Iron sinter

Endpoint summary

Description of key information

The endpoints skin and respiratory sensitisation are covered by read-across, the justification is given in the report attached to IUCLID section 13.2.

 

Skin sensitisation

An in vivo skin sensitisation study with triiron phosphide (Fe3P) according to OECD guideline 429 is available. Based on the information from this LLNA study it is concluded that the substance triiron phosphide does not show any skin sensitisation potential.

 

Respiratory sensitisation

Relevant information with respect to respiratory sensitisation may be available from case reports, epidemiological studies, medical surveillance and reporting schemes. Data from some animal studies may be indicative of the potential of a substance to cause respiratory sensitisation by inhalation in humans and may provide supportive information in human evidence. Based on the information from repeated dose toxicity study via inhalation, there is no evidence on specific respiratory hypersensitivity in animal data following repeated inhalation exposure with iron oxide or carbonyl iron aerosol.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 June 2010 - 7 July 2010

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to official EC and OECD test guidelines, and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2002-04-24

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA/Ca

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan UK Ltd.
- Age at study initiation: approx. 8 - 12 weeks
- Weight at study initiation: 16.8 - 20.8 g
- Housing: Animals were housed individually in polycarbonate cages with woodflake bedding. The mice were also given Nestlets and a plastic shelter for environmental enrichment. Each animal was assigned an alpha-numeric code and identified uniquely within the study by tail marking. Each cage label was colour-coded and was identified uniquely with the study number, dose level and animal mark.
- Diet (ad libitum): Standard rodent diet (Rat and Mouse No. 1 Maintenance Diet); ad libitum
- Water (ad libitum): Potable water taken from the public supply; ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23°C
- Humidity (%): 40 - 70%
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light

Vehicle:

acetone/olive oil (4:1 v/v)

Concentration:

0, 25, 50 and 100% w/v

No. of animals per dose:

4 female mice

Details on study design:

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: The local lymph node assay
- Criteria used to consider a positive response: The test substance is regarded as a sensitizer if at least one concentration of the chemical results in a three-fold greater increase in 3HTdR incorporation compared to control values.

TREATMENT PREPARATION AND ADMINISTRATION: The mice were treated by daily application of 25 μl of each of one of these three concentrations, or control, to the dorsal surface of both ears for three consecutive days.

PRE-SCREEN TESTS:
A vehicle trial was conducted and the test substance showed that it formed a dark grey liquid suspension at 100% w/v in acetone:olive oil (4:1 v/v) which was satisfactory for dose administration.

TREATMENT PREPARATION:
The dose levels for the investigation were chosen based on the physical properties of the test substance e.g. solubility, viscosity. The test substance formulations were prepared on the day of dosing at the required concentrations.

MAIN STUDY.
Groups of mice were treated at one of three concentrations of the test substance. The mice were treated by daily application of 25 μL of the appropriate concentration of the test substance to the dorsal surface of each ear for three consecutive days (Days 1-3). The test substance was spread over the entire dorsal surface of the ear using the tip of a pipette.

Five days following the first topical application of test substance (Day 6) all mice were injected via the tail vein with 250 μL of phosphate buffered saline containing 3H-methyl Thymidinea (3HTdR: 80 μCi/mL) giving a nominal 20 μCi to each mouse.

Five hours following the administration of 3HTdR on Day 6 all mice were humanely killed by carbon dioxide asphyxiation and the draining auricular lymph nodes excised and pooled for each experimental group. 1.0 mL of phosphate buffered saline was added to the pooled lymph nodes for each group.

A single cell suspension of lymph node cells (LNC) was prepared by gentle mechanical disaggregation through a stainless steel gauze (200 mesh size). The pooled LNC were then washed by adding 10 mL phosphate buffered saline, pelleted at 190 x g for 10 minutes and resuspended. The cells were washed twice again and resuspended in 3 mL trichloroacetic acid (TCA: 5%) following the final wash.

After overnight incubation with 5% TCA at 4°C, the precipitate was recovered by
centrifugation and resuspended in 1 mL 5% TCA and transferred to 10 mL Ultima gold scintillation fluid on Day 7. 3HTdR incorporation was measured by β-scintillation counting. The proliferative response of LNC was expressed as radioactive disintegrations per minute per lymph node (dpm/node) and as the ratio of 3HTdR incorporation into LNC of test nodes relative to that recorded for control nodes (test/control ratio; Si value).

ANALYSIS OF RESULTS:
The test substance is regarded as a sensitizer if at least one concentration of the test substance results in a three-fold greater increase in 3HTdR incorporation compared to control values.

OBSERVATIONS:
- clinical signs: all animals were observed daily for signs of ill health or toxicity. The ears were also examined for signs of irritation.
- body weight: the weight of each mouse in the study was recorded on arrival (these data are not reported), Day 1 (first day of dosing) and prior to termination (Day 6).

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Statistics:

No statistical analysis was performed on this study.

Positive control results:

This positive control study is considered to be valid if the results from the hexyl cinnamic aldehyde (HCA) group have a three-fold greater increase in 3HTdR incorporation compared to control values.
In this assay the test/control ratios obtained for HCA at 10, 25 and 50% v/v were 2.3, 7.7 and 13.1. This indicates that Hexyl cinnamic aldehyde demonstrates the potential to induce skin sensitization (delayed contact hypersensitivity) and confirms the sensitivity.

Key result

Parameter:

SI

Value:

0.7

Test group / Remarks:

25 % w/v test substance

Key result

Parameter:

SI

Value:

0.5

Test group / Remarks:

50 % w/v test substance

Key result

Parameter:

SI

Value:

0.8

Test group / Remarks:

100 % w/v test substance

Cellular proliferation data / Observations:

CLINICAL OBSERVATIONS:
- There were no deaths and no signs of ill health or toxicity observed during this study, however the following observations were noted:

- Greasy fur was noted for all control and test animals post-dose from Day 1 for control animals and from Day 3 for all test animals. This sign had resolved completely in all animals by Day 5.

- Black dose residue on ears was noted for all test animals post-dose on Day 1. Wet fur was also noted for all test animals post-dose on Day 1. These signs had resolved completely in all animals by Day 4.

BODY WEIGHTS:
Body weight increases were recorded for all mice over the period of the study.

Interpretation of results:

GHS criteria not met

Conclusions:

Ferrophosphorus (Fe3P) is not regarded as a potential skin sensitizer and therefore should not be classified and labelled for skin sensitisation according to Regulation (EC) No. 1272/2008 and its subsequent adaptations.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Details on the test item is missing.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

Route for challenge exposure was intradermal and epidermal. 10 exposures for induction was conducted. 20 guinea pigs were tested, but there were no information about sex, housing and feeding conditions.

GLP compliance:

not specified

Remarks:

not specified in the publication

Type of study:

Maurer optimisation test

Justification for non-LLNA method:

The study was conducted prior to the implementation of LLNA method under REACH and development of OECD guidelines.

Specific details on test material used for the study:

not specified
not applicable

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance

Day(s)/duration:

week 1 (4 intradermal injections)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance and Freund's Complete Adjuvant (FCA)

Day(s)/duration:

week 2 (3 intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance and Freund's Complete Adjuvant

Day(s)/duration:

week 3 (3 intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance

Day(s)/duration:

14 days after the last intradermal induction (week 6)

Adequacy of challenge:

not specified

Route:

epicutaneous, occlusive

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance

Day(s)/duration:

10 days after intradermal challenge (week 8); exposure duration: 24 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20 animals for testing group
20 animals for control group

Details on study design:

The skin sensitisation potential of the test substance was tested using 20 guinea pigs. Induction was done by intradermal application of 0.1% test solution. During second and third week of induction the test substance was dissolved in FREUND's adjuvant and applicated. After resting phase of 14 days, challenge exposure via intradermal application took place and followed by resting phase of 10 days. Then epidermal challenge exposure was done.

Skin reactions were observed after intradermal application conducted during the first week of induction as well as challenge exposures (each time 24 hours after administration) and for every application of each testing animal, the approximate reaction volume was calculated by diameter of reactions and increase of skinfold thickness. Individual threshold value was calculated by diameter of reactions from induction and scattering, which was compared to reaction volume from challenge exposure. All animals whose values from challenge exposure were higher than the individual treshold were evaluated as sensitizer. Incidences of positive animals per test group for intradermal and epidermal challenge exposure scored by the Draize scala were statistically compared to control groups.

Challenge controls:

20 guinea pigs were used as control group (tested with 40% propylene glycol)

Positive control substance(s):

not specified

Positive control results:

not specified

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

4

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

1

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

11

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

4

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Group:

positive control

Remarks on result:

not measured/tested

Reading:

2nd reading

Group:

positive control

Remarks on result:

not measured/tested

Interpretation of results:

GHS criteria not met

Conclusions:

Red iron oxide is not sensitising to skin. The substance did not meet the criteria for classification as a sensitiser according to Regulation (EC) No 1272/2008 and subsequent adaptations.

Reference 3

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Details on the test item is missing.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

Route for challenge exposure was intradermal and epidermal. 10 exposures for induction was conducted. 20 guinea pigs were tested, but there were no information about sex, housing and feeding conditions.

GLP compliance:

not specified

Remarks:

not specified in the publication

Type of study:

Maurer optimisation test

Justification for non-LLNA method:

The study was conducted prior to the implementation of LLNA method under REACH and development of OECD guidelines.

Specific details on test material used for the study:

not specified
not applicable

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1 % of test substance

Day(s)/duration:

week 1 (4 intradermal injections)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40 %

Concentration / amount:

0.1 % of test substance and Freund’s Complete Adjuvant (FCA)

Day(s)/duration:

week 2 (3 intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40 %

Concentration / amount:

0.1 % of test substance and Freund’s Complete Adjuvant

Day(s)/duration:

week 3 (3 intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40 %

Concentration / amount:

0.1 % of test substance

Day(s)/duration:

14 days after the last intradermal induction (week 6)

Adequacy of challenge:

not specified

Route:

epicutaneous, occlusive

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1 % of test substance

Day(s)/duration:

10 days after intradermal challenge (week 8); exposure duration: 24 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20 animals for testing group
20 animals for control group

Details on study design:

The skin sensitisation potential of the test substance was tested using 20 guinea pigs. Induction was done by intradermal application of 0.1% test solution. During second and third week of induction the test substance was dissolved in FREUND's adjuvant and applicated. After resting phase of 14 days, challenge exposure via intradermal application took place and followed by resting phase of 10 days. Then epidermal occlusive challenge exposure was done.

Skin reactions were observed after intradermal application conducted during the first week of induction as well as challenge exposures (each time 24 hours after administration) and for every application of each testing animal, the approximate reaction volume was calculated by diameter of reactions and increase of skinfold thickness. Individual threshold value was calculated by diameter of reactions from induction and scattering, which was compared to reaction volume from challenge exposure. All animals whose values from challenge exposure were higher than the individual treshold were evaluated as sensitizer. Incidences of positive animals per test group for intradermal and epidermal challenge exposure scored by the Draize scala were statistically compared to control groups.

Challenge controls:

20 guinea pigs were used as control group (tested with 40% propylene glycol)

Positive control substance(s):

not specified

Positive control results:

not specified

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

4

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

1

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

7

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

0

Total no. in group:

19

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Group:

positive control

Remarks on result:

not measured/tested

Reading:

2nd reading

Group:

positive control

Remarks on result:

not measured/tested

Interpretation of results:

GHS criteria not met

Conclusions:

Black iron oxide is not sensitising to skin. The substance did not meet the criteria for classification as a sensitiser according to Regulation (EC) No 1272/2008 and subsequent adaptations.

Reference 4

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not specified

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Details on the test item is missing.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Version / remarks:

1981-05-12

Deviations:

yes

Remarks:

Route for challenge exposure was intradermal and epidermal. 10 exposures for induction was conducted. 20 guinea pigs were tested, but there were no information about sex, housing and feeding conditions.

GLP compliance:

not specified

Remarks:

not specified in the publication

Type of study:

Maurer optimisation test

Justification for non-LLNA method:

The study was conducted prior to the implementation of LLNA method under REACH and development of OECD guidelines.

Specific details on test material used for the study:

not specified
not applicable

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance

Day(s)/duration:

week 1 (4 intradermal injections)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance and Freund's Complete Adjuvant (FCA)

Day(s)/duration:

week 2 (3 intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance and Freund's Complete Adjuvant (FCA)

Day(s)/duration:

week 3 (3intradermal applications)

Adequacy of induction:

not specified

Route:

intradermal

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test dubstance

Day(s)/duration:

14 days after the last intradermal induction (week 6)

Adequacy of challenge:

not specified

Route:

epicutaneous, occlusive

Vehicle:

propylene glycol

Remarks:

40%

Concentration / amount:

0.1% of test substance

Day(s)/duration:

10 days after intradermal challenge (week 8); exposure duration: 24 hours

Adequacy of challenge:

not specified

No. of animals per dose:

20 animals for testing group
20 animals for control group

Details on study design:

The skin sensitisation potential of the test substance was tested using 20 guinea pigs. Induction was done by intradermal application of 0.1% test solution. During second and third week of induction the test substance was dissolved in FREUND's adjuvant and applicated. After resting phase of 14 days, challenge exposure via intradermal application took place and followed by resting phase of 10 days. Then epidermal challenge exposure was done.

Skin reactions were observed after intradermal application conducted during the first week of induction as well as challenge exposures (each time 24 hours after administration) and for every application of each testing animal, the approximate reaction volume was calculated by diameter of reactions and increase of skinfold thickness. Individual threshold value was calculated by diameter of reactions from induction and scattering, which was compared to reaction volume from challenge exposure. All animals whose values from challenge exposure were higher than the individual treshold were evaluated as sensitizer. Incidences of positive animals per test group for intradermal and epidermal challenge exposure scored by the Draize scala were statistically compared to control groups.

Challenge controls:

20 guinea pigs were used as control group (tested with 40% propylene glycol)

Positive control substance(s):

not specified

Positive control results:

not specified

Reading:

1st reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

4

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

negative control

Dose level:

40% propylene glycol

No. with + reactions:

1

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

5

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 1st reading is after intradermal provocation

Reading:

2nd reading

Hours after challenge:

24

Group:

test chemical

Dose level:

0.1% testing solution

No. with + reactions:

0

Total no. in group:

20

Clinical observations:

not specified

Remarks on result:

other: 2nd reading is after epidermal provocation

Reading:

1st reading

Group:

positive control

Remarks on result:

not measured/tested

Reading:

2nd reading

Group:

positive control

Remarks on result:

not measured/tested

Interpretation of results:

GHS criteria not met

Conclusions:

Yellow iron oxide is not sensitising to skin. The substance did not meet the criteria for classification as a sensitiser according to Regulation (EC) No 1272/2008 and subsequent adaptations.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Introductory remark on read-across:

In this dossier, the endpoint skin and respiratory sensitisation is not addressed by substance-specific information, but instead by a weight of evidence approach based on collected information for all substances of the iron oxide category. Three target substances covered by this read-across (Iron sinter; Iron ores, agglomerates; Mill scale) consist primarily of different iron oxides, as described in the technical dossier section 1.2 Composition. The predominant characteristic of the iron oxides is the inertness being a cause of their chemical stability and very poor reactivity. This is shown by a very low dissolution in water and artificial physiological fluids as well as a very low in vivo bioavailability after oral administration. This very low reactivity, solubility and bioavailability leads to a complete lack of skin and respiratory sensitising properties. Iron is a transition-metal and is subject at its surface to passivation by the formation of a passive oxide (i. e. iron oxide) coating. In particular, for iron metal and granules, the oxide layer will form a quantitatively continuous layer to envelop the entire particle irrespective of product form. In view of this, it may be assumed that human exposure is secondary to that of iron oxide and that the liberation of ionic iron shows a slower kinetics, compared with soluble iron salts. Further information on the read-across approach is given in the report attached to IUCLID section 13.2.

 

Human data

One reference describing human data on skin sensitisation could be identified. The testing for skin sensitisation potential of iron oxide substances was described. After a thorough reliability screening, this reference was considered of limited relevance for hazard assessment purposes. The criteria for quality, reliability and adequacy of experimental data under REACH for hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X) are not fulfilled. For information purposes, the reference is discussed briefly below, highlighting their findings and the reasons for their exclusion from health hazard assessment:

Motolese, A. et al. (1993) investigated the skin sensitising properties of 29 allergens among them red and yellow iron oxide in 190 workers (126 enamellers and 64 decorators, 119 females and 71 males) from 5 ceramics factories using occupational test series. The participants were tested with 2% red iron oxide in petrolatum and 2% yellow iron oxide in petrolatum using Finn Chambers on Scanpor tape (patch test) which also contained the remaining 27 allergens including nickel sulfate or cobalt chloride. Furthermore, 2% red iron oxide in petrolatum and 2% yellow iron oxide were tested in 92 healthy volunteers that were not ceramics workers, but cadets of a military academy using the same testing conditions as for workers. The results showed that 7/190 (3.7%) of the participants had positive reactions to red iron oxide and 0/190 (0%) of the participants had positive reactions to yellow iron oxide. In addition, no positive reactions were observed in the healthy volunteers. This reference had several reporting and experimental deficiencies:

The workers and healthy volunteers were not fully described, since age, medical history about allergy or medication, exposure history and persistence or absence of healthy effects were not specified. Presence of aggravating factors in home and workplace was not specified which makes it impossible to identify any confounding factors that might influence the results. Furthermore, the volume of the test solution was not mentioned, and the reading of skin reactions was done just once at 24 hours after removal of the test substance, but at least two readings are required according to the recommendations of the European Society of Contact Dermatitis guideline. Then, the scoring system was not mentioned, but generally, the scoring criteria recommended by International Contact Dermatitis Research Group (ICDRG) should be used. Positive control and extent of exposure (frequency, magnitude and duration of repeated induction patches followed by challenge patch) were not described. The test substance was obtained directly from the chemical industries supplying ceramic producers and no description of the test item was given (purity and impurities unknown).

Another reference was also identified, representing an investigation of skin sensitisation in humans. Different iron substances were investigated via a patch test, as follows: ferrous (II) sulfate, ferrous (II) ammonium sulfate, ferrous (III) ammonium sulfate, iron (III) oxide, and ferric (III) chloride. The reference lacks significance due to, e.g., poor test item characterisation as well as lacking control groups, information on participants and information on exposure duration/site. It is therefore concluded that the reference does not fulfil the criteria for quality, reliability and adequacy of experimental data for the fulfilment of data requirements under REACH and hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X). The study given below was included in the IUCLID for information purposes only:

Hemmer, W. et al. (1996): there was no information about identity and purity of the test substances. The information about the study design including extent of exposure duration as well as skin site were missing. They did not include either positive or negative controls in their study design. There were inconsistencies of the number of tests for every test substance, so that the number of tests varied for each test substance. There was no information about the sex, age, health medication or ethics of the 623 patients, they only described the two cases with reconfirmed positive results.

 

Animal data:

An in vivo skin sensitisation study with triiron phosphide (Fe3P) was conducted by Bull (20210) according to OECD 429 (2002). Groups of four female CBA/Ca mice were treated with the substance in acetone/olive oil at concentrations of 25, 50 and 100 % (w/v) on three consecutive days. A negative and positive control group (hexyl cinnamic aldehyde) were run concurrently. On day five, all mice were injected 3H-methyl thymidine and they were sacrificed on day 6. Draining lymph nodes were excised and pooled for each experimental group followed by preparation of the lymph nodes for β-scintillation counting. Stimulation indices (SI) were calculated for each concentration and a SI showing a three-fold increase is considered to indicate the potential of skin sensitisation. No potential of skin sensitisation was observed in this study (Si indices: 0.7, 0.5 and 0.8 % for 25, 50 and 100 % concentrations, respectively).

In the study by Maurer (1979), the skin sensitisation potential of black, red and yellow iron oxide was tested. Groups of 20 guinea pigs were treated with the substances. Induction was done by intradermal application of 0.1% substance in 40 % propylene glycol. During the first week, the substance was applied without FREUND’s adjuvant, however, the substance was dissolved in FREUND's adjuvant and applicated during the second and third week of induction. After resting phase of 14 days, challenge exposure via intradermal application took place and followed by resting phase of 10 days. Then epidermal challenge exposure was done. Skin reactions were observed after intradermal application was conducted during the first week of induction as well as challenge exposures (each time 24 hours after administration) and for every application of each testing animal, the approximate reaction volume was calculated by diameter of reactions and increase of skinfold thickness. Individual threshold value was calculated by diameter of reactions from induction and scattering, which was compared to reaction volume from challenge exposure. All animals whose values from challenge exposure were higher than the individual threshold were evaluated as skin sensitizer. Incidences of positive animals per test group for intradermal and epidermal challenge exposure scored by the Draize scale were statistically compared to control groups. For the challenge control group, 20 guinea pigs were tested with 40% propylene glycol. All three iron oxides including black, red and yellow iron oxide were found not to be skin sensitizer.  The study is considered as reliable with restriction (RL2), details on the shortcomings are reported in the IUCLID study record.

 

Conclusion

Two references presenting data on skin sensitisation in humans are available. After a thorough reliability screening, these references were considered of limited relevance for hazard assessment purposes. The criteria for quality, reliability and adequacy of experimental data under REACH for hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X) are not fulfilled. The studies were included for information purposes only.

Information about iron oxide substances demonstrates that these substances are extremely poorly soluble in water, show very low in vitro bioaccessibility over a whole range of surrogate biological media and are poorly bioavailable. Detailed toxicokinetic investigations did not reveal any significant absorption and excretion. Triiron phosphide is considered to behave similar as the iron oxide category substances. Therefore, read-across can be made from this substance.

Based on the information from the available one skin sensitisation toxicity study with triiron phosphide (according to OECD 429 and under GLP), it is concluded that this substance has no skin sensitisation potential. In addition three guinea pig maximisation tests did not show any skin sensitising properties for three different iron oxides (yellow: FeOOH, red: Fe2O3, black: Fe3O4).

Overall, there is no concern with regard to skin sensitising properties for the members of the iron category substances. The conduct of skin sensitisation study with a source substance of the iron category cannot be expected to contribute any relevant information to the assessment of (otherwise negative) information on skin sensitisation.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Introductory remark on read-across:

In this dossier, the endpoint skin and respiratory sensitisation is not addressed by substance-specific information, but instead by a weight of evidence approach based on collected information for all substances of the iron oxide category. Three target substances covered by this read-across (Iron sinter; Iron ores, agglomerates; Mill scale) consist primarily of different iron oxides, as described in the technical dossier section 1.2 Composition. The predominant characteristic of the iron oxides is the inertness being a cause of their chemical stability and very poor reactivity. This is shown by a very low dissolution in water and artificial physiological fluids as well as a very low in vivo bioavailability after oral administration. This very low reactivity, solubility and bioavailability leads to a complete lack of skin and respiratory sensitising properties. Iron is a transition-metal and is subject at its surface to passivation by the formation of a passive oxide (i. e. iron oxide) coating. In particular, for iron metal and granules, the oxide layer will form a quantitatively continuous layer to envelop the entire particle irrespective of product form. In view of this, it may be assumed that human exposure is secondary to that of iron oxide and that the liberation of ionic iron shows a slower kinetics, compared with soluble iron salts. Further information on the read-across approach is given in the report attached to IUCLID section 13.2.

 

Human data

Human data on respiratory sensitisation including lung functions tests, bronchial challenge tests, or other immunological tests could not be identified.

Another 35 references investigated occupational iron oxide inhalation exposure and effects on the respiratory system. These investigations were conducted with occupationally exposed workers to iron oxides.  These references lack significance due to, e.g., exposure parameters unknown (composition and amount of fumes) as well as lacking of information on co-exposure and smoking habits. It is therefore concluded that the reference does not fulfil the criteria for quality, reliability and adequacy of experimental data for the fulfilment of data requirements under REACH and hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X). The studies given below were included in the IUCLID for information purposes only:

Buerke, U. et al. (2002): the co-exposure to other elements (Cr, Ni, Mn, Al, Cu, Ti, SS) besides iron oxide in the welding fume and the different smoking habits of the welders are unknown.

Charr, R. (1955): exposure parameters (composition and amount of welding fume) and the smoking habits of the most welders are unknown.

Charr, R. (1956): exposure parameters (composition and amount of welding fume) and the smoking habits of the welders are unknown.

Funahashi, A. et al. (1988): exposure parameters (composition and amount of welding fume) and the smoking habits of the welders are unknown.

Groh, J.A. (1944): exposure parameters (composition and amount of welding fume) and the smoking habits of the welders are unknown.

Guidotti, T.L. et al. (1978): exposure parameters (composition and amount of welding fume) and the smoking habits of the welder are unknown.

Kleinfeld, M. et al. (1969): the composition of the welding was not specified, thus relevance cannot be judged.

McCormick, L.M. et al. (2008): the amount and composition of the welding fume is unknown.

Näslund, P.E.; Högstedt, P. (1982): the composition and duration of exposure of the welding fume were not specified.

Offermann, P.V.; Finley, C.J. (1992): the amount and composition of the welding fume (welding with galvanised steel and inhalation of carbonyl fumes) are unknown.

Patel, K.C. et al. (1977): the amount and composition of the welding fume, the simultaneously exposition to asbestos and the unknown smoking habits were not specified.

Stern, R.M. et al. (1988): the composition of the welding fume was not described, thus relevance cannot be judged.

Sander, O.A. (1947): exposure parameters (composition and amount of welding fume), the smoking habits and sex of the oxyacetylene cutters were not specified.

Mann, B.T.; Lecutier, E.R. (1957): the subjects were exposed to different mixtures of several compounds during the welding process. The smoking habits of the arc welder were not specified.

Jones, J.G.; Warner, C.G. (1972): the subjects were exposed to different mixtures of several compounds during the welding process.

Harding, H.E. et al. (1958): the subjects were exposed to different mixtures of several compounds during the welding process. The smoking habits of the cases are missing.

Hamlin, L.E. et al. (1950): the subjects were exposed to different mixtures of several compounds in the fumes and dusts.

Doig, A.T.; McLaughlin, A.I.G. (1936): the subjects were exposed to different mixtures of several toxic compounds of arc welding fumes. The smoking habits of the welders are missing.

Doig, A.T.; McLaughlin, A.I.G. (1948): the subjects were exposed to different mixtures of several toxic compounds of arc welding fumes. The smoking habits of the welders were not specified.

Attfield, M.D.; Ross, D.S. (1978): the subjects were exposed to a mixture of several toxic compounds (Mn, Ni, Cr, Zn, Pb, nitrogen oxide and asbestos). The fume level concentration and the smoking habits of the welders were not specified.

Enzer, N.; Sander, O.A. (1938): individuals were exposed to different mixtures without amount and concentration measurement. The smoking habits of the welders were not specified.

NIOSH (1976): the welders were subjected to mixed exposure and information on confounding factors such as smoking habits are missing.

NIOSH (1983): this study checked if the dust concentration of iron oxide in a plant were below or above (ACGIH TLV's 1981). No direct results (e.g., clinical signs, histology) for human health were stated. The welders were subjected to mixed exposure, and the smoking habits are not described.

NIOSH (1977): the welders were subjected to mixed exposure, and the smoking habits were missing.

Fawcitt, R. (1943): the exposure to radon and diesel exhaust gas is unknown. Amount and composition of mixed dust exposure and smoking habits are not described. A counting and statistical analysis of cases and diagnoses were not performed.

Morgan, W.K.C. (1978): confounding exposure to cigarette consumption (smoking of 1/2 a pack cigarettes per day), unclear aetiology of the health effects.

Moore, E. et al. (1987): individuals were co-exposure with 13 % quartz and 40 % iron.

Kleinfeld, M. et al. (1968): miners and sinters were subjected to mixed dust exposure (silicates, and free silica), and there was a possible exposure to other agents (radon, ozone, nitrous oxides, or substances in the welding fume).

Stewart, M.J.; Faulds, J.S. (1934): the exposure was a mixture of iron, silica and other components. The exposure parameters, and smoking habits are not described.

Harding, H.E. (1948): the subjects were exposed to a mixture of iron oxide and silver dust (silica). The smoking habits of the silver finisher are missing.

Barrie, H.J.& Harding, H.E. (1947): the silver finishers were subjected to mixed exposure to iron oxide and silver dust. The smoking habits of the silver finisher are not described.

McLaughlin, A.I.G. et al (1945): the silver finishers were subjected to mixed exposure of iron oxide, silver and cotton dust. The smoking habits of the silver finishers are not described.

Buckell, M. et al. (1946): the iron tuner and grinders subjected to mixed exposure of different compounds. The amount of exposure and the missing smoking habits of the iron tuner and grinders are not described.

Pendergrass, E.P.; Leopold, S.S. (1945): grinders were subjected to mixed exposure of the grinders dust. The smoking habits of the grinders were not specified.

Teculescu, D.; Albu, A. (1973): the authors stated that the dust contained only pure iron oxide, although mixed exposure cannot be excluded due to the manufacturing process of red iron oxide, which used iron carbonate, natrium carbonate and iron sulphate.

 

Animal data

No formally recognised and validated animal tests currently exist for respiratory sensitization. However, the existing repeated dose toxicity data from animal studies are used as indicative of the lack of respiratory sensitising properties of all members of the iron category substances.

In a subacute inhalation toxicity study, 48 male rats per group were exposed to three different aerosolized iron oxide powders (Fe2O3, Fe3O4 and FeOOH). Exposure was 6-hours/day on five days/week for two consecutive weeks. The rats were exposed to mean actual concentrations of 185.6 mg/m³ Fe3O4, 210.2 mg/m³ Fe2O3 and 195.7 mg/m³ FeOOH (Pauluhn, 2005). The repeated exposure to the aerosolized iron oxides was not associated with any specific clinical signs, changes in body temperature or body weights. Histopathological evaluation of rat lungs exposed to the different iron oxides revealed findings consistent with a 'poorly soluble particle' effect after the 2-week exposure period, including the 3-month post-exposure period. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs was not observed (Pauluhn, 2005). The comparative assessment of the three different iron oxides revealed the same quality and time course of responses, i.e., marked differences of any toxicological significance between the test specimens were not observed. This supports the conclusion, that Fe3O4 can serve as a surrogate for FeOOH and Fe2O3.

For Fe3O4 valid subacute and subchronic inhalation studies are available (Pauluhn, 2006a; Pauluhn, 2006b). In the subacute inhalation toxicity study 30 male rats were exposed to 10.1, 19.4, 45.6 and 95.8 mg/m³ Fe3O4 for 6 hours/day, 5 days/week for 4 weeks and serially sacrificed 1, 8, 24 weeks after the 4 weeks exposure period. Clinical signs were recorded daily before and after exposure or once per week during the post-exposure period. At each serial sacrifice, inflammatory endpoints were determined in bronchoalveolar lavage (BAL). Rats were subjected to gross pathological examination and histopathology (nasal passages, trachea, lung, liver, spleen, kidneys, testes and thymus). The repeated 4-week exposure to the aerosolized dry powder was not associated with specific clinical signs or consistent changes in body weights. Changes in organ weights occurred and consisted of increased lung and lung-associated lymph nodes (LALN) weight at 45.6 mg/m³ and above. Histopathological evaluation of rat lungs exposed to Fe3O4 revealed finding consistent with a poorly soluble particle effect. Conclusive evidence of bioavailable iron or iron particles that were translocated to extrapulmonary organs to any appreciable extent was not found. Extrapulmonary effects causally linked to the exposure of Fe3O4 were not found at any exposure concentration and time point (Pauluhn, 2006b). In the subchronic inhalation toxicity study in rats (20 male and 20 female rats per group) the animals were exposed 6 hours/day, 5 days/week for 13 weeks to 4.7, 16.6 and 52.1 mg/m³ Fe3O4. During the study, the body weights were determined twice weekly and clinical signs were recorded daily before and after exposure. At sacrifice, inflammatory endpoints were determined in BAL. Histopathology focused on the entire respiratory tract (nasal passages, trachea, lung, lung associated lymph nodes) and included all extrapulmonary organs as suggested by OECD 413. At sacrifice biological specimens were collected for hematology, clinical pathology and urinalysis (Pauluhn, 2006a). The repeated exposure of rats during a study period of 13 weeks was not associated with any specific clinical signs. Hematology, clinical pathology and urinalysis were unobtrusive. Neither analytical nor toxicological evidence existed that free, biosoluble iron was liberated from the inhaled dust to any appreciable extent. However, the neutrophils in male rats and some biochemical markers were elevated at 4.7 mg/m³ and above (Pauluhn, 2006a). The NOAECs for Fe3O4 are 10.1 mg/m³ for the subacute exposure and 4.7 mg/m³ for subchronic exposure in rats (Pauluhn, 2006a; Pauluhn, 2006b).

The results of this inhalation RDT study by Pauluhn (2006a) in rats can generally be regarded as reliable without restrictions, since the study was conducted according to OECD guideline 413 (2008) and under GLP.

The results of this inhalation RDT study by Pauluhn (2006b) in rats can generally be regarded as reliable with restrictions, since the study was conducted according to OECD guideline 412 (1998) and under GLP.

However, only males were tested in the study. There were no haematological or clinical biochemistry analyses performed. In addition, the adrenals were not weighed or histopathologically examined after sacrifice. Furthermore, the humidity of air in the chamber during the exposure was very low. There is also no description of the method for determining the iron content in the organs.

This reference by Pauluhn (2005) had several reporting and experimental deficiencies:

This study was conducted as a dose range finding study according to OECD 412 (1981) and under GLP. However, only male rats were tested without justification, and only one dose was tested which does not allow a dose-response related analysis.  A haematological examination and clinical biochemistry in blood were not conducted. Furthermore, the organ weight of the adrenals was missing, and a histopathological examination of adrenals and the heart were not performed.

Warheit, D.B. et al. (1991) investigated on the pulmonary response in male rats (Crl:CD BR) after short-term inhalation to carbonyl iron aerosol. Groups of 6 or 14 rats were exposed to carbonyl iron aerosol at a concentration of 110 mg/m³ air (analytical concentration) for 6 h per day over a total period of 3 days via nose-only inhalation. The bronchoalveolar lavage fluid (BALF) was analysed for total cell count, differential cell count, total protein level, alkaline phosphatase activity, and lactate dehydrogenase activity directly after the last exposure as well as 1 day, 2 days, 8 days, 1 month, and 2 months after the last exposure. Moreover, the rat lungs were examined via histopathology and TEM analysis. Further, airway and parenchymal cell turnover was determined in a radio-labelling experiment. The lung burden in carbonyl iron-exposed rats was estimated to be 620 µg iron/lung. Short-term inhalation exposure did not induce significantly altered BALF parameters at any time point, when compared to the sham control group. The airway and parenchymal cell turnover rates were not significantly different from controls. The histopathological examination did not reveal any pulmonary lesions at any time post exposure.

The reference had some reporting and experimental deficiencies.  

The purity of the test material was not specified. This study was not in accordance with any subacute inhalation toxicity guideline and only male rats were used for the toxicity evaluation. The number of animals per group and time point (n = 6) was low, and thus, robustness is only limited. A justification for the concentration tested is not provided. The use of only one dose group precludes dose-response relationship evaluations. Details on the test animals (e.g. weight at study initiation and test group randomisation) and housing conditions (e.g. environmental conditions and group sizes) are missing. The investigations are restricted to pulmonary effects. Information on food consumption, body weight development, clinical chemistry, haematology, and histopathology results of other organs than lung is missing. Methodology on lung burden analysis and aerosol generation is insufficiently described. The study was considered not reliable [RL=3], due to significant methodological deficiencies.

In the study by Warheit et al. (1997), male rats were exposed to carbonyl iron particles 6 hours/day, 5 days/week for 4 weeks via inhalation at concentrations of 5, 50, and 250 mg/m³ and evaluated at selected intervals through 6 months postexposure (0 hour, 1 week, and 1, 3, and 6 months). Indices of pulmonary inflammation as well as alveolar macrophage clearance functions (morphology, in vivo and in vitro phagocytosis, and chemotaxis), cell proliferation, and histopathology endpoints were measured at several post-exposure time periods through 6 months. In addition, amounts of carbonyl iron in lungs and tracheobronchial lymph nodes were measured to allow an evaluation of particle clearance and translocation patterns. Exposure to high dust concentrations of carbonyl iron particles produced sustained pulmonary inflammation, enhanced proliferation of pulmonary cells, impairment of particle clearance, deficits in macrophage function, and the appearance of macrophage aggregates at sites of particle deposition.

The publication shows significant methodological deficiencies in the experimental set up and documentation. Test material was insufficiently characterised (no purity or impurities). Only male rats were tested. The type of inhalation exposure was not specified. There is no description of the exposure chamber/apparatus. The method for verification of carbonyl iron concentrations in the exposure air was not described. The study was considered not reliable [RL=3], due to significant methodological deficiencies.

 

Summary entry – Repeated dose toxicity. inhalation

Another three references were also identified, representing an investigation of repeated dose toxicity via inhalation route. These experiments were conducted with rats or guinea pigs receiving hematite, diiron trioxide or carbonyl iron via inhalation (whole body, head-nose or nose-only).The study designs are not in accordance with accepted guidelines and are therefore of limited relevance for chemicals hazard assessment. The references usually lack significance due to, e.g., poor test item characterisation, low number of animals used, missing dose response relationship, or unjustified dosing regime. It is therefore concluded that the references do not fulfil the criteria for quality, reliability and adequacy of experimental data for the fulfilment of data requirements under REACH and hazard assessment purposes (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X). The studies given below were included in the IUCLID for information purposes only:

Haynes, F. (1931): the type and composition of dust was not reported, exposure conditions were poorly defined. The publication shows significant methodological deficiencies in the experimental setup and documentation (test material was not characterised, exposure concentration and method of aerosol generation were not specified). Only selected endpoints (histopathology of lungs and trachea) were investigated, and the investigated endpoints are not required for building an expert judgement and further assessment of the test substance under REACH (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X).

Ma-Hock, L. (2015 (A)): the study duration of 5 days is too short for a short-term repeated dose toxicity study. Only male rats were tested. Only two dose groups were examined which does not allow a dose-response related analysis. The number of animals per group (n= 3-5) is not sufficient to perform an appropriate statistical analysis.

Ma-Hock, L. (2015 (B)): the study duration is too short for a short-term repeated dose toxicity study. Only one dose group was examined which does not allow a dose-response related analysis. Test material was insufficiently characterised (chemical name, no purity or impurities). The number of animals per group (n= 3-5) is not sufficient to perform an appropriate statistical analysis.

Warheit, D.B. et al. (1996): the publication shows significant methodological deficiencies in the experimental set up and documentation. The experimental design is insufficiently documented. Frequency of exposure was not specified. Test material was insufficiently characterised (source, purity, impurities). Only male rats were tested and the number of animals per group was not given in publication. Furthermore, analytical parameters of the exposure atmosphere were measured (air flow, exposure concentration, and MMAD) were measured but not reported. Only selected parameters (cytotoxicity and pulmonary inflammatory responses (LDH and differential neutrophil levels in BAL fluid), alveolar macrophage functional parameters and histopathology of lung, trachea and heart) were investigated, and the investigated endpoints are not required for building an expert judgement and further assessment of the test substance under REACH (ECHA guidance R4 in conjunction with regulation (EC) 1907/2006, Annexes VII-X).

 

Conclusion

Animal data:

In repeated dose toxicity studies via inhalation by Pauluhn (2006), there was no evidence of sustained lysosomal, inflammatory or cytotoxic processes at any exposure concentrations and time point. Findings of poorly soluble particle effect in lungs of rats exposed to black iron oxide was accompanied by concentration-dependent bronchiolo-alveolar hypercellularity and focal septal thickening, especially at locations of alveolar macrophages loaded with iron oxide particles. These signs of inflammation occur at the highest exposure concentration and is due to substantially delayed clearance of particles as a result of lung overload. Inflammatory infiltrates or tissue remodelling was not observed at any exposure concentration and postexposure time point. At the end of the postexposure period, decrease in incidence and/or severity at highest exposure concentration was observed which is related to iron oxide exposure. Extrapulmonary effects were not found.

Furthermore, Warheit et al. (1991) showed no pulmonary lesions or altered bronchoalveolar lavage fluid parameters at any time point post carbonyl iron 28-day inhalation exposure. In addition, Warheit et al. (1997) revealed sustained pulmonary inflammatory response to carbonyl iron particle exposure. Macrophage accumulation increased from week 1 through 1 month postexposure and the remain constant through the following 5 month postexposure period, the impaired clearance of particle was caused by defective phagocytic and chemotactic potential of alveolar macrophages. The sustained pulmonary inflammation, enhanced proliferation, impairment of particle clearance and defective macrophage function were observed only at exposure of high particle concentrations. In summary, there is no evidence on specific respiratory hypersensitivity in animal data following repeated inhalation exposure with iron oxide or carbonyl iron.

Based on the information from the available two repeated dose toxicity studies with iron oxide (according to OECD 412 or 413 and under GLP) and two repeated dose toxicity studies with carbonyl iron, data showed no evidence on specific respiratory hypersensitivity of the substances in animal data. Iron oxide substances are also considered not to be respiratory sensitisers based on a read-across concept. Details on the read-across approach are given in the report generated in accordance with the ECHA Read-across Assessment Framework (March 2017) attached to IUCLID section 13.

Justification for classification or non-classification

Skin sensitisation

Based on the in vivo skin sensitisation studies with triiron phosphide and three different iron oxides, the substance is considered not to be a skin sensitiser. This is corroborated by human data. Therefore, the substance is not classified for skin sensitisation according to Regulation (EC) No. 1272/2008.

Respiratory sensitisation

Based on repeated dose toxicity inhalation studies with iron oxide and iron according to OECD guideline 412 or 413, the substances are considered not to be a respiratory sensitiser. Therefore, no classification as respiratory sensitiser according to Regulation (EC) No. 1272/2008 is applicable.