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Not sensitising

Key value for chemical safety assessment

Skin sensitisation

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Endpoint:
skin sensitisation, other
Remarks:
in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August-December 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented and corresponded to the requirements of the recommended Annex V Test Guidelines.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
There was one deviation from the study protocol which was concerned with the relative humidity (section 6.2 Husbandry). At some days of the study the relative humidity was higher than 70%.
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Appropriate guinea pig maximisation test available which would not justify conducting an additional LLNA due to animal welfare.
Specific details on test material used for the study:
- Name of test material (as cited in study report): ALLSTAB LP 3139 dibasic lead phosphite
- Molecular formula (if other than submission substance): 2PbO x PbHPO3 x 0.5 H2O
- Physical state: fine white powder
- Analytical purity: 99.3%
- Lot/batch No.: 0210510067
- Expiration date of the lot/batch: > 24 months after shipping
- Storage condition of test material: At room temperature. Shelf Life: min. 24 months (sfter shipment), when stored in sealed containers at temperatures below 40 degrees centigrade.
Species:
guinea pig
Strain:
other: pirbright white
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation:
- Weight at study initiation: males: 459-545 g; females: 416-530 g
- Housing: The guinea pigs were kept in collective housing up to a maximum of 5 animals per cage in a battery of cages, equipped with a paper disposal system.
- Diet (e.g. ad libitum): "2040 Teklad Global Guinea Pig Diet" (pelleted diet, batch no. K080) offered ad libitum.
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking nipples.
- Acclimation period: 19 days (range finding); 22 days (main test)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 degrees centigrade
- Humidity (%): 37-76%
- Air changes (per hr): 16 times/ hour and filtered adequately
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light with light on at 7:00AM


IN-LIFE DATES: From: To:
Route:
intradermal and epicutaneous
Vehicle:
other: For the intradermal injection, the test article was diluted with aqua ad iniectabilia and Freund's complete adjuvant to a final concentration of 5%. For the dermal application, the solid test article was used as 50% formulation in petrolatum.
Concentration / amount:
Intradermal injection 5% of the test article
Dermal application 50% in petrolatum
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: For the dermal application, the solid test article was used as 50% formulation in petrolatum.
Concentration / amount:
Dermal application 50% in petrolatum
No. of animals per dose:
10 test and 5 control animals
Details on study design:
RANGE FINDING TESTS: The range finding test was performed to determine the concentration of the test article to be used in the main test. For the intradermal injection, the test article was diluted with aqua ad iniectabilia (Delta-Pharma, Pfullingen) and Freund's complete adjuvant (FCA; batch no. 62K8933; SIGMA, Steinheim) to a final concentration of 5.0%. Two animals were employed, skin reactions being recorded 48 and 72 hours after treatment. For the dermal application, the solid test substance was used 50% in petrolatum. A closed patch exposure was effected by means of an occlusive bandage using cellulose swabs, Leukosilk and non-irritating tape Elastoplast, which enveloped the whole animal's trunk. Two animals were employed and skin reactions were recorded 48 and 72 hours post application.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3 injection sites
- Exposure period: Seven days after injection, the injection sites were covered occlusively for 48 hours.
- Test groups: 10
- Control group: 5
- Site: Clipped intracapsular region on either side of the spine.
- Frequency of applications: Three pairs of intradermal injections (0.1 ml)
- Duration: Seven days later, the previous injection sites were covered occlusively for 48 hours with a patch carrying the test article (50%) or, in control animals, the control article petrolatum.
- Concentrations: Test Group: 1) FCA 50% (v/v) diluted in aqua ad iniectabilia, 2) testt article 5% in peanut oil, 3) test article 5% in aqua ad iniectabilia/FCA. Control Group: FCA 50% (v/v) diluted in aqua ad iniectabilia, 2) peanut oil, 3) peanut oil 50% (v/v) diluted in FCA.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: Both control and test animals were subjected to a challenge exposure 14 days after the second stage of the induction.
- Exposure period: 24 hours
- Test groups: 10
- Control group: 5
- Site: 5 x 5 cm clipped skin area on each flank
- Concentrations: The test substance was applied at the concentration of 50% to the left flank and the control substance petrolatum to the right in a volume of 0.5 g using the patch technique described under 6.2.1. In each case, the duration of the exposure was 24 hours under an occlusive dressing.
- Evaluation (hr after challenge): 24 and 48 hours after challenge.
Challenge controls:
Both control and test animals were subjected to a challenge exposure 14 days after the second stage of the induction. The challenge test was performed on a 5 x 5 cm clipped skin area on each flank. The test substance was applied at the concentration of 50% to the left flank and the control substance petrolatum to the right in a volume of 0.5 g using the patch technique described under 6.2.1. In each case, the duration of the exposure was 24 hours under an occlusive dressing.
Positive control substance(s):
no
Remarks:
The sensitivity of the test system and the reliability of the experimental technique is assessed at least every 6 months by use of "4-aminobenzoic acid ethyl ester (benzocaine)" which is known to induce skin sensitisation in guinea pigs.
Vehicle:
other: petrolatum
Concentration:
50 and 25 % in Vaseline (petrolatum)
No. of animals per dose:
10
Details on study design:
The sensitivity of the test system and the reliability of the experimental technique is assessed at least every 6 months by use of "4-aminobenzoic acid ethyl ester (benzocaine)" which is known to induce skin sensitisation in guinea pigs. This test was conducted as a Magnusson & Kligman test according to the OECD Guideline for the Testing of Chemicals, OECD 406, 17 July 1992 and to the EEC Directive 2001/59/EEC, 6 August 2001.
Positive control results:
Sensitisation rate (50%) at 24 hours: 70% Sensitisation rate (50%) at 48 hours: 70%
Sensitisation rate (25%) at 24 hours: 30% Sensitisation rate (25%) at 48 hours: 20%

Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
0 %

There were no skin reactions after the dermal application in the induction phase. No allergic skin reactions were observed in test animals after the challenge exposure 24 and 48 hours after patch removal. No findings were observed in control animals.

The sesitisation rate, i.e. the number of animals showing an alergic response expressed as a percentage of the total number of animals, was determined 24 and 48 hours after patch removal and was 0% in test animals in each case. The corresponding reaction rate in control animals was 0%.

Interpretation of results:
other: Not classified under CLP criteria
Conclusions:
According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 november 1999 (BGB1. I, p. 2233), the test article "ALLSTAB LP 3139 dibasic lead phosphite" can be classified as a "non-sensitiser since no allergic responses were observed in test animals after the adjuvant test according to Magnusson & Kligman.
Executive summary:

The potential skin sensitising properties of the test article "ALLSTAB LP 3139" were assessed in the guinea pig maximisation sensitisation test carried out as an adjuvant test according to the Magnusson & Kligman maximisation test method, using 10 test and 5 control animals in the main test. Following the induction exposure to the test article (50% in petrolatum) or the vehicle petrolatum (control article), the animals of both groups were subjected two weeks later to a challenge exposure with the test article (50% in petrolatum) as well as the control article. Responses to the challenge procedure were evaluated 24 and 48 hours after the end of the exposure period.

Results: No allergic reactions occurred in test animals 24 and 48 hours after the end of the challenge procedure. The sensitisation rate was 0%. No findings were observed in control animals (reaction rate: 0%).

Evaluation: According to nthe EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p.2233), the test article "ALLSTAB LP 3139 dibasic lead phosphite" can be classified as a "non-sensitiser" since no allergic responses were observed in test animals under the experimental conditions described.

Endpoint:
skin sensitisation, other
Remarks:
in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August-December 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented and corresponded to the requirements of the recommended Annex V Test Guidelines.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
Two deviations: No. 1 section 6.1 Animal Specification - Four control animals were used, since one of the male control animals died during the acclimatisation period. No.2: section 6.2 Husbandry - On some days the relative humidity was higher than 70%.
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Appropriate guinea pig maximisation test available which would not justify conducting an additional LLNA due to animal welfare.
Specific details on test material used for the study:
- Name of test material (as cited in study report): LITHARGE lead oxide
- Molecular formula (if other than submission substance): PbO
- Molecular weight (if other than submission substance):
- Smiles notation (if other than submission substance):
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig.
- Substance type:
- Physical state: fine, yelllow powder
- Analytical purity: 99.8% lead (II) oxide
- Impurities (identity and concentrations):
- Composition of test material, percentage of components: PbO: 99.8; metallic Pb: <0.01; Pb3O4: 0.003; Cu:<0.0001: Fe: 0.0008
- Isomers composition:
- Purity test date:
- Lot/batch No.: 210213
- Expiration date of the lot/batch: May 2005
- Radiochemical purity (if radiolabelling):
- Specific activity (if radiolabelling):
- Locations of the label (if radiolabelling):
- Expiration date of radiochemical substance (if radiolabelling):
- Stability under test conditions:
- Storage condition of test material: At room temperature
- Other:
Species:
guinea pig
Strain:
other: pirbright white
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation:
- Weight at study initiation: males 461-492 g; females: 405-484 g
- Housing: The guinea pigs were kept in collective housing up to a maximum of 5 animals per cage in a battery of cages, equipped with a paper disposal system.
- Diet (e.g. ad libitum): 2040 Teklad Global Guinea Pig Diet offerred ad libitum.
- Water (e.g. ad libitum):Tap water as for human consumption was continuously available ad libitum via drinking nipples.
- Acclimation period: 19 days (range finding); 22 days (main test)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 degrees centigrade. Maximum and minimum temperature and humidity were monitored daily.
- Humidity (%): The relative humidity was kept between 37 and 76%.
- Air changes (per hr): 16 times per hour and filtered adequately.
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light with light on at 7:00 AM.


IN-LIFE DATES: From: To:
Route:
intradermal and epicutaneous
Vehicle:
other: For the intradermal injection, the test article was diluted with aqua ad iniectabilia and Freund's complete adjuvant to a final concentration of 5%. For the dermal application, the solid test article was used as 50% formulation in petrolatum.
Concentration / amount:
Intradermal injection 5% of the test article
Dermal application 50% in petrolatum
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: For the dermal application, the solid test article was used as 50% formulation in petrolatum.
Concentration / amount:
Dermal application 50% in petrolatum
No. of animals per dose:
10 test and 4 control animals
Details on study design:
RANGE FINDING TESTS: Two animals were employed and skin reactions were recorded 48 and 72 hours post applicationem. For the both the intradermal injection and the dermal application. For the intradermal injection, the test article was diluted with aqua ad iniectabilia and Freund's complete adjuvant to a final concemtration of 5%. Two animals were employed, skin reactions being recorded 48 and 72 hours after treatment. For the dermal application, the solid test article was used as 50% formulation in petrolatum. A closed patch exposure was effected by means of an occlusive bandage using cellulose swabs and non-irritating tape which enveloped the whole animal's trunk.


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: Seven days after injections, the injection sites were covered occlusively for 48 hours.
- Test groups: 10
- Control group: 4
- Site: Injections were made in the clipped intracapsular region on either side of the spine
- Frequency of applications: Three pairs of intradermal injections (0.1 ml)
- Duration: Seven days later, the previous injection sites were covered occlusively for 48 hours with a patch carrying the test article (50%) or, in control animals, the control article petrolatum.
- Concentrations: Test Group 1) FCA 50% (v/v) diluted in aqua ad iniectabilia, 2) test article 5% in peanut oil, 3) test article 5% in aqua ad iniectabilia/F CA. Control group: 1) FCA 50% (v/v) diluted in aqua ad iniectabilia, 2) peanut oil, 3) peanut oil 50% (v/v) diluted in FCA.


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 14 days after the second stage of the induction
- Exposure period: 24 hours
- Test groups: 10 test animals
- Control group: 4 control animals
- Site: The challenge test was performed on a 5 x 5 cm clipped skin area on each flank.
- Concentrations: The challenge test was applied at the concentration of 50% to the left flank and the control article petroleum to the right in a volume of 0.5 g using the patch tehnique.
- Evaluation (hr after challenge): 24 and 48 hours after patch removal the appearance of the challenge and re-challenge skin sites was observed and skin responses were graffed on the basis of the classification system according DRAIZE. The animals were weighed before treatment and at the end of the study. All findings were recorded with respect to duration and severity on special report forms.


OTHER:
Challenge controls:
Both control and test animals were subjected to a challenge exposure 14 days after the second stage of the induction. The challenge test was performed on a 5 x 5 cm clipped skin area on each flank. The test article was applied at the concentration of 50% to the left flank and the control article petrolatum to the right in a volume of 0.5 g using the patch technique. In each case, the duration of the exposure was 24 hours under an occlusive dressing.
Positive control substance(s):
no
Remarks:
The sensitivity of the test system and the reliability of the experimental technique is assessed at least at every 6 months by use of "4-aminobenzoic acid ethyl ester (benzocaine)" which is known to induce skin sensitisation in guinea pigs.
Vehicle:
other: petrolatum
Concentration:
50 and 25% in Vaseline (petrolatum)
No. of animals per dose:
10
Details on study design:
The sensitivity of the test system and the reliability of the experimental technique is assessed at least every 6 months by use of "4-aminobenzoic acid ethyl ester (benzocaine) which is known to induce skin sensitisation in guinea pigs. This test was conducted as a Magnusson & Kliggman test according to the OECD Guideline for Testing of Chemicals, OECD 406, 17 July 1992 and to the EEC Directive 2001/59/EEC, 6 August 2001. The last test with acceptable levels of responses to this substance was performed from April 8 to 2 May 2003.
Positive control results:
Sensitisation rate 50% at 24 h: 70% Sensitisation Rate 50% at 48 h: 70%
Sensitisation rate 25% at 24 h: 30% Sensitisation Rate 25% at 48 h: 20%
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
50% in petrolatum
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
None

No allergic skin reactions occurred in test animals 24 and 48 hours after the end of the challenge procedure. The sensitisation rate was 0%. No findings were observed in control animals (reaction rate :0%).

Interpretation of results:
other: Not classified under CLP criteria
Conclusions:
According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p. 2233) testconditions described, the test substance "LITHARGE lead oxide" can be classified as a "non-sensitiser" since no allergic responses were observed in test animals under the experimental conditions described.
Executive summary:

The potential skin sensitising properties of the test article "LITHARGE lead oxide" were assessed in the guinea pig maximisation sensitisation test carried out as an adjuvant test according to the Magnusson & Kligman Maximisation test method, using 10 test and 5 control animals in the main test. Following the induction exposure to the test article (50% in petrolatum) or the vehicle petrolatum (control article), the animals of both groups were subjected two weeks later to a challenge exposure with the test article (50% in petrolatum) as well as the control article. Responses to the challenge procedure were evaluated 24 and 48 hours after the end of the exposure period.

Results: -No allergic skin reactions occurred in test animals 24 and 48 hours after the end of the challenge procedure. The sensitisation rate was 0%

-No findings were observed in control animals (reaction rate: 0%).

Evaluation: According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p.2233) test conditions described, the test article "LITHARGE lead oxide" can be classified as a "non-sensitiser" since no allergic responses were observed in test animals under the experimental conditions described.

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Pyrochlore:

The overall chemical and physiological properties of pyrochlore are principally characterised by a degree of inertness because of the specific synthetic process (calcination at high temperatures, approximately 1000°C), rendering the substance to be of a unique, stable crystalline structure in which the majority of atoms are tightly bound and not prone to dissolution in environmental and physiological media. This has been shown in in-vitro bioaccessibility testing for antimony, in which dissolved Sb concentrations were below 105µg/L even at the highest loading of 0.1g/L, thus implying a solubility of < 0.12% of antimony. Hence, Sb can be considered as not bioavailable and is not regarded concerning toxicological and environmental effects.

On the other hand, lead dissolution levels were much higher (up to 6.2 mg/L at pH 1.7) and therefore have to be regarded concerning toxicological and environmental aspects. No substance-specific data on the toxicity of pyrochlore are available, so that instead read-across to lead oxide and sparingly soluble lead compounds was conducted.

Lead:

Three studies according to OECD 406 with the substances dibasic lead phosphite, dibasic lead phthalate and LITHARGE lead oxide have been performed. Animal and human data specifically evaluating skin or lung sensitisation were not found. However, in view of the lack of toxicity, irritation or reports of sensitisation from occupational exposure settings, lead and sparingly soluble lead compounds do not appear to pose risk of sensitisation and classification for these endpoints is not indicated.

Migrated from Short description of key information:

Based on the assumption that lead is the only significantly bioavailable from the pigment pyrochlore, all available data suggests this pigment does not have skin sensitisation potential.

Respiratory sensitisation

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

Considering the absence of evidence of respiratory sensitization responses, this endpoint is not expected to be of concern for lead and lead compounds.

Migrated from Short description of key information:

While is no particular study addressing respiratory sensitisation in experimental animals, there is no information suggesting lead compounds to cause such effects in animals.Taking into account the complete absence of skin sensitization potential of lead compounds, respiratory sensitisation is not expected to be of concern for the lead compound considered in this chemical safety report.

Justification for classification or non-classification

Pyrochlore:

The overall chemical and physiological properties of pyrochlore are principally characterised by a degree of inertness because of the specific synthetic process (calcination at high temperatures, approximately 1000°C), rendering the substance to be of a unique, stable crystalline structure in which the majority of atoms are tightly bound and not prone to dissolution in environmental and physiological media. This has been shown in in-vitro bioaccessibility testing for antimony, in which dissolved Sb concentrations were below 105 ug/L even at the highest loading of 0.1g/L, thus implying a solubility of < 0.12% of antimony. Hence, Sb can be considered as not bioavailable and is not regarded concerning toxicological and environmental effects.

On the other hand, lead dissolution levels were much higher (up to 6.2 mg/L at pH 1.7) and therefore have to be regarded concerning toxicological and environmental aspects. No substance-specific data on the toxicity of pyrochlore are available, so that instead read-across to lead oxide and sparingly soluble lead compounds was conducted.

Lead:

According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 november 1999 (BGB1. I, p. 2233), the test article "ALLSTAB LP 3139 dibasic lead phosphite" can be classified as a "non-sensitiser since no allergic responses were observed in test animals after the adjuvant test according to Magnusson & Kligman.

According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p. 2233), thetest article PEBETAL dibasic lead phthalate can be classified as a "non-sensitiser" since no allergic responses were observed in test animals after the adjuvant test according to Magnusson & Kligman.

According to the EEC Directive 2001/59/EEC, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p. 2233) testconditions described, the test article "LITHARGE lead oxide" can be classified as a "non-sensitiser" since no allergic responses were observed in test animals under the experimental conditions described.

All sensitization test results were unequivocally negative and are considered to be representative of results to be expected for other sparingly soluble inorganic lead compounds.

Based upon the preceding observations, there is no indication that any of the sparingly soluble high production volume lead compounds (including lead metal) require classification for skin sensitisation.