Registration Dossier

Administrative data

Description of key information

- Skin irritation: OECD 404, 3 New Zealand White rabbits: barely perceptible erythema

in 1 animal after 1 hours, 1 animal after 24 h and in one animal after 72 hours. Conclusion: not irritating to the skin.
- Eye irritation: OECD 405, 3 New Zealand White rabbits: no corneal opacity and iritis findings; conjunctival congestion, during evaluation after 1, 24, 48 and 72 the test rabbits showed changes in form of erythema and oedema of eye conjunctiva. All changes reversibled after 72h or 7 days. No positive responders. Conclusion: not irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23.05 - 27.06.2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: well-documented GLP-Guideline Study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Three white rabbits of New Zealand strain coming from conventional Reproductive Farm of Rabbits, Balice were used in the test.
The rabbits were quarantined for at least 5 days and observed carefully during this time.
One 5.5-month-old male rabbit weighing 4,02 kg and two 6 and 5-month-old female rabbits weighing 2.99 kg and 3.11 kg were used in the study.

During quarantine and experiment the animals were kept in air-conditioned rooms with the following parameters:
- temperature: 18 - 22 °C;
- relative air humidity: 50 - 80%;
- artificial fluorescent lighting: 12 hours light / 12 hours darkness.
The animals were kept individually in metal cages with dimensions: 60 x 35 x 40 cm. Each cage was equipped with label containing information on study protocol number, start date of the experiment, sex and animal number.

The animals were given ad libitum standard granulated fodder "LSK" produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz and drinking tap water.
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g unchanged test material
Duration of treatment / exposure:
4 hours
Observation period:
Observations of skin were performed after 1, 24, 48 and 72 hours as well as 7 days since the end of exposure.
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: about 6 cm2.
- Type of wrap if used: The
gauze patches were covered with PCV foil and fixed with sticking plaster. The rabbit’s trunk was covered with lignin and elastic bandage was used to make circular protecting band.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 4 hours of exposure, the band and gauze patches were taken off and the residual test material was removed using water.
- Time after start of exposure: 4 h
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 72h
Score:
1
Max. score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 72 h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 72h
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 24h
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 72h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 72h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 72h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
During observation after 1 hour since the end of exposure, faint erythema (barely visible) was stated on treated skin of all three rabbits.
During observation after 24 hours since the end of exposure, faint erythema (barely visible) was stated on treated skin of rabbits No 1 and 2. No pathological changes on skin of rabbit No 3 were noticed.

During observation after 48 and 72 hours since the end of exposure faint erythema (barely visible) was observed on treated skin of rabbit No 1. Rabbit No 2 showed no pathological changes.
During observation after 7 days no pathological changes on treated skin of rabbit No 1 were stated.
Other effects:
At the start of the experiment rabbit No 1 weighed 4.02 kg, rabbit No 2 - 2.99 kg while rabbit No 3 - 3.11 kg. At the end of the experiment body weight of rabbits amounted: rabbit No 1 – 4.1 kg, rabbit No 2 – 3.11 kg and rabbit No 3 – 3.27 kg.

Chelate with name: Fe (III) IDHA, Point evaluation of acute skin irritation/corrosion study for rabbits

Rabbit No

Observation type

Evaluation after

Average after 24, 48 and 72 h

1 h

24h

48h

72 h

7 days

1

erythema

1

1

1

1

0

1

oedema

0

0

0

0

0

0

2

erythema

1

1

0

0

-

0.3

oedema

0

0

0

0

-

0

3

erythema

1

0

0

0

-

0

oedema

0

0

0

0

-

0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item Fe (III) IDHA does not irritate skin of rabbits.
Executive summary:

Acute skin irritation/corrosion study of Chelate with name: Fe (III) IDHA for rabbits was performed according to OECD Guideline for Testing of Chemicals No 404/Method B.4. as well as Principles of Good Laboratory Practice (GLP - OECD, 1997). The study was performed with white rabbits of New Zealand strain. The tested substance was administered in amount of 0.5 g as a single dose to shaved skin of three rabbits and covered with appropriate band. The exposure time was 4 hours. After 1, 24, 48, 72 hours and 7 days since the end of exposure skin condition was examined. During observations all test rabbits showed changes on skin in form of erythema.

Classification of the test material was performed according to Regulation 1272/2008. Taking into account the obtained results, one may state that Chelate with name: Fe (III) IDHA does not irritate skin of rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 of May till 27 of June 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: conventional Reproductive Farm of Rabbits, Balice
- Age at study initiation: 6-month-old
- Weight at study initiation: 3,60 kg
- Housing:
- Diet (e.g. ad libitum): standard granulated fodder "LSK" produced by Wytwórnia Koncentratów i Mieszanek Paszowych AGROPOL, Motycz
- Water (e.g. ad libitum): tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 – 22
- Humidity (%): 52 - 70% (few times above 70%);
- Photoperiod (hrs dark / hrs light): artificial fluorescent lighting: 12 hours light / 12 hours darkness

The animals were kept individually in metal cages with dimensions: 60 x 35 x 40 cm. Each cage was equipped with label containing information on study code, start date of the experiment, sex and animal numbers.

IN-LIFE DATES: The test material was administered to rabbits’ eyes on: 31.05.2007 (rabbit No 1) and 04.06.2007 (rabbits No 2 and 3). The experiment was terminated on 07.06.2007 (rabbit No 1 and 2) and 14.06.2007 (rabbit No 3).
Vehicle:
unchanged (no vehicle)
Controls:
other: The second eye was used as the control one.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g of unchanged test substance as a single
- Concentration (if solution): not applied

Duration of treatment / exposure:
single administration
Observation period (in vivo):
After 1, 24, 48,72 hours and 7 days since administration of the test material condition
of cornea, iris and conjunctiva was evaluated.
Number of animals or in vitro replicates:
3
Details on study design:
The test material in form of powder was administered in amount of 0,1 g as a single dose to conjunctival sack of one eye to one rabbit (rabbit No 1), by gentle distraction of lower eyelid. Then both eyelids were kept together for a moment to protect loosing of the test material. The second eye was used as the control one. Following evaluation of the treated eye, in order to confirm the obtained results, the test material was administered in the same way to rabbits No 2 and 3.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: classification on the basis of OECD Guideline No 405 / EU Method B.5
Cornea
Opacity: degree of density (readings should be taken from most dense area) *
- No ulceration or opacity: 0
- Scattered or diffuse areas of opacity (other than slight dulling of normal lustre), details of iris clearly visible: 1
- Easily discernible translucent area, details of iris slightly obscured: 2
- Nacrous area, no details of iris visible, size of pupil barely discernible: 3
- Opaque cornea, iris not discernible through the opacity: 4
Maximum possible: 4
* The area of corneal opacity should be noted
Iris:
- Normal: 0
- Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia or injection, iris reactive to light (a sluggish reaction is considered to be an effect): 1
- Hemorrhage, gross destruction, or no reaction to light: 2
Maximum possible: 2
Conjunctivae:
Redness (refers to palpebral and bulbar conjunctivae, excluding cornea and iris)
- Normal: 0
- Some blood vessels hyperaemic (injected): 1
- Diffuse, crimson colour, individual vessels not easily discernible: 2
- Diffuse beefy red: 3
Maximum possible: 3

Chemosis:
Swelling (refers to lids and/or nictating membranes)
- Normal: 0
- Some swelling above normal: 1
- Obvious swelling, with partial eversion of lids: 2
- Swelling, with lids about half closed: 3
- Swelling, with lids more than half closed: 4
Maximum posible: 4

TOOL USED TO ASSESS SCORE: not recorded
Irritation parameter:
conjunctivae score
Remarks:
erythema
Basis:
animal #1
Time point:
other: average after 24 - 72 h
Score:
1.7
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
oedema
Basis:
animal #1
Time point:
other: average after 24- 72h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
erythema
Basis:
animal #2
Time point:
other: average after 24-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 48h
Irritation parameter:
conjunctivae score
Remarks:
oedema
Basis:
animal #2
Time point:
other: average after 24-72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible within: 48h
Irritation parameter:
conjunctivae score
Remarks:
erythema
Basis:
animal #3
Time point:
other: average after 24-72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
oedema
Basis:
animal #3
Time point:
other: average after 24-72h
Score:
0.3
Max. score:
1
Reversibility:
fully reversible within: 48h
Irritant / corrosive response data:
During observations only changes in eye conjunctiva were stated. During evaluation after 1 hour since the test material administration, all rabbits showed erythema of eye conjunctiva – in form of diffuse crimson redness, congestion of third eyelid and circumcorneal injections. Rabbits No 1 and 3 showed slight
oedema while rabbit No 2 distinct oedema with partial eversion of eyelids. Additionally all rabbits showed oedema of third eyelid and excretion – on eyelids and
eyelids hair in rabbits no 1 and 2 and slight amount of excretion in rabbit No 3.
During evaluation after 24 hours since the administration, all rabbits showed congestion of third eyelid, circumcorneal injection and erythema of eye conjunctiva – in form of diffuse crimson redness in rabbits No 1 and 2 and in form of blood vessels hyperaemia (injection) in rabbit No 3. In all rabbits slight oedema of third eyelid was stated. Additionally all rabbits showed excretion – on eyelids and eyelids hair in rabbit No 1 and slight amount of excretion in rabbits No 2 and 3.
During observation after 48 hours since administration, all rabbits showed erythema – in form of diffuse crimson redness in rabbit No 1 and in form of blood vessels congestion (injection) in rabbits No 2 and 3. Additionally rabbit No 1 showed circumcorneal injection, oedema of third eyelid and excretion on eyelids and eyelids hair.
During evaluation after 72 hours since administration rabbits No 1 and 3 showed erythema in form of blood vessels congestion (injection) and congestion of third eyelid. Additionally rabbit No 1 showed circumcorneal injection, oedema of third eyelid and excretion on eyelids and eyelids hair. Rabbit No 2 showed no pathological changes.
During evaluation after 7 days since administration no pathological changes were stated in eyes of rabbits No 1 and 3.
Other effects:
At the start of the experiment the rabbits weighed: 3,73 kg (rabbit No 1), 3,56 kg (rabbit No 2) and 3,52 kg (rabbit No 3). At the end of the test body weight of rabbits amounted appropriately: 3,84 kg; 3,60 kg and 3,54 kg.

Chelate with name: Fe (III) IDHA - Point evaluation of acute eye irritation/corrosion study for rabbits

Rabbit No

Part of eye

Evaluation after

Average of evaluation after 24, 48 and 72 h

1h

24h

48h

72h

7 days

1

cornea

 

0

0

0

0

0

0

Iris

 

0

0

0

0

0

0

conjunctiva

erythema

2

2

2

1

0

 

oedema

1

1

1

1

0

 

2

cornea

 

0

0

0

0

-

0

Iris

 

0

0

0

0

-

0

conjunctiva

erythema

2

2

1

0

-

 

oedema

2

1

0

0

-

 

3

cornea

 

0

0

0

0

0

0

Iris

 

0

0

0

0

0

0

conjunctiva

erythema

2

1

1

1

0

 

oedema

1

1

0

0

0

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Fe (III) IDHA does not irritate eyes of the rabbits.
Executive summary:

Acute eye irritation/corrosion study of Chelate with name: Fe (III) IDHA for rabbits was performed according to OECD Guideline for Testing of Chemicals No 405/Method B.5. as well as Principles of Good Laboratory Practice (GLP - OECD,1997).

The study was performed with three white rabbits of New Zealand strain. The test material in form of powder was administered in amount of 0.1 g to conjunctival sack of one eye to each rabbit. After 1, 24, 48, 72 hours and 7 days since administration of

the test material, condition of cornea, iris and conjunctiva was evaluated. During evaluation after 1, 24, 48 and 72 the test rabbits showed changes in form of erythema and oedema of eye conjunctiva.

Classification of the test material was performed according to Regulation 1272/2008. Taking into account the obtained results, one may state that Chelate with name: Fe (III) IDHA does not irritate eyes of rabbits.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation

Acute skin irritation/corrosion study of Chelate with name: Fe (III) IDHA for rabbits was performed according to OECD Guideline for Testing of Chemicals No 404/Method B.4. as well as Principles of Good Laboratory Practice (GLP - OECD, 1997). The study was performed with white rabbits of New Zealand strain. The tested substance was administered in amount of 0.5 g as a single dose to shaved skin of three rabbits and covered with appropriate band. The exposure time was 4 hours. After 1, 24, 48, 72 hours and 7 days since the end of exposure skin condition was examined. During observations all test rabbits showed changes on skin in form of erythema.

Classification of the test material was performed according to Regulation 1272/2008. Taking into account the obtained results, one may state that Chelate with name: Fe (III) IDHA does not irritate skin of rabbits.

Eye irritation

Acute eye irritation/corrosion study of Chelate with name: Fe (III) IDHA for rabbits was performed according to OECD Guideline for Testing of Chemicals No 405/Method B.5. as well as Principles of Good Laboratory Practice (GLP - OECD,1997).

The study was performed with three white rabbits of New Zealand strain. The test material in form of powder was administered in amount of 0.1 g to conjunctival sack of one eye to each rabbit. After 1, 24, 48, 72 hours and 7 days since administration of

the test material, condition of cornea, iris and conjunctiva was evaluated. During evaluation after 1, 24, 48 and 72 the test rabbits showed changes in form of erythema and oedema of eye conjunctiva.

Classification of the test material was performed according to Regulation 1272/2008. Taking into account the obtained results, one may state that Chelate with name: Fe (III) IDHA does not irritate eyes of rabbits.


Justification for selection of skin irritation / corrosion endpoint:
only one study available

Justification for selection of eye irritation endpoint:
only one study available

Justification for classification or non-classification

Skin irritation

According to the classification criteria outlined in the section 3.2.2.2. (Guidance on the Application of CLP criteria, June, 2015), if a substance causes a mean value of ≥ 2.3 - ≤ 4.0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or inflammation persists to the end of the observation period in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling, or in some cases where there is pronounced variability of response amoung animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above, the classification as Skin Irritant (Category 2) is assigned. The average irritation scores from gradings at 24, 48 and 72 hours were 1.0 0.3, and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Based on these results, there were no positive responders. All scores were under the cut-off value (2.3) triggering classification and labelling .Therefore, Fe(III)IDHA does not meet the criteria for classification and labelling for skin irritation in accordance with European regulation (EC) No. 1272/2008.

Eye irritation

According to the classification criteria outlined in the section 3.3.2.2. (Guidance on the Application of CLP criteria, June, 2015), if a substance cause positive but reversible reactions such as corneal opacity (score≥1), iritis (score≥1), conjunctival redness (score≥2) or conjunctival oedema (chemosis) (score≥2) in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after application, the classification as Eye Irritant (Category 2) is assigned.

The average irritation scores from gradings at 24, 48, and 72 hours for corneal opacity and iritis were 0.0 for three animals. Conjunctivae (erythema) mean scores of 1.7, 1.0 and 1.0 were yielded for animal 1, 2 and 3, respectively. Further, conjunctivae (oedema) mean scores of 1.0, 0.3 and 0.3 are reported for the three tested animals, respectively. Based on these results, there were no positive responders regarding corneal opacity, iritis and conjunctivae (erythema and chemosis). All scores were under the cut-off values triggering classification and labelling. Therefore, the substance does not need to be classified and labelled as eye irritant according to Regulation (EC) No. 1272/2008.