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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-10-11 to 2017-05-23
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Remarks:
Only deviations from the study plan: minor environmental fluctuations, not considered to have impacted the outcome of the study or interpretation of the study results.
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Remarks:
Only deviations from the study plan: minor environmental fluctuations, not considered to have impacted the outcome of the study or interpretation of the study results.
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The GPMT method (OECD 406) was preferred above the LLNA (OECD 429) since previous experience with water soluble rare earth compounds learned that there is an increased risk for false positive results when performing the LLNA.

Test material

Constituent 1
Reference substance name:
trichloropraseodymium; heptahydrate
Cas Number:
10025-90-8
Molecular formula:
PrCl3.7H2O
IUPAC Name:
trichloropraseodymium; heptahydrate
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): Praseodymium trichloride heptahydrate
- Physical state: Solid
- Appearance: Green crystalline powder
- Further information on test material confidential.
Specific details on test material used for the study:
A correction factor of 1.51 was applied to correct for the presence of hydration water in the test item. Concentrations were calculated to anhydrous form.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Hartley
Remarks:
CRL:HA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at at first dosing (Day 1): ca. 6 weeks
- Weight at randomisation (Day -1): 302-345 g
- Housing: Due to capacity reasons, animals were housed in Macrolon cages size III during the preliminary study with the approval of IACUC until size IV became available for the main study, with 5 animals/cage to allow socialisation. Lignocel 3/4-S Hygienic Animal Bedding was available to animals during the study.
- Diet (e.g. ad libitum): ad libitum, Cunigra Diet for Rabbits (produced by Bonafarm-Bábolna Takarmány Ltd., Hungary). Batch number: NN16204276 GR, expiry date: 15 January 2017, and Batch number: NG16102998 GRAN, expiry date: 05 February 2017.
- Water (e.g. ad libitum): ad libitum, tap water from municipal supply as for human consumption, containing at least 50 mg/100 mL ascorbic acid. The drinking water is routinely analysed and is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.
- Acclimation period: At least 5 days before start of treatment under laboratory conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.0–21.6°C
- Humidity (%): 24–60%
- Air changes (per hr): 15-20 air exchange/hour
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
physiological saline
Concentration / amount:
concentration: 0.1% (w/v)
volume: 0.1 mL
Day(s)/duration:
day 1 of treatment
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
concentration: 75% (w/v)
volume: 0.5 mL
Day(s)/duration:
day 8 of treatment, 48 hours of exposure
Adequacy of induction:
highest technically applicable concentration used
Challenge
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
concentration: 10% (w/v)
volume: 0.5 mL
Day(s)/duration:
day 22 of treatment, 24 hours of exposure
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
Preliminary test: 8 animals
Main test: 10 in the test group, 5 in the control group
Details on study design:
RANGE FINDING TESTS
- A day prior to the test, the hair was removed from the right and left sides of the animals (approximately 5x5 cm). The hair removal was performed carefully to ensure animals are closely shaven.
- A series of test item concentrations were tested to identify the primary irritation following intradermal injection and dermal application: 0.01, 0.05, 0.1, 0.5, 1, 2.5 and 5% (w/v) formulations in physiological saline were used for intradermal injections and 10, 25, 50 and 75% (w/v) formulations in physiological saline were used for dermal application.
- For the intradermal application, 0.1 mL per concentration was injected intradermally into the hair free skin of the animals. Two concentrations were injected on the right side and another two concentrations on the left side of the animals. The highest concentration (5%) was also tested in a 1:1 mixture (v/v) of Freund's Complete Adjuvant and physiological saline solution. Each concentration was injected in duplicate. Two animals were used per concentration.
- For the dermal application, the volume of the concentrations was 0.5 mL. A closed patch exposure was performed by means of an occlusive bandage using similar treatment procedures as for the main study. The time of exposure for the dermal application was 48 hours. One concentration was used on the right side and another concentration on the left side of the animals. Two animals per concentration were used.
- Local effects were examined and scored 1, 24, 48 and 72 hours after the treatment or after patch removal.
- Skin effects were scored for erythema and oedema, and any other observations of changes to the skin were recorded as well.
- In the intradermal application, the concentrations between 0.5 and 5% (w/v) in physiological saline and the formulation of 5% (w/v) with FCA caused a maximum of well-defined erythema but with areas of 6 mm or more of white, yellow, grey or brown alteration of the skin surface, with apparently no blood circulation. Previous experience showed that such patches with a size >= 6 mm can result in unacceptable ulceration. At 0.1 and 0.05%, the patches had a maximum size of 3 and 2 mm, respectively, and at 0.01% no adverse effects were noted. Therefore the maximum concentration that can be used for intradermal treatment was considered to be 0.1%.
- In the dermal application, the highest tested concentration of 75% (w/v) in physiological saline (which was also the highest achievable concentration in the vehicle) resulted in very slight erythema, which was observed during the whole observation period. The concentration of 50% (w/v) in physiological saline caused very slight erythema in one animal (observation at 1 h only). At a concentration of 25% (w/v) in saline, very slight erythema was observed at 1 h which were reversible within 24 h. No symptoms were observed at 10% (w/v) in saline.

MAIN STUDY
A INDUCTION EXPOSURE
A1. INTRADERMAL INDUCTION EXPOSURE (day 1)
- No. of exposures: Three pairs of intradermal injections (0.1 mL/site).
- Test groups (the first listed nearest the head): 2 injections of Freund's Complete Adjuvant and physiological saline solution in a 1:1 (v/v) mixture, 2 injections of 0.1% test item in saline, 2 injections of 0.1% test item, formulated in a 1:1 mixture (v/v) of Freund's Complete Adjuvant and physiological saline solution.
- Control group (the first listed nearest the head): 2 injections of Freund's Complete Adjuvant and physiological saline solution in a 1:1 (v/v) mixture, 2 injections of saline, 2 injections of vehicle, formulated in a 1:1 mixture (v/v) of Freund's Complete Adjuvant and physiological saline solution.
- Site: Scapular region. On the day before treatment, an area approximately 5x5 cm on the scapular region of the animals was clipped free of hair and was carefully shaved.
- Frequency of applications: One application.
- Skin reactions were observed and recorded as follows: 24 hours after treatment

A2. DERMAL INDUCTION EXPOSURE (day 8)
- Since the 75% (w/v) formulation of the test item in saline was skin irritant in the dermal dose range finding study, the test area was not painted with 10% sodium dodecyl sulphate.
- Site: The same scapular region which received the intradermal injections was used for dermal induction exposure.
- Test groups: A 2.5x2.5 cm sterile gauze patch (approximately 4 layers of porous gauze pads) was saturated with approximately 0.5 mL of the test item at 75% (w/v) concentration in saline and placed over the injection sites (scapular region). The gauze patches were kept in contact with the skin by a patch with a surrounding adhesive hypoallergenic plaster. The treated areas were covered for 48 hours with a fully occlusive foil (Closed Patch Test). After the patch removal, any remaining test item was removed with a wet gauze swab. Following the dermal induction treatment, the animals were left untreated for 14 days prior to challenge applications.
- Control group: The control group was treated with 0.5 mL vehicle (saline) using the same method.
- Frequency of applications: One application.
- Skin reactions were observed and recorded as follows: 1, 24, 48 and 72 hours after patch removal

B. CHALLENGE EXPOSURE (day 22)
- Site: Approximately 24 hours before the treatment, the hair was removed from an area of approximately 5x5 cm on the left and right sides of each animal.
- Test and control groups: A 2.5x2.5 cm patch of sterile gauze was saturated with approximately 0.5 mL of the test item at 10% (w/v) concentration in saline (highest non-irritant dose) and applied to the left side of all animals (both the test and the control animals). The right shaved side area of all animals was treated with the vehicle (saline). The gauze patches were kept in contact with the skin by a patch with a surrounding adhesive hypoallergenic plaster. The treated areas were covered for 24 hours with a fully occlusive foil (Closed Patch Test). After the patch removal, any remaining test item was removed with a wet gauze swab.
- Frequency of applications: One application.
- Skin reactions were observed and recorded as follows: 24 and 48 hours after patch removal

OBSERVATIONS AND SCORING
- Body weight was recorded with a precision of 1 g at randomisation (Day -1), then at least weekly, including Day 25 prior to euthanasia. The mean values and the standard deviations were calculated and reported.
- Mortality/clinical signs: Daily recorded during the test.
- Detailed clinical observations were made on all animals outside the home cage in a standard arena before the first treatment (on the day of randomisation) and at least weekly thereafter. The dermal irritation scores (in case of dermal induction exposures) were evaluated according to the scoring system by Draize (1959).

- Erythema and eschar formation:
0 = No erythema
1 = Very slight erythema (barely perceptible)
2 = Well defined erythema
3 = Moderate to severe erythema
4 = Severe erythema (beef redness) to slight eschar formation (injuries in depth)

- Oedema formation:
0 = No oedema
1 = Very slight oedema (barely perceptible)
2 = Slight oedema (edges of area well defined by definite raising)
3 = Moderate oedema (raised approx. 1 mm)
4 = Severe oedema (raised more than 1 mm and extending beyond area of exposure)

After the challenge exposure, each animal was examined and scored 24 and 48 hours after the end of the exposure period.

Grading was performed according to the following system (classification of skin sensitisation):
0 = no visible change
1 = discrete or patchy erythema
2 = moderate and confluent erythema
3 = intense erythema and swelling

TERMINAL PROCEDURE
Terminal animals were sacrificed under pentobarbital anaesthesia.
Challenge controls:
A 2.5x2.5 cm patch of sterile gauze was saturated with approximately 0.5 mL of the test item at 10% (w/v) concentration in saline (highest non-irritant dose) and applied to the left side of all animals (both the test and the control animals). The right shaved side area of all animals was treated with the vehicle (saline).
Positive control substance(s):
yes
Remarks:
2-mercaptobenzothiazole

Results and discussion

Positive control results:
Challenge with the test item 2-mercaptobenzothiazole elicited discrete or moderate erythema (score 1 or 2) on the skin surface of previously sensitised guinea pigs. The mean scores were 1.40 (100% of animals) at the 24 hours observation and 0.90 (90% of animals) at the 48 hours observation. In the control group the mean of the scores was 0.00. On the basis of the results of the reliability test, the test item 2-mercaptobenzothiazole was classified as a skin sensitiser. This demonstrates that the Magnusson and Kligman method (OECD 406) in this laboratory is considered to be reliable.

In vivo (non-LLNA)

Resultsopen allclose all
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% (w/v) in saline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No signs of systemic or local toxicity observed in any of the animals. No mortality observed.
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10% (w/v) in saline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No signs of systemic or local toxicity observed in any of the animals. No mortality observed.
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% (w/v) in saline
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic or local toxicity observed in any of the animals. No mortality observed.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% (w/v) in saline
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No signs of systemic or local toxicity observed in any of the animals. No mortality observed.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
50% (w/v) 2-mercaptobenzothiazole in aqueous methylcellulose solution (concentration not reported)
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
Discrete or moderate erythema (score 1 or 2) on the skin surface of previously sensitised guinea pigs.
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
50% (w/v) 2-mercaptobenzothiazole in aqueous methylcellulose solution (concentration not reported)
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
Discrete or moderate erythema (score 1 or 2) on the skin surface of previously sensitised guinea pigs.
Remarks on result:
positive indication of skin sensitisation

Any other information on results incl. tables

Clinical observations/mortality/body weight

- No signs of systemic or local toxicity were observed in any of the animals.

- No mortality was observed during the study.

- There were no notable differences in body weight between the test animal group and the control group.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Challenge with the test item (praseodymium trichloride) evoked no positive responses in the test animals previously sensitised with the test item or in the control group. The net response value represented an incidence rate of 0% and the net score value of 0.00. In conclusion, under the conditions of the present assay, the test item praseodymium trichloride was shown to have no skin sensitisation potential and is consequently classified as a non-sensitiser, according to current EU-regulations.