Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Based on in vitro tests performed with prednisolone and QSAR studies with 16alpha-hydroxyprednisolone, the test substance is not deemed irritating to skin or eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-compliant guideline study, available as unpublished report, fully adequate for assessment.The restriction is due to the use of the read across approach: the test was performed not with hydroxyprednisolone but with prednisolone, a substance which is very similar in structure and physical/chemical properties.
Qualifier:
according to guideline
Guideline:
other: OECD 439
GLP compliance:
yes (incl. QA statement)
Irritation / corrosion parameter:
other: other: Optic density (OD) at 570 nm.
Value:
60.96
Remarks on result:
other:
Remarks:
Basis: mean of the nine experiments.. Max. score: 100.0. (migrated information)

Optic density (OD) at 570 nm

 REPLICA  1  2  3  4  5  6  7  8  9
 Blank 0.090   0.089  0.092  0.093  0.090  0.090  -  -  -
 Negative control  1.273  1.407  1.422  1.451  1.445  1.440  1.412  1.416  1.418
 Positive control  0.130  0.143  0.142  0.140  0.141  0.143  0.139  0.141  0.146
 Prednisolone  0.780  0.910  0.905  0.946  0.915  0.914  0.907  0.901  0.884

   Average OD  Acceptability  Result  SD %  Acceptability (%)  Result
 Negative control  1.32  1.2 ≤ OD ≤ 2.5  Complying  3.762  ≤ 18  Complying
 Positive control  3.74  < 40 %  Complying  2.837  ≤ 18  Complying

 SAMPLE  % VIABILITY  ACCEPTABILITY
 PREDNISOLONE  60.96  > 50 %
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: OECD GHS
Conclusions:
On the basis of the results, interpreted according to OECD 439 and SKINETHIC SOP (January 2009), the test product "PREDNISOLONE" must be considered NOT IRRITANT for the skin.
Executive summary:

This in vitro skin irritation test was performed with prednisolone, a compound which has been demonstrated to be very similar in structure, physicochemical properties and toxicological profile to hydroxyprednisolone in the Analogue Approach - Read across Hydroxyprednisolone document (2013, see section 13). Due to the fact hydroxyprednisolone and prednisolone have nearly the same chemical structure, the same interaction with bio-molecules, living cells and tissue and metabolic pathway is expected. Therefore, a read across from hydroxyprednisolone to data obtained with prednisolone is scientifically justified.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-compliant guideline study, available as unpublished report, no restrictions, fully adequate for assessment. The restriction is due to the use of the read across approach: the test was performed not with hydroxyprednisolone but with prednisolone, a substance which is very similar in structure and physical/chemical properties.
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
ANNEX - A Sequential Testing Strategy for Eye Irritation and Corrosion .
Qualifier:
according to guideline
Guideline:
other: Draft Updated ICCVAM Recommended HET-CAM Protocol.
Principles of method if other than guideline:
Results from in vitro or ex vivo tests: Substances that have demonstrated corrosive or severe irritant properties in an in vitro or ex vivo test that has been validated and accepted for the assessment specifically of eye or skin corrosivity/irritation, need not be tested in animals. It can be presumed that such substances will produce similar severe effects in vivo.
Even if HET-CAM assay heve not achieved the OECD validation, it is accepted for the purpose of "TESTING AND EVALUATION STRATEGY FOR EYE IRRITATION/CORROSION" as reported in ANNEX of test method B.5.
GLP compliance:
yes (incl. QA statement)
Vehicle:
physiological saline
Remarks:
B. Braun Melsungen, lot n. 017A122, expiry date: 03/2013.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Prednisolone 100 % applied to an area of 25 % of the chorioallantoic membrane.

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.3 mL of standard solution (0.9 % NaCl)
- Lot/batch no. 017A122
Duration of treatment / exposure:
The reaction on the CAM were observed over a period of 5 minuted monitoring the appearance of:
Haemorrhage (bleeding);
Vascular lysis (blood vessel disintegration);
Coagulation (protein denaturation intra- and extravascular).
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure: Prednisolone was left in contact with the egg membrane for 5 minutes.

SCORING SYSTEM: the time for each reaction to occur was recorded and an irritation score (IS) was calculated:
IS = [(301-sec H)/300] x 5 x S+ [(301-sec L)/300] x 7 x S + [(301-sec C)/300] x 9 x S

sec = second of first occurence of reaction
H = Haemorrhage
L = Vascular Lysis
C = Coagulation
S = 0.1 if H, C, L is grade 1 (weak reaction)
S = 0.5 if H, C, L is grade 2 (moderate reaction)
S = 1 if H, C, L is grade 3 (strong reaction)
The mean score was calculated from irritation scores for each egg for each test group.

TOOL USED TO ASSESS SCORE: hand-slit lamp / biomicroscope / fluorescein
Irritation parameter:
in vitro irritation score
Run / experiment:
Mean
Value:
0
Remarks on result:
no indication of irritation
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The eye irritancy potential of the test item was investigated in the chorioallantoic membrane assay.
The test item was tested as provided by the sponsor in order to find any irritancy potential.
The calculated mean irritation score was 0.
The test item was classified as non-irritant.
The positive and negative controls were within the historical control data range demonstrating the validity and sensitivity of the test.
Executive summary:

This in vitro eye irritation test was performed with prednisolone, a compound which has been demonstrated to be very similar in structure, physicochemical properties and toxicological profile to hydroxyprednisolone in the Analogue Approach - Read across Hydroxyprednisolone document (2013, see section 13). Due to the fact hydroxyprednisolone and prednisolone have nearly the same chemical structure, the same interaction with bio-molecules, living cells and tissue and metabolic pathway is expected. Therefore, a read across from hydroxyprednisolone to data obtained with prednisolone is scientifically justified.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The potential of 16alpha-hydroxyprednisolone to be corrosive or irritating to skin and eyes was assessed usingIn vitrotests performed with prednisolone and QSAR studies performed with prednisolone and hydroxyprednisolone. Like prednisolone, hydroxyprednisolone is predicted to be non-irritant to eye or skin and therefore not classified in accordance with Regulation (EC) No 1272/2008.

Skin irritation:

An in vitro biological assay (OECD 435) based on the membrane barrier test method for skin corrosion CORROSITEX was carried out. On the basis of the results, interpreted according to OECD 435, the test substance "PREDNISOLONE" is classified asNOT CORROSIVEfor the skin. (Eurofins Biolab 2010/1000 AMi). Anin vitrobiological assay (OECD 439) based on the three-dimensional Reconstituted Human Epithelium (RHE) SKINETHIC test was carried out. On the basis of the results, interpreted according to OECD 439 and SKINETHIC SOP (January 2009), the test product "PREDNISOLONE" was consideredNOT IRRITANTfor the skin (Eurofins Biolab 2010/1006 AMi).

A QSAR study, carried out with Toxtree v.2.1.0 (2010), predicted that 16alpha-hydroxyprednisolone were not irritating or corrosive to skin based on a decision support system (DSS) developed by the German Federal Institute for Risk Assessment (BfR) using physico-chemical exclusion rules. The predictions were based on the exclusion rules that Melting Point[°C] is > 55 for 16alpha-hydroxyprednisolone.

Eye irritation:

In thein vitrobiological assay (Draft Updated ICCVAM Recommended HET-CAM Protocol) (BSL Bioservice 104856) the irritancy potential of prednisolone was investigated in the chorioallantoic membrane. The calculated mean irritation score was 0. Thus prednisolone was classified as non-irritant. Positive and negative controls to demonstrate the validity and sensitivity of the test were used. According to the evaluation criteria prednisolone was classified as non-irritant to mucous membranes. Thus, no irritation can be expected if prednisolone comes in contact with the eyes.

A QSAR study carried out with Toxtree v.2.1.0 (2010), based on a decision support system (DSS) developed by the German Federal Institute for Risk Assessment (BfR) uses physico-chemical exclusion rules, excludes the potential activity irritating or corrosive to eye of 16alpha-hydroxyprednisolone. The prediction are based on the exclusion rules, of the skin irritation/corrosion endpoint, that Melting Point[°C] is > 55 for 16alpha-hydroxyprednisolone. According to international risk assessment guidelines, skin corrosion potential excludes further considerations on a similar hazardous potential to eyes, since the chemical has already proved to have corrosive properties (Tsakovska et al., 2005). Thus the above effects induced by local contact to skin are also assumed to be predictive of eye damage.

Justification for classification or non-classification

In accordance to Directive 67/548/EEC, classification is not necessary for irritation / corrosion based on the available data.