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Description of key information

In the key skin irritation study with the test item Fe(Na)HBED the average scores for erythema (1.3, 0.3 and 2.0) and for oedema (0.3, 1.7 and 0.0) calculated for each of the three animals for three consecutive days (at 24, 48 and 72 hours after exposure, respectively) do not exceed cut-off-values defined in the CLP. 
In the key eye irritation study conducted with Fe(Na)HBED the mean values of the scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. The values did not exceed the trigger values leading to classification and labelling according to CLP. The test substance is not irritating to skin and 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:
2008-07-15 to 2008-10-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
changes in air humidity
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
changes in air humidity
Principles of method if other than guideline:
Few times during experiment the relative air humidity was above 70%. It did not influence study course and results.
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Reproductive Farm of Rabbits, Balice
- Age at study initiation: Two 9-month-old males (rabbit No 1 and No 2) and one 11-month-old male (rabbit no 3)
- Weight at study initiation: rabbit No 1 weighed 3.8 kg, rabbit No 2: 3.7 kg and rabbit No 3: 3.7 kg
- Housing: The animals were kept individually in air-conditioned room in metal cages with dimensions (length x width x height): 60 x 35 x 40 cm.
- Diet (e.g. ad libitum): ad libitum. standard granulated "LSK" 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): 20-24
- Humidity (%): 45-90
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: The test item was applied to rabbits’ skin on: 2008-07-15 (rabbit No 1), 2008-07-22. (rabbit No 2 and No 3). The study was finished on: 2008-07-29 (rabbit No 1) and 2008-08-12 (rabbit No 2 and No 3).
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Remarks:
The test item was moistened with few drops of water, and then laid on the prepared skin
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g (on multilayered gauze patch)

VEHICLE
- Amount(s) applied (volume or weight with unit): The test item was moistened with few drops of water, and then laid on prepared skin of one rabbit
Duration of treatment / exposure:
4 hours
Observation period:
Observations of skin were performed after 1, 24, 48 and 72 hours as well as 7, 14 and 21 days after the end of exposure.
Number of animals:
Two 9-month-old males (rabbit No 1 and No 2) and one 11-month-old male (rabbit no 3) were used in experiment.
Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: 6%
- 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): yes
- Time after start of exposure: 4 hours

SCORING SYSTEM: Skin condition was evaluated according to the scoring system of OECD Guideline No 404 / Method B.4.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean value at 24, 48 and 72 hours
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean value at 24, 48 and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 21 day
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean value at 24, 48 and 72 hours
Score:
1.7
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean at 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean value at 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean value at 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no effect
Irritant / corrosive response data:
During reading after 1 hour since the end of exposure, well defined erythema was stated on treated area of skin of all rabbits. No oedema of skin was stated in rabbits.
During reading after 24 hours since the end of exposure, well defined erythema was still observed on treated area of skin of all rabbits. Barely perceptible oedema of skin was stated in rabbit No 1 and No 2.
During reading after 48 hours since the end of exposure, barely perceptible erythema was stated in rabbit No 1 whereas well defined erythema was observed in rabbit No 2 and No 3. No oedema of treated skin was stated.
During readings after 72 hours and 7 days since the end of exposure, barely perceptible erythema of skin was stated in rabbits No 1 and No 3, well defined erythema - in rabbit No 2.
During reading after 14 days since the end of exposure, no pathological changes were stated on treated area of skin of rabbit No 1. Barely perceptible
erythema of skin was stated in rabbits No 2 and No 3.
During reading after 21 days since the end of exposure, no pathological changes were stated on treated area of skin of rabbits.
Other effects:
The animals gained in the body weight: at the end of experiment rabbit No 1 weighed 4.0 kg, rabbit No 2 – 3.8 kg and rabbit No 3 – 3.6 kg.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance is not irritating to skin since mean values for erythema and oedema calculated for each animal for three consecutive days (24, 48 and 72 hours) did not exceed the trigger values leading to classification and labelling according to CLP.
Executive summary:

Acute skin irritation/corrosion study with Fe (III) HBED (CAS 1061328 -86 -6) according to the OECD TG 404 was conducted in 3 White New Zealand rabbits (Gruszka, 2008). The powdered test item in amount of 0.5 g was applied as a single dose to the shaved skin of the rabbits and covered with an appropriate band. The test substance was held 4 hours in contact with the skin by semi-occlusive dressing. Skin condition was evaluated after 1, 24, 48, and 72 hours as well as after 7, 14 and 21 days after the end of exposure. The mean values of the scores for erythema and oedema were calculated for each animal. Erythema and oedema were observed on skin of rabbits. Well-defined erythema was observed in all animals at 1-hour and at 24-hour readings. Erythema became barely perceptible on day 7 in two animals and on day 14 in third animal and was fully reversible within 21 days of observation period. Very slight oedema was noted only in two animals at 24-hour reading and disappeared completely after 48 hours after exposure. No pathological changes were noted on treated skin of animals. Mean scores over 24, 48 and 72 hours for each animal were 1.3, 0.3 and 2.0 for erythema and 0.3, 1.7 and 0.0 for oedema. These values do not exceed cut-off-values defined in the Guidance on the Application of Regulation (EC) No. 1272/2008, and do not trigger classification and labeling as skin irritant.

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:
2008-07-15 to 2008-10-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
changes in air humidity
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
changes in air humidity
Principles of method if other than guideline:
Few times during the entire experiment the relative air humidity was above 70%. It did not influence study course and results.
No other deviations from guideline / method were stated during the entire experiment.
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Reproductive Farm of Rabbits, Balice
- Age at study initiation: two 5-month-old (rabbit No 1 and No 3) and one 5.5-month-old (rabbit No 2).
- Weight at study initiation:the rabbit No 1 weighed 2.8 kg, rabbit No 2 – 3.0 kg and rabbit No 3 – 2.3 kg
- Housing: The animals were kept individually in metal cages with dimensions (length x width x height): 60 x 35 x 40 cm.
- Diet (e.g. ad libitum): ad libitum (standard granulated fodder "LSK" 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): 20-22
- Humidity (%): 45-90
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2008-08-18 (rabbit No 1) and 2008-09-16 (rabbit No 2 and No 3) To: 2008-09-01 (rabbit No 1) and 2008-09-19 (rabbit No 2 and No 3).
Vehicle:
unchanged (no vehicle)
Remarks:
test material was dissolved in water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL (0.042 g)
Duration of treatment / exposure:
single exposure
Observation period (in vivo):
Condition of cornea, iris and conjunctiva was evaluated after 1, 24, 48 and 72 hours as well as 7 and 14 days since administration of test item.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no data

SCORING SYSTEM: The evaluation was performed according to the scoring system of OECD Guideline No 405 / Method B.5. (Annex 7).
Results of study were evaluated according to the Annex to Decree of Ministry of Health of September 2nd, 2003 (Acts Daily No 171, Position 1666).

TOOL USED TO ASSESS SCORE: no data
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
of scores for 3 animals
Time point:
other: at 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no effect
Irritation parameter:
iris score
Basis:
mean
Remarks:
of scores for 3 animals
Time point:
other: at 24, 48 and 72 hours
Score:
0
Max. score:
2
Remarks on result:
other: no effect
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean at 24, 48 and 72 hours
Score:
1.3
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean at 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: mean at 24, 48 and 72 hours
Score:
0.7
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean at 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean at 24, 48 and 72 hours
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean at 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no effect
Irritant / corrosive response data:
After administration of test item, pathological changes in iris and conjunctiva of rabbits’ eyes were stated. No pathological changes were stated in cornea. During reading after 1 hour since administration of test item, congestion of iris was stated in eyes of three rabbits, reaction of pupil to light was normal. Diffuse crimson redness (individual vessels hardly visible) was stated in conjunctivas of eyes of three rabbits. Furthermore, congestion of nictating membrane and circumcorneal injection were observed in rabbits. Swelling of conjunctiva, swelling of nictating membrane and excretion on lids, lids’ hair and considerable part of eye region were also stated in rabbits.
During reading after 24 hours since administration of test item, no pathological changes in irises of rabbits were stated. Diffuse crimson redness was still observed in conjunctivas of rabbit No 1 and No 2; congestion of some blood vessels was stated in conjunctiva of rabbit No 3. Congestion of nictating membrane was observed in three rabbits, circumcorneal injection was stated in rabbit No 2. Swelling of nictating membrane was observed in rabbits No 1 and No 2, slight swelling of conjunctiva was stated in rabbit No 1. No swelling of conjunctiva was stated in rabbit No 3. Excretion (on lids and lids’ hair) was stated only in rabbit No 2.
During reading after 48 hours since administration of test item, the following changes in conjunctivas were stated: erythema in form of congestion of some blood vessels and congestion of nictating membrane – in three rabbits; circumcorneal injection – in rabbit No 1. Slight swelling of conjunctiva and swelling of nictating membrane were stated in rabbit No 1. No swelling of conjunctiva and no excretion
were stated in rabbit No 2.
During reading after 72 hours since administration of test item, changes in conjunctiva were stated only in rabbit No 1. These were: erythema in form of congestion of some blood vessels, congestion of nictating membrane, circumcorneal injection and swelling of nictating membrane. No pathological changes were stated in rabbit No 2 and No 3.
During reading after 7 days since administration of test item, the following changes were observed in conjunctiva of rabbit No 1: erythema in form of congestion of some blood vessels, congestion of nictating membrane and circumcorneal injection. No swelling of conjunctiva was stated.
During reading after 14 days since administration of test item, no pathological changes were stated in eye of rabbit No 1.
Other effects:
Body weight of animals
At the start of experiment the rabbit No 1 weighed 2.8 kg, rabbit No 2 – 3.0 kg and rabbit No 3 – 2.3 kg. At the end of experiment rabbit No 1 weighed 2.9 kg, rabbit No 2 – 3.1 kg and rabbit No 3 – 2.8 kg.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. The mean scores for 2 out of 3 animals do not exceed trigger values for classification and labelling defined in the CLP. The test substance Fe (III) HBED is considered to be not irritating to eyes.
Executive summary:

Acute eye irritation/corrosion study with Fe (III) HBED according to the OECD TG 405 was conducted in New Zealand White rabbits (Gruszka, 2008). The test item in amount of 0.042 g (volume of 0.1 mL) was administered to conjunctival sack of one eye of each rabbit. The second eye served as control. Condition of cornea, iris and conjunctiva was evaluated after 1, 24, 48 and 72 hours as well as 7 and 14 days since administration of test item. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. The interpretation of results was carried out according to the classification criteria laid down in the Regulation (EC) No. 1272/2008 (CLP). After administration of test item, changes in iris and conjunctiva of rabbits’ eyes were observed during readings. No pathological changes were stated in cornea of all animals at all reading time points. At 1-hour reading, congestion of iris was observed in eyes of three rabbits, but reaction of pupil to light was normal. No lesions in iris of all animals were observed at further evaluation time points. The highest conjunctivae score of 2 (diffuse crimson redness (individual vessels were hardly visible)) was noted in three animals at 1 hour reading and was still present in two animals after 24-hour reading. Conjunctival reaction in form of congestion of some blood vessels and congestion of nictating membrane were present in three rabbits at 48-hour reading. These effects were fully reversible within 72 hours after treatment in two rabbits and on the day 14 in the third rabbit. Furthermore, congestion of nictating membrane, circumcorneal injection, swelling of conjunctiva, swelling of nictating membrane and excretion on lids, lids’ hair and considerable part of eye region were observed in all rabbits (score of 1 at 1-hour and at 24-hour reading). Circumcorneal injection and slight swelling of conjunctiva and swelling of nictating membrane remained until 72-hour reading in one rabbit, while no effects were seen anymore in another rabbits.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. The mean scores for 2 out of 3 animals do not exceed trigger values for classification and labelling defined in the CLP. The test substance Fe (III) HBED is considered to be not irritating to eyes.

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

Additional information

Skin irritation

Acute skin irritation/corrosion study with Fe(Na)HBED (CAS 1061328 -86 -6) according to the OECD TG 404 was conducted with 3 White New Zealand rabbits (Gruszka, 2008). The powdered test item in amount of 0.5 g was applied as a single dose to the shaved skin of the rabbits and covered with an appropriate band. The test substance was held 4 hours in contact with the skin by semi-occlusive dressing. Skin condition was evaluated after 1, 24, 48, and 72 hours as well as after 7, 14 and 21 days after the end of exposure.The mean values of the scores for erythema and oedema were calculated for each animal.Erythema and oedema were observed on skin of rabbits.Well-defined erythema was observed in all animals at 1-hour and at 24-hour readings. Erythema became barely perceptible on day 7 in two animals and on day 14 in third animal and was fully reversible within 21 days of observation period. Very slight oedema was noted only in two animals at 24-hour reading and disappeared completely after 48 hours after exposure. No pathological changes were noted on treated skin of animals. Mean scores over 24, 48 and 72 hours for each animal were 1.3, 0.3 and 2.0 for erythema and 0.3, 1.7 and 0.0 for oedema. These values do not exceed cut-off-values defined in the Guidance on the Application of Regulation (EC) No. 1272/2008, and do not trigger classification and labelling as skin irritant.

Eye irritation

Acute eye irritation/corrosion study with Fe(Na)HBED according to the OECD TG 405 was conducted in New Zealand White rabbits (Gruszka, 2008). The test item in amount of 0.042 g (volume of 0.1 mL) was administered to conjunctival sack of one eye of each rabbit. The second eye served as control. Condition of cornea, iris and conjunctiva was evaluated after 1, 24, 48 and 72 hours as well as 7 and 14 days since administration of test item.The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal. The interpretation of results was carried out according to the classification criteria laid down in the Regulation (EC) No. 1272/2008 (CLP).After administration of test item, changes in iris and conjunctiva of rabbits’ eyes were observed during readings.No pathological changes were stated in cornea of all animals at all reading time points. At 1-hour reading, congestion of iris was observed in eyes of three rabbits, but reaction of pupil to light was normal. No lesions in iris of all animals were observed at further evaluation time points. The highest conjunctivae score of 2 (diffuse crimson redness (individual vessels were hardly visible)) was noted in three animals at 1 hour reading and was still present in two animals after 24-hour reading. Conjunctival reaction in form of congestion of some blood vessels and congestion of nictating membrane were present in three rabbits at 48-hour reading. These effects were fully reversible within 72 hours after treatment in two rabbits and on the day 14 in the third rabbit. Furthermore, congestion of nictating membrane, circumcorneal injection, swelling of conjunctiva, swelling of nictating membrane and excretion on lids, lids’ hair and considerable part of eye region were observed in all rabbits (score of 1 at 1-hour and at 24-hour reading). Circumcorneal injection and slight swelling of conjunctiva and swelling of nictating membrane remained until 72-hour reading in one rabbit, while no effects were seen anymore in another rabbits.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 1.0 and 0.7 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity. The mean scores for 2 out of 3 animals do not exceed trigger values for classification and labelling defined in the CLP. The test substance Fe(Na)HBED is considered to be not irritating to eyes.


Justification for selection of skin irritation / corrosion endpoint:
Guideline and GLP key study

Justification for selection of eye irritation endpoint:
Guideline

Justification for classification or non-classification

Based on the results of the acute skin and eye irritation studies, Fe(Na)HBED is not subject to classification and labelling for irritation effects according to Directive 67/548/EEC and Regulation 1272/2008/EC.