Registration Dossier

Administrative data

Description of key information

No skin sensitisation study with chromium (III) oxide is available. However, based on the information available from a skin sensitisation study (OECD 406; GLP) with basic chromium (III) sulphate , it was concluded using a category read-across concept that chromium (III) oxide is not sensitising either.The approach for read-across is described in detail in the document attached in IUCLID section 13.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 June - 6 July 2006
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
1992-07-17
Deviations:
no
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
An appropriate Buehler test is available which would not justify conducting an additional LLNA due to animal welfare.
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratory Animal Breeders, 88353 Kißlegg, Germany
- Females nulliparous and non-pregnant: yes
- Microbiological status of animals: only healthy animals exhibiting no clinical signs were used for the study. The animals were not vaccinated or treated against infections either before receipt, or during the adaptation or study period.
- Age at study initiation: 5 - 6 weeks
- Weight at study initiation: 331 - 397 g
- Housing (study period): groups of two or five animals per Noryl cages; bedding material: low-dust wood shavings (Rettenmaier & Söhne, GmbH & co. 73494 Rosenberg, Germany.
- Diet (ad libitum): "PROVIMI KLIBA 3420 - Maintenance Diet for Guinea Pigs" (Supplier: PROVOMI KLIBA AG)
- Water (ad libitum): tap water
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Relative humidity: 40 - 70 %
- Air changes: ≥ 10/hr
- Photoperiod (hrs dark / hrs light): 12/12
Route:
epicutaneous, semiocclusive
Vehicle:
physiological saline
Concentration / amount:
80 % test item formulation
Day(s)/duration:
Days 0, 7 and 14 (exposure duration: 6 hours)
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
physiological saline
Concentration / amount:
80 % test item formulation
Day(s)/duration:
day 28 (exposure duration: 6 hours)
No. of animals per dose:
Test animals: 20 animals
Control: 10 animals
Details on study design:
RANGE FINDING TESTS:
- Induction:
In a dose range-finding test three concentrations (25, 50 and 80 %) and the vehicle were tested in each case on five guinea pigs. The suitable areas of the body were shaved 30 minutes before treatment. The patches loaded with 0.5 mL of the test item formulations or the vehicle were applied to each animal under occlusive conditions for 6 hours. At the end of the exposure period, the remaining test item was removed with sterile physiological saline solution. Twenty-one hours later the treated areas were shorn. The dermal reactions were evaluated 30 and 54 hours after the start of the application.
No signs of irritation were seen at concentrations of up to 80% (the highest tested) (6-hour occlusive application).
Based on the results of the dose range-finding study, the following concentration was selected for the inductions: 80%

- Challenge:
The challenge concentration was determined on 2 guinea pigs which were treated in the same manner as the control animals during the inductions. The concentrations (25, 50 and 80 %) used for this range-finding study were selected on the basis of the range-finding tests for the induction concentration.
The patches loaded with 0.5 mL of test item formulations or the vehicle were applied to each animal under occlusive conditions for 6 hours. At the end of the exposure period, the remaining test item was removed with sterile physiological saline solution. Twenty-one hours later the treated areas were shorn. The dermal reactions were evaluated 30 and 54 hours after the start of the application.
No signs of irritation were seen at concentrations of up to 80% (the highest tested) (6-hour occlusive application).
Based on the results of the dose range-finding study, the following concentration was selected for the challenge: 80%

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: three
- Frequency of applications: once per week
- Site: Thirty minutes or 24 hours prior to test formulation appplication the skin of the left flank was shaved.
The animals in the test item group were treated with a hypoallergic patch loaded with the test item applied to the left flank. The patches were held in place on the skin using "ORABAND"® adhesive plaster. In the case of the control group animals, a hypoallergic patch loaded only with the vehicle was applied to the left flank and fixed with a strip of "ORABAND"® adhesive tape for each of the inductions. The patches were removed after an exposure period of six hours, and any remaining test item was removed with sterile physiological saline solution.
The volume applied per animal was 0.5 mL
- Concentrations:
Test animals: 80% of test item formulation
Control animals: vehicle
The treatment areas were visually assessed 30 hours after initiation of exposure.

B. CHALLENGE EXPOSURE
- No. of exposures: one
- Site: backs and right flanks of the animals were shorn 24 hours prior to the challenge treatment. A hypoallergenic patch loaded with the 80% test item formulation was applied and fixed to the right flank of each animal in the control and test item group. As a control a patch loaded only with the vehicle was applied and fixed also to the right flank. The patches were held in place on the skin with a ORABAND self-adhesive tape for 6 hours.
The volume applied per animal was 0.5 mL.
At the end of the six-hours exposure period, the patches were removed and the remaining test item was rinsed away with sterile physiological saline solution.Twenty- one hours later the skin of the animals was shorn in the region of the treatment sites.
- Concentrations (test and control animals): 0% and 80%
- Evaluation (hr after challenge): 24 and 48 hours

C. OBSERVATIONS:
- clinical signs: at least once daily
- body weights: on day 1 before the first induction and after the last evaluation on day 31 in the control group and the test item group and at day 24 in the range-finding group.
Challenge controls:
Five control animals were challenged with 80% test material (in physiological saline) and vehicle alone.
Positive control substance(s):
yes
Remarks:
alpha hexyl cinnamic aldehyde (vehicle: physiological saline solution; epicutanous: 40 % test item; challenge: 20 % test item)
Positive control results:
Challenge with 20% positive control (in saline) resulted in dermal effects in 9/20 animals (45% response).
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
80%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
80%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
80%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
80%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Reading:
other: challenge
Group:
positive control
Dose level:
20 % of the positive control
No. with + reactions:
9
Total no. in group:
20
Clinical observations:
Skin effects (grade 1) were observed in 9/20 animals.

- dermal reactions during the induction phase were limited to one animal following the second and third exposures (Grade 1 erythema, desquamation). Similar findings were not seen in this animal following challenge.

- clinical signs: appearance and behaviour of the test item group animals were not different from the control group.

- body weight: by the end of the study the mean body weight of the treatment group animals was in the same range than that of the control group.

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not a skin sensitiser.
According to Regulation (EC) No 1272/2008 and subsequent adaptations, the substance does not require classification as skin sensitiser.
Executive summary:

The potential of the test material (a mixture of basic chromium sulphate, sodium sulphate and water) to induce delayed contact hypersensitivity (skin sensitisation) was investigated in a three-induction Buehler study using female Hartley guinea pigs. The concentrations of the test material used for induction and challenge applications were based on the results of a preliminary study. The results of an acceptable positive control study are also reported, confirming the sensitivity of the assay. Induction was performed on 20 test animals using 6 -hour semi-occlusive application of 0.5 ml test material (80% in physiological saline); a total of three applications were made over a three-week period. Ten control animals were similarly treated using vehicle. Two weeks following the final induction application, all test and control animals were challenged using a 6- hour semi-occlusive application of the test material (80%). Dermal reactions were assessed at 24 and 48 hours following patch removal. No dermal reactions were seen in test or control animals. No evidence of sensitisation was seen under the conditions of this study.

The substance tested in this study is considered to be a worse case based on its higher water solubility, dermal penetration and pH. The negative results of this study can therefore be confidently extrapolated to chromium (III) oxide.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Animal data

No evidence of skin sensitisation was seen in the GLP- and guideline-compliant Buehler key study (in accordance with OECD 406) with the source substance chromium hydroxide sulphate.

Furthermore, the release of chromium from chromium (III) Oxide into artificial sweat was investigated in a bioaccessibility study. Since the dissolution of chromium was very low (< 0.0071%) it can be concluded that the potential for chromium (III) oxide to cause sensitisation due to dissolved chromium (III) is highly unlikely.

Human data

In the joint ECHA background document of the Committee for Risk Assessment and the Committee for Socio-economic Analysis (2012) it is stated, that

“Trivalent chromium has a high protein binding capacity and easily binds to non-specific proteins to form stable complexes within the epidermis. The result is that only little chromium (III) penetrates the skin (Thyssen and Menné, 2010).”

It is further discussed that the majority of the human data reported for work-related dermatitis of e.g. hands, arms and legs is related to workers in tanneries. Several studies report on occupational allergic contact dermatitis (ACD) from exposure to chromium in tanneries or the manufacture of articles of leather. Depending on the process conditions during skin or hide tanning, the chromium (III) substance used in these processes can be oxidised under formation or chromium (VI). The EU supported project Chrom6less, concluded that the formation of chromium (VI) could be efficiently prevented by the application of a number of process specific measures.

Based on the weight of evidence taken from studies in humans the ECHA background document concludes: “The overall conclusion from the available evidence is that chromium (III) in leather is a far less potent sensitiser than chromium (VI) and that reports of primary sensitisation to chromium (III) in humans are uncommon.”

Based on the information discussed above, it can be concluded that chromium (III) substances are not primary sensitizers in humans, which is further supported by negative findings in animals. Specifically, dichromium trioxide is of very low water solubility, shows very little percutaneous absorption and is therefore void of skin sensitisation potency.

 

 

References

ECHA (2012) Committee for Risk Assessment (RAC) and Committee for Socio-economic Analysis (SEAC). Background document to the Opinion on the Annex XV dossier proposing restrictions on Chromium VI in leather articles, Document numbers ECHA/RAC/ RES-O-0000001412-86-09/S1, ECHA/SEAC/RES-O-0000002419-71-02/S2

 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

There is no evidence in the literature that occupational exposure to chromium (III) oxide can cause respiratory sensitisation (occupational asthma).

Justification for classification or non-classification

The substance does not possess a skin sensitisation potential and does not require classification as skin sensitiser according to Regulation (EC) No 1272/2008 and subsequentadaptations.