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EC number: 205-288-3 | CAS number: 137-30-4
- Life Cycle description
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- Endpoint summary
- Appearance / physical state / colour
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- Toxicological Summary
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Endpoint summary
Administrative data
Description of key information
Key, report number 0878/1096, Split Adjuvant Test (guinea pig):
skin sensitizing
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (non-LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 10 May - 09 Jun 1988
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 406 (Skin Sensitisation)
- Version / remarks:
- adopted in 1981
- Deviations:
- yes
- Remarks:
- GPMT is the preferred technique.
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 81-6 (Skin Sensitisation)
- Version / remarks:
- adopted in 1984
- Deviations:
- no
- Remarks:
- No deviations to the Split Adjuvant Test.
- GLP compliance:
- yes
- Type of study:
- split adjuvant test
- Justification for non-LLNA method:
- The study was initiated prior to the implementation of the LLNA method.
- Species:
- guinea pig
- Strain:
- Dunkin-Hartley
- Sex:
- female
- Details on test animals and environmental conditions:
- TEST ANIMALS
- Source: Charles River Wiga, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approximately 2 month
- Weight at study initiation: 287 - 413 g
- Housing: Groups of two animals were housed in metal cages with wire-mesh floors.
- Diet: standard diet (Hope Farms, Woerden, Netherlands) including ascorbic acid (1600 mg/kg bw), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 days (7 days for the animals of the primary experiment)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 60 - 85
- Photoperiod (hrs dark / hrs light): 12/12 - Route:
- epicutaneous, occlusive
- Vehicle:
- corn oil
- Concentration / amount:
- 0.2 mL at a concentration of 25% (w/w) in corn oil
- Day(s)/duration:
- patches were renewed on Day 1, 2, 4 and 7 and removed on Day 9
- No.:
- #1
- Route:
- epicutaneous, occlusive
- Vehicle:
- corn oil
- Concentration / amount:
- 1, 5 and 10% in corn oil
- Day(s)/duration:
- 24 h (starting on Day 21)
- No. of animals per dose:
- 20 females (treatment group) and 10 fmelaes (control group)
- Details on study design:
- RANGE FINDING TESTS:
A primary irritation experiment was fconducted first. The purpose of this test was to determine the concentrations to be applied in the challenge phase. Four guinea pigs were shaved and their flank was exposed for 24 h to an amount of 0.05 mL at 5, 10, 25 and 50% (w/w) of the test substance in corn oil occlusively administered by means of four Square chambers. 24 h after removal of the dressings, no erythema was seen. 48 h after removal of the dressings, most animals showed very slight erythema and one animal at the concentration of 10% and 20% severe erythema. One additional animal received 0.5 mL of the test substance, 50% in corn oil for 24 h, on a patch of Metalline for the evaluation of the toxicity of the compound. In this case, very slight erythema and scaliness was observed. No systemic toxic effects resulted from these treatments with ziram in any of the animals.
MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 4 (epicutaneous)
- Exposure period: continiously up to 9 days
- Test groups:
Epicutaneous 1: 0.2 mL of test substance, 25% (w/w) in corn oil was applied on Day 1
Epicutaneous 2: 0.2 mL of test substance, 25% (w/w) in corn oil was applied on Day 2
Epicutaneous 3: 0.2 mL of test substance, 25% (w/w) in corn oil was applied on Day 4
Injection 1: 0.1 mL of Freund’s complete adjuvant was injected intradermally in both sides of the exposure site.
Epicutaneous 4: 0.2 mL of test substance, 25% (w/w) in corn oil was applied on Day 7
- Control group: Animals of the control group received injections of Freund’s complete adjuvant on Day 4 only.
- Site: back
- Frequency of applications: 4 times
- Duration: continiously up to Day 9
- Concentrations: 25% (w/w) in corn oil
B. CHALLENGE EXPOSURE
- No. of exposures: 1 (challenge)
- Day(s) of challenge: Challenge was performed three weeks after intradermal induction on Day 21.
- Exposure period: 24 h
- Test groups: test substance and vehicle only
- Control group: test substance and vehicle only
- Site: flank
- Concentrations: 0, 1, 5 and 10% (w/w) in corn oil
- Evaluation (hr after challenge): 24 and 48 h after removal of the dressing
OTHER:
The test animals were observed for mortality/moribundity. Clinical signs were recorded. - Challenge controls:
- Yes, the treatment group, which were induced with the test substance but treated only with corn oil in the challenge phase.
- Positive control substance(s):
- yes
- Remarks:
- The assay was checked for reliability in a separate study on guinea pigs using formaldehyde solution as a positive control substance.
- Positive control results:
- A positive control experiment was carried out in February 1987 in order to validate the animals and the test procedure. Test substance was formaldehyde solution 37%. In the induction phase, 5% (w/w) test solution in Milli-Ro water was applied. In the challenge phase, 0.5, 2 and 5% (w/w) test substance in Milli-Ro water was applied. A sensitization rate of 50% was obtained to the 0.5% concentration.
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 0% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 1% (epicutaneous)
- No. with + reactions:
- 2
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 5% (epicutaneous)
- No. with + reactions:
- 5
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 10% (epicutaneous)
- No. with + reactions:
- 6
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 0% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 1% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 5% (epicutaneous)
- No. with + reactions:
- 1
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- skin reaction with grade 1; no skin reaction with a grade > 1 observed
- Key result
- Reading:
- 1st reading
- Hours after challenge:
- 24
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 10% (epicutaneous)
- No. with + reactions:
- 1
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Remarks:
- skin reaction with grade 1; no skin reaction with a grade > 1 observed
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 0% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 20
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 1% (epicutaneous)
- No. with + reactions:
- 2
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 5% (epicutaneous)
- No. with + reactions:
- 3
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- test chemical
- Dose level:
- induction: 25% (epicutaneous); challenge: 10% (epicutaneous)
- No. with + reactions:
- 3
- Total no. in group:
- 20
- Remarks on result:
- positive indication of skin sensitisation
- Remarks:
- any skin reaction of grade 2 or more where counted
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 0% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 1% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 5% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- 2nd reading
- Hours after challenge:
- 48
- Group:
- negative control
- Dose level:
- induction: 0% (epicutaneous); challenge: 10% (epicutaneous)
- No. with + reactions:
- 0
- Total no. in group:
- 10
- Remarks on result:
- no indication of skin sensitisation
- Key result
- Reading:
- other: not specified
- Group:
- positive control
- Dose level:
- induction: 5% (epicutaneous); challenge: 0.5, 2 and 5% (epicutaneous)
- Remarks on result:
- other: A sensitization rate of 50 % was obtained to the 0.5 % concentration.
- Remarks:
- The positive control was previosuly investigated, no challenge duration, number of animals and number reactions were not provided.
- Interpretation of results:
- other: According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for skin sensitisation Category 1 (H317) is warranted.
- Conclusions:
- The study (Split Adjuvant Test) was conducted according to EPA OPP 81-6 and OECD guideline 406, under GLP and is considered valid and reliable. Adult female guinea pigs were induced by epicutaneous applications of the test substance, 25% (w/w) in corn oil and afterwards challenged with a series of test substance concentrations (10%, 5%, and 1%, w/w). Under the test conditions, the test substance produced a sensitizing reaction to the skin of guinea pigs with a skin sensitisation rat of 30 and 15% at the higest test substance concentration 24 and 48 h after patch removal. According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, classification for skin sensitisation Category 1 (H317) is warranted.
Reference
Clinical signs and fatalities
Other than dermal irritation during induction, clinical signs
related to exposure of the test substance were not observed. All animals
survived to the scheduled termination of the in life phase.
Skin reactions
Control group
There were no skin reactions observed in the control animals, except
for one animal which showed red spots in reaction to the 5% and 10% test
substance concentration.
Test substance group
The test substance, suspended in corn oil at several concentrations
(0, 1, 5 and 10%) and administered epicutaneously to guinea pigs in the
challenge phase, resulted in a skin response (considering any skin
reaction at grade 2 or more) to the 0, 1, 5 and 10% concentration in 0,
2, 5 and 6 animals, respectively 24 h after the challenge phase. This
corresponded to 0, 10, 25 and 30% sensitization rate in the animals
challenged with 0, 1, 5 and 10% of the test material, respectively at
the 24 h reading time point. At the 48 h reading time point, skin
responses to the 0, 1, 5 and 10% concentration were observed in 0, 2, 3
and 3 animals, respectively. This corresponded to 0, 10, 15 and 10%
sensitization rate in the animals challenged with 0, 1, 5 and 10% of the
test material, respectively at the 48 h reading time point.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed (sensitising)
- Additional information:
Respiratory irritation was observed after single inhalation exposure of rats (Report number: UCB 314/89684 and 378/2) (for details, please refer to the respective study records and the endpoint discussion provided under “Irritation”. In conclusion, classification for STOT-SE 3 (H335) is warranted according to the classification criteria of the CLP Regulation (EU) No. 1272/2008.
In the key study (Report number: 0878/1096), skin sensitising properties of the test substance were evaluated in guinea pigs according to the Split Adjuvant Test (EPA OPP 81-6 and OECD 406) in compliance with GLP. Adult female guinea pigs were induced by epicutaneous applications of the test substance, 25% (w/w) in corn oil. After being challenged with a series of test substance concentrations (1, 5 and 10% w/w), positive skin responses were observed in 0, 2, 5 and 6 animals challenged with 0, 1, 5 and 10% w/w, respectively 24 h after the challenge phase (counting any skin reaction with grade 2 or more). This corresponded to 0, 10, 25 and 30% sensitization rate in the animals challenged with 0, 1, 5 and 10% of the test material, respectively at the 24 h reading time point. At the 48 h reading time point, skin responses to the 0, 1, 5 and 10% concentration were observed in 0, 2, 3 and 3 animals, respectively. This corresponded to 0, 10, 15 and 15% sensitization rate in the animals challenged with 0, 1, 5 and 10% of the test material, respectively at the 48 h reading time point. There were no skin reactions observed in the control animals, except for one animal, which showed red spots in reaction to the 5% and 10% test substance concentration. The results of the study led to a sensitization rate of 30 and 15% at the higest test substance concentration 24 and 48 h after patch removal, which indicates that the test substance exhibited sensitizing properties in the conducted test.
Contrary results were obtained by a Guinea Pig Maximization Test (GPMT). The study was conducted in compliance with B.6 of the Directive 84/449/EEC and GLP, but is only mentioned here for purpose of data completeness (Report number: 4399/T/031/95). 20 female Dunkin Hartley guinea pigs received an intradermal induction by injection of the test substance as 0.02% solution in sterile water followed by a percutaneous induction of 75% test substance as a paste in sterile water. For the challenge reaction, the animals were exposed dermally to 75% of the test substance as a paste in sterile water 21 days after the intradermal induction. A second group of 10 animals served as a control group. 2 animals died during the study. Examination of these animals revealed changes in the lungs. These effects reflect more probably the health status of the animals and are probably not consecutive to treatment with the test substance. Reaction to the test substance was observed in 2/18 surviving animals of the test group 24 h after the challenge. Also 2/10 control animals exhibited reaction to the test substance at 24 h. After 48 h, no animals of either the treatment or the control group showed signs of any skin reactions. Therefore, it was concluded, that the test substance had no skin sensitizing properties in this test.
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Based on the available data, the test item induced skin sensitization in guinea pigs. Therefore, the substance is classified as skin sensitising category 1 (H317) according to Regulation (EC) No 1272/2008 and Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation, Index No. 006-012-00-2).
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