Registration Dossier

Administrative data

Description of key information

Reliable animal data were found indicating that lead oxide, lead phosphite and dibasic lead phthalate lack irritating properties for the skin or the eyes.

Sparingly soluble lead compounds do not exhibit irritant or corrosive properties in acute inhalation studies. There are no reports of respiratory irritation in occupationally exposed workers.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
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.
Justification for type of information:
Appropriate in vivo study was already available. No need to perform in vitro study.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
There was one deviation from the study protocol which was concerned with the relative humidity (section 6.2 Husbandry). On some days of the study the relative humidity was higher than 70%.
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Name of test material (as cited in study report): PEBETAL dibasic lead phthalate
- Physical state: fine, white powder
- Analytical purity: 74.15% Pb= 97.6% Pebetal
- Composition of test material, percentage of components: ash: 79.3%; water: 0.2%
- Lot/batch No.: D1/4296
- Expiration date of the lot/batch: July 31, 2004
- Storage condition of test material: At room temperature; Shelf life; at least one year after dispatch
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann
- Age at study initiation:
- Weight at study initiation: 2.97, 3.09, 3.26 kg
- Housing: The rabbits have been housed individually in a battery of cages with a cage size 100 x 45 x 40 cm (L x B x H), equipped with a paper disposal system.
- Diet (e.g. ad libitum): Teklad Global Rabbit Diet (pelleted diet, batch no. K088). Offered ad libitum.
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking nipples.
- Acclimation period: The animals were acclimatised to the laboratory for more than 5 days. Animals were housed at the testing facility for 20 days or several months.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- degrees centigrade
- Humidity (%): 44-72%
- Air changes (per hr): Air was changed about 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:
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Remarks:
The skin of the back of all animals was clipped 24 hours before treatment and examined for potential lesions. The untreated left side of the back served as control.
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.5 g
Duration of treatment / exposure:
4 hours
Observation period:
24, 48, and 72 hours after the exposure period.
Number of animals:
Three male rabbits
Details on study design:
TEST SITE
- Area of exposure: The right side of the back of the rabbit.
- % coverage:
- Type of wrap if used: The test article was applied to a gauze patch and then applied to the skin. To ensure good contact with the skin, 2-3 drops of peanut oil were used. The closed patch exposure was effected by means of a semi-occlusive bandage using Ypsiplast , nonirritating tape Elastoplast and Stulpa, which enveloped the whole of the animal's trunk.


REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:


SCORING SYSTEM:
Irritation parameter:
other: Grading of Skin Reaction as stipulated by OECD 404
Basis:
mean
Time point:
other: 24, 48 and 72 hours after the 4 hour exposure
Score:
0
Max. score:
0
Irritant / corrosive response data:
No signs of erythema or oedema were observed. The mean grades at 24, 48 and 72 hours after the end of exposure were "0" in each animal.
Other effects:
No toxic effects with respect to the general condition were observed.
Interpretation of results:
other: Not classified under EU (CLP) criteria. However, a conclusion cannot be made on GHS criteria.
Conclusions:
The test substance was classified on the basis of the mean values of skin reactions 24,48, and 72 hours after the end of the 4-hour exposure according to the criteria specified by the EEDC Directive 2001/59/EEC of 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999
(BGB1.I, p.2233). When applied to the skin, the test substance is classified as "non-irritant".
Executive summary:

The potential toxicity of "PEBETAL dibasic lead phthalate" was assessed in an acute dermal irritation/corrosion test on three albino rabbits. In each animal, 0.5 g of the solid test substance was applied on the right side of the dorsal clipped region, the untreated ledt side served as control. Exposure duration was 4 hours. Both sides were examined at 1, 24, 48 and 72 hours after the end of exposure.

The following results were obtained:

-No signs of erythema and oedema were observed.

-No general toxic effects were seen.

-The mean grades at 24, 48 and 72 hours after the end of exposure were "0" in each animal.

The test substance was classified on the basis of the mean values of skin reactions 24, 48 and 72 hours after the end of the 4 -hour exposure according to the criteria specified by the EEC Directive 2001/59/EEC of 6 August 2001 and the Gefahrstoffverordnung (GefDtoffV) of 15 November 1999 (BGB1.I, p.2233). When applied to the skin, the test substance "PEBETAL dibasic lead phthalate" may therefore be classified as "non-irritant".

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
August 2002-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
Justification for type of information:
Appropriate in vivo study was already available. No need to perform in vitro study.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Specific details on test material used for the study:
- Name of test material (as cited in study report): PEBETAL dibasic lead phthalate
- Physical state: fine, white powder
- Analytical purity: 74.15% Pb = 97.6% Pebetal
- Composition of test material, percentage of components: ash: 79.3%; water: 0.2%
- Lot/batch No.: D1/4296
- Expiration date of the lot/batch: July 31,2004
- Storage condition of test material: At room temperature; shelf life - at least one year after dispatch
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann
- Age at study initiation:
- Weight at study initiation: 3.11, 3.25, and 3.27 kg
- Housing: Cage size of 100 x 45 x 40 cm (L x B x H), equipped with a paper diposal system.
- Diet (e.g. ad libitum): Teklad Global Rabbit Diet ad libitum
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking nipples
- Acclimation period: Animals used in the test were housed at the testing facility and acclimatised for 27 days or several months


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3 degrees Centigrade
- Humidity (%): between 30-70%
- Air changes (per hr): 16/hr 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:
Vehicle:
unchanged (no vehicle)
Remarks:
The untreated left eye served as the control
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 g of the solid test article
Duration of treatment / exposure:
72 hours
Observation period (in vivo):
72 hours - 7 days
Number of animals or in vitro replicates:
3 male rabbits
Details on study design:
Three male rabbits used in the test were acclimatised to laboratory conditions for 27 days or several months. Twenty four hours before treatment, the eyes of all animals were examined for potential ocular lesions. Since the animals did not show ocular abnormalities, they were allocated to the test.

The solid test article was used as supplied by the sponsor. One of the animals was treated in advance in order to assess ocular reactions to the test articles. The animal was treated with 0.1 g of the solid test article, which was introduced into the conjunctival sac of the right eye after gently pulling the lower lid away from the eyeball. The lid was then gently held together for about 1 sec in order to limit loss of the test article. The untreated left eye served as control. Since there was no remarkable response to the instillation of the test article within a few days, the further two animals were treated subsequently in the same manner. Ocular reactions were assessed 1,24,48, and 72 hours after instillation and thereafter once daily up to day 7 according to the "Grades for ocular lesions." In addition to the examination of the eyes, general clinical observation was conducted. Ocular reactions were classified on the basis of calculated mean grades at 24,48 and 72 hours after treatment according to the EEC Directive 2001/59/EEC of 6 August 2001 and Gefahrstoffverordnung (GefStoffV) 0f 15 November 1999 (BGB1. I, p.2233).
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #1
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
1
Reversibility:
fully reversible within: 7 days after instillation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #2
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
1
Reversibility:
fully reversible within: 7 days after instillation
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #3
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
2.33
Reversibility:
fully reversible within: 7 days after instillation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
0.67
Reversibility:
fully reversible within: 7 days after installation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
0.33
Reversibility:
fully reversible within: 7 days after instillation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean value of scores recorded at 24, 48 and 72 hours calculated for each of three animals separately
Score:
2
Reversibility:
fully reversible within: 7 days after instillation
Irritant / corrosive response data:
Moderate redness of the conjunctivae (grade 2) was observed in all three animals at 1 hour after instillation. This finding was still apparent at 24 and 48 hours after instillation in animals no.1 and 2 or up to day 6 after instillation in animal no.3, evaluated with grade 3 at 24 hours after treatment. Discharge (grade 1 or 2) was seen in the animals at 1 hour after instillation and was still observed in animal no.3, evaluated with grade 3 at 24 hours after treatment. Discharge (grade 1 or 2) was seen in animals at 1 hour after instillation and was still observed in animal no.3 at 24 hours after instillation. Additionally, bloody vessels of the eyeball were seen in animal no.3 at 24 hours up to day 5 after instillation. In all animals, no ocular findings were seen at day 7 after instillation.
Other effects:
No general toxic effects were observed. The observed ocular findings were fully reversible within 7 days after instillation.

 

Mean values of ocular reactions at 24, 48 and 72 hours after treatment (test eye) R

 Cornea  Iris  Conjunctivae Redness  Conjunctivae Chemosis
 Rabbit 1 0.00 0.00 1.00 0.67
 Rabbit 2 0.00 0.00  1.00 0.33 
 Rabbit 3 0.00  0.00   2.33 2.00 

Key:

Conjunctivae redness 1.00 - Some blood vessels definitely hyperaemic

2.00- Diffuse, Crimson colour, individual vessels not easily discernible

Conjunctivae chemosis 0 -No swelling; 1.00 Any swelling above normal; 2.00 Obvious swelling with partial eversion of lids

Interpretation of results:
other: Not classified under EU (CLP) criteria. However, a conclusion cannot be made on GHS criteria.
Conclusions:
The mean grades of ocular reactions at 24, 48 and 72 hours after instillation were lower than the value classified as irritant by the EEC Directive 2001/59/EEC of 6 August 2001 and the Gefahrstoffverordnung (GefffStoffV) of 15 November 1`999 (BGB1. I, p,2233). When administered to the eye, the test substance "PEBETAL dibasic lead pthalate" may be classified as "non-irritant."
Executive summary:

The potential toxicity of "PEBETAL dibasic lead phthalate" was assessed in an acute eye irritation/corrosion test on 3 albino rabbits. In each animal, 0.1 g of the test substance was introduced into the conjunctival sac of the right eye, the untreated left eye served as control. Both eyes were examined at 1, 24, 48, and 72 hours post applicationem.

The following results were obtained;

Redness and chemosis of the conjunctivae, grade 2, were observed in the animals 1 hour after instillation and in one rabbit up to day 5 or 6 after instillation. Moderate discharge was observed in all animals at 1 hour after instillation and was seen in one out of three animals also at 24 hours after instillation. Additionally, bloody vessels of the eyeball were seen in one animal between 24 hours and day 6 after instillation.

No general toxic effects were observed.

The observed ocular findings were fully reversible within 7 days after instilllation in all animals.

The mean grades of findings were 1.00, 1.00, and 2.33 for redness of the conjunctivae and 0.67, 0.33 and 2.00 for chemosis of the conjunctivae

The mean grades of ocular reactions at 24,48 and 72 hours after instillation were lower than the value classified as irritant by the EEC Directive 2001/59/EEC of 6 August 2001 and the Gefahrstofffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p.2233) When administered to the eye, the test substance "PEBETAL dibasic lead phthalate" may be classified as "non-irritant."

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Reliable animal data were found indicating that lead oxide, lead phosphite and dibasic lead phthalate lack irritating properties for the skin or the eyes. The experimental data are reinforced by a lack of reports of skin or eye irritation in the many occupational exposure environments which provide opportunities for exposure of lead and sparingly soluble lead compounds to the skin and eyes. Classification for these endpoints is clearly not needed. Specific studies of lung irritation were not found, but the lack of inhalation toxicity from lead oxide in both acute toxicity testing and inhalation cancer bioassays combine with an absence of reports of lung irritation in occupational settings to suggest classification is not needed.

The substances for which data are available should permit data waiving for a number of other substances. The three tested compounds are all sparingly soluble (and thus unlikely to undergo significant dissolution when applied to the skin, eyes or inhaled. The tested compounds further include one compound with an organic anion and one with an inorganic anion. Literature searches have failed to identify anions in other sparingly soluble substances that would alter the irritant properties of other sparingly soluble lead salts. Finally, dermal, oral and inhalation toxicity studies for lead compounds are uniformly negative and further support a finding of no irritant properties. Data waiving for all irritant classification endpoints should thus be possible for metallic lead and other sparingly soluble lead salts (unless anions are present that literature searches suggest might impart irritating properties.

No studies were found documenting corrosive properties of lead and sparingly soluble lead compounds in either experimental animals or humans. Given the negative findings of acute toxicity and irritation studies and the absence of reports from occupationally exposed workers, corrosive properties are not to be expected of lead or its sparingly soluble compounds.


Justification for selection of skin irritation / corrosion endpoint:
Well-documented and corresponded to the requirements of the recommended Annex V test guidelines

Justification for selection of eye irritation endpoint:
Well-documented and corresponded to the requirements of the recommended Annex V test guidelines

Justification for classification or non-classification

No skin or eye irritation observed in experimental studies conducted according to Annex V test guidelines.

No evidence of respiratory irritation in rat acute toxicity studies up to 5mg/L and no reports of respiratory irritaion following extensive use of this substance in the workplace.