwierzęta były indywidualnie oznaczone [SPR/T/7]. W doświadczeniu użyto trzech samców w wieku: królik nr 1 – 9 miesięcy, królik nr 2 – 7 miesięcy i królik nr 3 – 11 miesięcy.

Warunki przetrzymywania zwierząt.

W okresie kwarantanny i doświadczenia zwierzęta przebywały w klimatyzowanym
pomieszczeniu o następujących parametrach:
- temperatura powietrza 20 – 22 °C
- wilgotność względna powietrza 50 – 90 %
- oświetlenie sztuczne, jarzeniowe; cykl oświetlenia: 12 godzin jasno - 12 godzin ciemno [SPR/T/9]. Zwierzęta przetrzymywano pojedynczo w metalowych klatkach, o wymiarach (długość x szerokość x wysokość): 60×35×40 cm. Każda klatka wyposażona była w wywieszkę zawierającą: numer protokołu badania, datę założenia i zakończenia doświadczenia, płeć i numer zwierzęcia [SPR/T/22].

Pasza i woda.

Zwierzętom podawano bez ograniczeń granulowaną standardową paszę laboratoryjną „LSK”, produkowaną przez Wytwórnię Koncentratów i Mieszanek Paszowych AGROPOL z Motycza oraz wodę wodociągową [SPR/T/15].
Type of coverage:
other: na płatki gazy
Vehicle:
other: Badany materiał, po roztarciu na proszek, naniesiono w ilości 0,5 g na kilkuwarstwowy płatek gazy o wymiarach 2,5 × 2,5 cm, zwilżono kilkoma kroplami wody.
Details on dermal exposure:

Badany materiał, po roztarciu na proszek, naniesiono w ilości 0,5 g na
kilkuwarstwowy płatek gazy o wymiarach 2,5 × 2,5 cm, zwilżono kilkoma kroplami wody.
Następnie płatek gazy nałożono na skórę jednego królika (królik nr 1). Narażana
powierzchnia skóry królika wynosiła ok. 6 cm2 Gazę osłonięto folią PCW i przytwierdzono do skóry przylepcem. Tułów królika owinięto warstwą ligniny oraz zabezpieczono elastyczną opaską i przylepcem. Po 4-godzinnym okresie narażania, przylepiec i płatek gazy zdjęto, a pozostałość badanego materiału usunięto ze skóry przy pomocy wody. Po ocenie narażanej skóry, w celu potwierdzenia wyników badania na jednym zwierzęciu, badany materiał nałożono na skórę kolejnych dwóch królików (królik nr 2 i nr 3) na okres 4 godzin. Sposób postępowania był taki sam, jak przy nakładaniu badanego materiału na skórę królika nr 1 [SPR/T/22].
Duration of exposure:
4 godziny
Doses:
0,5 g
No. of animals per sex per dose:
3 króliki - samce - po 0,5 g
Control animals:
yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Nie stwierdzono w czasie 14 dniowego testu.
Clinical signs:
other: W trakcie odczytu po 1 godzinie od zakończenia narażania, na skórze w miejscu nałożenia badanego materiału, u królika nr 2 stwierdzono bardzo słaby (ledwo dostrzegalny) rumień. U pozostałych królików zmian patologicznych na skórze ni
Gross pathology:
W trakcie badań makroskopowych u zwierząt nie stwierdzono zmian
patologicznych.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Zn (II) IDHA nie drażni skóry królików. Criteria used for interpretation of results: OECD GHS
Executive summary:

Na podstawie przeprowadzonego badania i według Załącznika do Rozporządzenia Ministra Zdrowia z dnia 2 września 2003 r. w sprawie kryteriów i sposobu klasyfikacji substancji i preparatów chemicznych (Dz.U. Nr 171 poz. 1666) można stwierdzić, że Zn (II) IDHA nie drażni skóry królików.

Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
2008
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 (CaNa2IDHA). The only difference between the target and the source substance is presence of calcium (Ca) cation instead Zn2+ cations. As calcium is an essential macro element required by all forms of life, is considered not to influence the toxicological activity.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
: W trakcie badania wilgotność względna powietrza kilkakrotnie przekroczyła wartość 70 %. Nie miało to wpływu na przebieg i wyniki badania. Nie stwierdzono innych odchyleń od wytycznej / metody.
GLP compliance:
yes (incl. QA statement)
Remarks:
G-024
Test type:
standard acute method
Species:
rat
Strain:
other:
Sex:
male/female
Details on test animals or test system 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.
Szczury przeszły minimum 5-dniową kwarantannę, w czasie której były
codziennie obserwowane [SPR/T/6]. W dniu przyjęcia zwierząt do kwarantanny
wykonano ogólne badanie lekarsko-weterynaryjne, a przed wprowadzeniem do
doświadczenia u zwierząt wykonano szczegółowe badanie lekarsko-weterynaryjne
[SPR/T/46]. Do doświadczenia wprowadzono zwierzęta nie wykazujące Żadnych
objawów klinicznych.

Wszystkie zwierzęta były indywidualnie oznaczone [SPR/T/7].

W doświadczeniu użyto pięciu 11-tygodniowych samców o średniej masie ciała
334 g i pięciu 10-tygodniowych samic o średniej masie ciała 225 g.


Warunki przetrzymywania zwierząt.

W okresie kwarantanny i doświadczenia zwierzęta przebywały w
klimatyzowanych pomieszczeniach o następujących parametrach:
– temperatura powietrza 21 – 23 °C
– wilgotność względna powietrza 35 – 80 %
– oświetlenie sztuczne, jarzeniowe; cykl oświetlenia: 12 godzin jasno - 12 godzin ciemno
[SPR/T/9].
Zwierzęta przetrzymywano w plastikowych klatkach z pokrywą z metalowych
prętów, o wymiarach (długość × szerokość × wysokość): 58×37×21 cm. Po naniesieniu
badanego materiału na skórę zwierząt, każde zwierzę przetrzymywano pojedynczo w
klatce. Po usunięciu badanego materiału ze skóry zwierząt, w kolejnych dniach
doświadczenia, zwierzęta przetrzymywano po 5 w jednej klatce, każdą płeć oddzielnie.
Jako ściółki Używano odpylonych wiórów drzewnych, sterylizowanych
promieniami UV [SPR/T/16, SPR/T/48]. Każda klatka była wyposażona w wywieszkę zawierającą nazwę badanego materiału, kod badania, stosowaną dawkę, datę założenia
i planowanej likwidacji doświadczenia, płeć i numery zwierząt [SPR/T/21].


Pasza i woda.

Zwierzętom podawano bez ograniczeń granulowaną standardową paszę
laboratoryjną „Murigran”, produkowaną przez Wytwórnię Koncentratów i Mieszanek
Paszowych AGROPOL z Motycza oraz wodę wodociągową [SPR/T/15].
Type of coverage:
other: na płatki gazy
Vehicle:
other: Badany materiał naniesiono na płatki gazy, zwilżono kilkoma kroplami wody
Details on dermal exposure:
Badany materiał roztarto na proszek i nałożono jednorazowo 10 szczurom (5
Samcom i 5 samicom) na skórę grzbietu w dawce 2000 mg/kg m.c. Powierzchnia skóry,
Na którą nakładano badany materiał wynosiła ok. 6 cm2
- 10% powierzchni ciała. Badany materiał naniesiono na płatki gazy, zwilżono kilkoma kroplami wody i następnie nałożono na przygotowaną skórę. Płatki gazy nakryto folią PCW. Następnie z opaski elastycznej i przylepca zrobiono okrężną opaskę zabezpieczającą. Po 24 godzinach opaskę i płatki gazy zdjęto, a pozostałość po badanym materiale usunięto ze skóry przy pomocy wody [SPR/T/21].
Duration of exposure:
24 godziny
Doses:

Badany materiał roztarto na proszek i nałożono jednorazowo 10 szczurom (5
samcom i 5 samicom) na skórę grzbietu w dawce 2000 mg/kg m.c. Powierzchnia skóry,
na którą nakładano badany materiał wynosiła ok. 6 cm2
- 10% powierzchni ciała. Badany
materiał naniesiono na płatki gazy, zwilżono kilkoma kroplami wody i następnie
nałożono na przygotowaną skórę. Płatki gazy nakryto folią PCW. Następnie z opaski
elastycznej i przylepca zrobiono okrężną opaskę zabezpieczającą. Po 24 godzinach
opaskę i płatki gazy zdjęto, a pozostałość po badanym materiale usunięto ze skóry przy
pomocy wody [SPR/T/21].
No. of animals per sex per dose:
5 samców; 5 samic, dawka jednorazowa 2000 mg/kg masy ciała
Control animals:
yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Nie stwierdzono w czasie 14 dniowego testu.
Clinical signs:
other: W trakcie 14-dniowego okresu doświadczenia, u badanych samców nie obserwowano zmian klinicznych na skórze w miejscu nałożenia badanego materiału. Od drugiego do trzeciego dnia obserwacji na narażanej skórze samicy nr 1, nr 3, nr 4 i nr 5 st
Gross pathology:
W trakcie badań makroskopowych u zwierząt nie stwierdzono zmian
patologicznych.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Executive summary:

Na podstawie przeprowadzonego badania, moŜna stwierdzić, że medialna dawka śmiertelna skórna (LD50) dla Zn (II) IDHA jest większa od 2000 mg/kg m.c.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
version of 22th March 1996.
GLP compliance:
yes
Test type:
other: Acute Toxic Class Method

Test material

Constituent 1
Chemical structure
Reference substance name:
tetrasodium;2-(1,2-dicarboxylatoethylamino)butanedioate
Cas Number:
144538-83-0
Molecular formula:
C8H7NNa4O
IUPAC Name:
tetrasodium;2-(1,2-dicarboxylatoethylamino)butanedioate
Test material form:
solid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
The acute toxicity experirnent was carried out with young-adult, SPF-bred Wistar rats (strain Hsd Cpb:WU, bred by Harlan Wmkelmann, Borchen, Germany).
At time of receipt male animals were 6 - 7 and females 8 - 9 weeks old. At the start of the study the mean initial weight ofmales was 326 g and offemales 242 g. The mean deviation in animal weights was less than 20 %. Females were nulliparous and not pregnant. The condition of the animals' health was checked before the start of experirnent. Only healthy animals, 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.

Houslng Conditions
The rats were housed individually, under conventional conditions, in Makrolon® Type-II cages on low-dust wood granules (supplier: Ssniff, Soest/Westphalia), at a room temperature of 22 ± 2° C, with a 12-hour light/dark cycle (artificial light from 6 a.m. to 6 p.m), a relative humidity of about 55 ± 5% and approximately 15 to 20 air exchanges per hour.
All animals of this experirnent were kept in one animal room. For reasons of capacity, animals from other toxicological experiments were temporarily housed in the same room. Confusion of the anima1 numbers or influence by one another were avoided by appropriate organisation of operations.

Cleanlng. Disinfectlon, Pest Control
The animal room was disinfected once a week (Tegol®2000). Continuous pest control was carried out in which 2 to 3 sticky traps of Killgerm Co., were placed in the animal room. The effect of the pesticide-free sticky traps is based on pheromone lures.


Nutrltion
The animals received fixed-formula standard diet Altromin® 1324 pellets (producer: 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 300 ml (as described by SPIEGEL A and OONNERT, R. Zschr. Versuchstierkunde1, 38 (1961)).

The nutritional composition and the contaminant content of the standard diet were routinely spot-checked and analysed. The tap water was of drinking quality (in accordance with the Drinking Water Statute of Dec. 05, 1990, Federat Law Gazette No. 66, issued on Dec. 12, 1990, pages 2612-2629). The results of the feed and water analyses have been filed. Available data provided no evidence of any influence on the study objective.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Remarks:
tap water
Details on dermal exposure:
The skin of the experimental animals on the back and the flanks was shaved approximately 24 hours before the start of experiment. During shaving, care was taken not to abrade skin, since this can lead to a change of permeability.

The substance was dosed according to dose and body weight; it was then applied as paste with tape water to the prepared skin area of approx. 100/o of the body surface and fixed with non­ irritant skin plaster (Fermoflexband, Beiersdorf AG).

The dressing was taken off after approximately 24 hours and possible substance residues on the skin were removed with luke-warm water.
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3 male and 3 female
Details on study design:
The animals were inspected several times on the day of administration (day I), 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 I), after one week and at the end of the 14-day observation period. The application volume for each individual animal was based on its body weight just before application.

Gross pathological examinations were done on all animals sacrificed under deep diethyl ether anesthesia at the end of study. Necropsy records were prepared for all animals.

Results and discussion

Preliminary study:
Yes, due to the pH value of> 11 only one male rat received the intended dosage. Because there was no indication for a pronounced increase of lethality or strong local effects (skin corrosivity) all other animals were treated according to the method choosen..
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
No anima1 died during the 14-day observation period.
Clinical signs:
other: No signs of systemic poisoning were observed after single application of a target dose of 2000 mg/kg body weight. As local skin irritations were observed at the area of the application site: reddenig (day 2) and encrustation from day 2 up to day 5 after
Gross pathology:
None of the animals sacrificed at the end of the 14-day observation period showed any noticeable gross pathological findings.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the present investigations, which showed no lethality with the target dose of 2000 mg/kg bw, the test substance is regarded to be relatively non-toxic after acute dermal exposure and not to be classified according to Regulation 1272/2008 (with amendments). Taking into account that not lethality and no signs of systemie toxicity were noted, the application of 1893 mg/kg bw instead of 2000 mg/kg bw as target dose does not limit the assessment of this study.
Executive summary:

Acute toxicological investigations of male and female Wistar rats were conducted after dermal exposure to lIDS, sodium salt.

The LD50 for male and female rats was greater than 2000 mg/kg (target dose) and was not exactly determined.

No signs of systemic poisoning were observed in male and female rats.

 The following signs were observed as signs of local skin irritations: reddenig and encrustation at the treatment are aas well as high leg gedgait

and vocalization in female rats.

Body weight development of male rats was not affected. Slightly reduced body weights in females in week 2.

No deaths occurred.

None of the animals sacrificed at the end of study showed any noticeable gross pathological findings.