Registration Dossier

Toxicological information

Endpoint summary

Currently viewing:

Administrative data

Description of key information

Inorganic lead compounds do not exhibit toxicity in acute toxicity tests with experimental animals. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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.
Justification for data waiving:
other:
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH
- Weight at study initiation: males:286-317 g: females: 192-199 g
- Housing: The rats were housed collectively at 3 animals per cage. Before animals arrived study room and cages were cleaned and disinfected. During study, room and cages were cleaned at regular intervals.
- Diet (e.g. ad libitum): Teklad Global 18% Rodent Diet offered ad libitum
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking water. Water subject to periodic bacteriological tests and to chemical analyses.
- Acclimation period: 23 days (females); 28 days (males)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/-3
- Humidity (%): 30-70
- Air changes (per hr): Air was changed about 16 times per hour and filtered adequately
- Photoperiod (hrs dark / hrs light): Artificia light was set to give a cyle of 12 hours light and 12 hours dark with light on at 7:00 AM.
Route of administration:
oral: gavage
Vehicle:
peanut oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20% formulation of the test article
- Amount of vehicle (if gavage):10 ml/kg
- Justification for choice of vehicle:
- Lot/batch no. (if required): 072K0107 SIGMA
- Purity:


MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg


DOSAGE PREPARATION (if unusual):


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Initially the dose of 2000 mag/kg was administered to 3 male rats. Since no mortality was observed within a few days, the test article was administered subsequently to 3 male rats at the same dose of 2000 mg/kg.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3 females and 3 males
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:The animals were examined 1 hr, 2 hr, 6 hr and 24 h after treatment and thereafter once daily up to day 14 of the study. Body weights were recorded immediately before treatment and days 7 and 14 p.a. (termination).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, necropsy
Preliminary study:
Initially, the dose of 2000 mg/kg was administered to 3 female rats. Since no mortality was observed within a few days, the test article was administered subsequently to 3 male rats at the same dose of 2000 mg/kg.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No male or female animal treated orally at the dose of 2000 mg/kg died prematurely
Clinical signs:
No clinical observations were observed in male and female animals during the 14-day observation period following the treatment at the dose of 2000 mg/kg.
Body weight:
There was no influence of the test article administered orally at the dose of 2000mg/kg on the body weight development in the male and female animals during the 14-day observation period.
Gross pathology:
Gross pathological examinations on day 14 p.a. (terminal necropsy) did not reveal test article-related findings.
Other findings:
spontaneous death n=0
killed in extremis n=0
terminal sacrifice 14 days p.appl. n=6

Animal no. Specific Findings
1-5 no specific findings
6 uterus: hydrometra
Interpretation of results:
practically nontoxic
Remarks:
Migrated information LD50 > 2000 mg/kg may be classified as "non-toxic" Criteria used for interpretation of results: EU
Conclusions:
LD 50 >2000 mg/kg When administered by the oral route. The test article may therefore be classified as "non-toxic."
Executive summary:

The acute oral toxicity of LITHARGE lead oxide was investigated according to ATC method in one step using 3 male and 3 female rats. Three female animals were given a single oral administration of the test article Litharge lead oxide at a dose of 2000 mg/kg. Clinical observations were carried out at regular intervals during the 14-day observation period. Body weights were determined immediately before treatment and on 7 days and 14 p.a. Gross pathological examinations were carried out immediately at termination on all animals.

The following results were obtained:

-No animals died during the course of the 14-day observation period following the dose of 2000 mg/kg.

-No abnormal clinical signs were observed

-There was no influence of the treatment on the body weight development in all male and female animals during the 14-day observation period.

-Gross pathological examinations on day 14 p.a. did not reveal test article-related findings.

According to the EEC Directive 2001/59, 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1. I, p.2233), the test article LITHARGE lead oxide can be classified as "non-toxic", since the oral LD50 value after 24 h and 14 days is expected to be higher than 2000 mg/kg in male and female Wistar rats.

These results can be assigned to lead titanium trioxide since a read across based on a grouping of substances (Pb substances) is applied.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 001 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
August 2003- February 2004
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 data waiving:
other:
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
other: Charles River Deutschland GmbH - CD
Sex:
male/female
Details on test animals and environmental conditions:
Age at start of adaptation: males: approx. 45 days
females: approx. 56 days

Body Weight at start of administration males: 217-233 g
females: 195-211 g
Number 10 (5 male and 5 female animals)
Duration of experiment: at least 5 adaptation days, 1 test day and 2 recovery weeks

Diet - ssniff R/M-H V11534 served as food (ssniff Spezialdiaten GmbH, D-59494 Soest;composition: see Appendix 2). Feeding was discontinued approx. 16 hours before exposure; only tap water was ten available ad libitum. Periodic analysis of the food for contaminants based on EPA/USA is conducted at least twice a year by LUFA-ITL (limitation for contaminants in the diet: see Appendix 2). Certificates of analysis of the composition and
for contaminants were provided by the manufacturer and are QUA archived.

Housing - Granulated textured wood was used as bedding material for the cages. The cages were changed and cleaned twice a week. Periodic analysis of the bedding material for contaminants based on EPA/USA is conducted at least once a year by LUFA-ITL (limitation for contaminants in the bedding material: see Appendix 2. During the 14-day observation period the animals were kept by sex in groups of 2-3 animals in MAKROLON cages (type III) at a room temperature of 22 degrees C +/-3 degreesC (maximum range) and a relative humidity of 55%+/- (maximum range). Deviations from the maximum range caused for example dfuring cleaning procedures are dealt with in SPOPs. The rooms were lit (150 lux at approx. 1.5 m room height) and darkened for periods of 12 hours each.

Drinking water - Drinking water in bottles was offered ad libitum. Drinking waater is examined according to the "Deutsche Trinkwasserverordnung 2001' [German Regulations on drinking water 2001] by the Hamburger Wasserwerke, D20539 Hamburg, at least four times a year (limitation for contaminants in the drinking water: see Appendix 2). In addition, drinking water samples taken at LPT are analysed by
LUFA-ITL once a year for means of bacteriological investigations according to the German "Deutsche Trinkwasserverordnung 2001, Anlage 1' [German Regulations on drinking water 2001, Addendum 1].




























Route of administration:
inhalation
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
The study was carried out using a dynamic inhalation chamber (air changes/h (>/= 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER. The apparatus consists of a cylindrical exposure chamber (volume 40L) which holds a maximum of 20 animals in pyrex tubesat the edge of the chamber in a radial position. The dust of the test item was generated with a rotating brush dust generator. The generator was fed with compressed air (0.5 bar) from a compressor (air was taken from the surrounding atmosphere of the laboratory room and filtered using an in-line disposable gas-filter). At the bottom of the exposure chamber, the air was sucked off at a lower flow rate than it was created by the spray-jet in order to produce a homogeneous distribution and a positive pressure in the exposure chamber. A manometer and an air-flow meter was used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary. The oxygencontent in the inhalation chamber was 21%. It was determined at the beginning and at the end of the exposure with a DRAGER Oxygen-analysis test set (DRAGER Tube Oxygen 67 28 081). The whole exposure system was mounted in an inhalation facility to protect the laboratory staff from possiblehazards.
Concentration (mg/L air): 5.05
Air flow entrance (L/h): 900
Air flow exit (L/h): 800
Air changes (changes per hour): 22.5
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Drager Tube Oxygen 67 28 081, Minisart SM 17598 0.45 UM (sample filter), Vacuubrand, MZ 2C6
Duration of exposure:
ca. 4 h
Concentrations:
5.05 mg/L air - actual concentration; nominal concentration - 848.9 mg/L air; 5.834 um mass median aerodynamic diameter; 1.061 mg/L air respirable amount particle size
No. of animals per sex per dose:
1 group of 5 males and 5 females
Control animals:
no
Details on study design:
After completion of exposure, the animals were observed for a period of 14 days. During and following exposure, observations were made and recorded systematically; individual records were maintained for each animal. A careful clinical examination was made at least once daily until all symptoms subsided, thereafter each working day. Observations on mortality were made at least once daily to minimize loss of animals to the study, e.g. necropsy or refrigeration of those animals found dead and isolation or sacrifice of weak or moribund animals, Cageside observation included, but were not limited to: changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, as well assomatomotor activity and behaviour pattern. Particular attention was directed to observation of tremor, convulsions, salivation, diahhoea, lethargy, sleep and coma. Individual weights were determined before the exposure and weekly after exposure. Changes in weight were calculated and recordedwhen survival exceeds one day. At the end of the test, the surviving animals were weighed and sacrificed. Necropsy of animals was carried out and allgross pathological changes were recorded.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5.05 mg/L air
Exp. duration:
4 h
Mortality:
No mortality occurred
Clinical signs:
No clinical signs of toxicity
Body weight:
No inhibition of body weight gain
Gross pathology:
No abnormalities were detected at necropsy.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information requires no classification Criteria used for interpretation of results: EU
Conclusions:
Under the present test conditions, the LC50-value for CD rats following inhalation of a dust of Litharge (Lead oxide) for 4 hours can be expected above an actual concentration of 5.05 mg/L air. According to the EC-Commission directive of September 1st, 1993 on the approximation of the laws, regulations and administrative provision relating to the classification packaging and labelling of dangerous substances (67/548/EC and its subsequent amendments) and the results obtained under the present test conditions, Litharge (Lead Oxide) requires no classification.
Executive summary:

The aim of the present experiment was to obtain information on the acute toxicity following single 4 -hour inhalation exposure of rats to Litharge (Lead Oxide) in an acute toxicity study designed as a test limit. Rats were exposed to a dust of Litharge (Lead oxide) at an actual concentration of 5.05 +/-0.010mg Litharge/L air for 4 hours by inhalation using a dynamic nose-only exposure chamber. In the inhalation chamber, close to the animals' noses, the particles had a mass median aerodynamic (MMAD) of 5.834UM as determined with a cascade impactor. The Geometric Standard Deviation (GSD) of the MMAD was calculated as 4.814. The geometric mean diameter of the supplied test item was 11.430 um as determined with a Malvern Mastersizer. Under the present test conditions, a 4-hour exposure to a dust of Litharge (lead oxide at a concentration of 5.05 +/-0.10 mg Litharge/L air revealed no clinical signs of toxicity. No mortality occurred. No abnormalities were detected at necropsy. All animals gained the expected weight throughout the study period. The LC50 can be expected above an actual concentration of 5.05 mg Litharge/L air for 4 hours at 14 days. According to the EC-Commission directive 67/548/ECC and its subsequent amendments on the approximation of the laws, regulations, and administrative provision relating to the classification, packaging and labelling of dangerous substances and the results obtained under the present test conditions. Litharge (Lead oxide) requires no classification.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
5.05 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
August 2003-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 data waiving:
other:
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
There was one deviation from the study protocol which was concerned with the relative humidity (section 6.2 husbandry). On some of the study days, the relative humidity was higher than 70%.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Winkelmann GmbH
- Weight at study initiation: male 285-323 g; female: 187-218 g
- Housing:Before the animals arrived, the study room and cages were cleaned and disinfected. During the study, the room and cages were cleaned at regular intervals. The rats were hpoused individually in cages (Makrolon II).
- Diet (e.g. ad libitum): Teklad Global 18% Protein Rodent Diet (pelleted diet, batch no.204986) offered ad libitim.
- Water (e.g. ad libitum): Tap water as for human consumption was continuously available ad libitum via drinking bottles. Samples of drinking water are subjected to bacteriological tests, including the determination of chlorinated hydrocarbons, heavy metals and arsenic.
- Acclimation period: range finding: 15 days; main test: 21 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Room temperature was adjusted to 22 +/-3
- Humidity (%): The relative humidity was kept between 38 and 78%. Maximum and minimum temperature and humidity were monitored daily.
- Air changes (per hr): Air was changed about 16 times per hour and filtered adequately.
- Photoperiod (hrs dark / hrs light): Artificial light was set to give a cycle of 12 hours light and 12 hours dark with light on at 7:00 AM.
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: One day before each treatment, the fur was clipped from a dosal area of approx. 5X10 cm in each animal. The skin was subsequently examined for abrasions. Since the skin was healthy and intact, all animals were used for the test and coloured for individual identification.
- % coverage:
- Type of wrap if used: An occlusive dressing using a 4X5 cm patch (filter paper), Leukosilk and Elastoplast. To ensure good contact of the test article with the skin, a few drops of peanut oil were placed on the patch.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Patch Removal
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg body weight
- Concentration (if solution): The test article was used undiluted as supplied by the Sponsor
- Constant volume or concentration used: yes/no
- For solids, paste formed: No.


VEHICLE
- Amount(s) applied (volume or weight with unit): The solid test article was used undiluted as supplied by the Sponsor.
- Concentration (if solution):
- Lot/batch no. (if required): 210213
- Purity: 99.8% PbO
Duration of exposure:
The exposure period was 24 hours
Doses:
The rats were given a single dermal administration of the test artcle of 2000 mg/kg body weight.
No. of animals per sex per dose:
5 male and 5 female
Control animals:
not required
Details on study design:
In each animal a number of clinical-toxicological signs were evaluated according to a modified IRWIN Screening procedure (S. Irwin; Comprehensive Observational Assessment, Psychopharmacologia 134, 222-257, 1968) and observed findings were recorded. The animals were examined until 10min. p.a. and at the following post-treatment intervals: 1h, 2h, 6h, 24h and thereafter once daily up to day 14. Because of the occlusive dressing, the evaluation of some parameters were excluded until the 24-h observation time point. After patch removal, dermal irritation was evaluated once daily for14 days according to a scheme based on Draize. Body weights were recorded immediately before treatment and on days 7 and 14 p.a. (termination).
Preliminary study:
The range finding test was conducted using 2 female animals which were treat
ed with the dose of 2000 mg.kg body weight. There were no deaths in the preliminary study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No animal died during the course of the main test after the single dermal administration of 2000 mg/kg.
Clinical signs:
No abnormal clinical signs were observed. No skin irritation findings were seen.
Body weight:
After the first week, the body weight development was slightly influenced in most animals rather due to the administration procedure using the occlusive dressing than to the test article treatment. Decelerated weight gain was seen in one female animal (no. 10) as well as in one male animal (no.2) and slightly reduced body weight was seen in four female animals (no. 6 to 9). After two weeks, the weight gain was in the normal range known for wistar rats at this age.
Gross pathology:
Gross pathological examinations at day 14 p.a. (terminal necropsy) revealed no findings.
Other findings:
No specific findings.

On the basis of the results obtained after a single dermal administration of the test article "LITHARGE lead oxide" to Wistar rats, the LD50 values after 24 h and 14 days were as follows: Male and female > 2000 mg/kg

Interpretation of results:
practically nontoxic
Remarks:
Migrated information LD50 > 2000 mg/kg may be classified "non-toxic." Criteria used for interpretation of results: other: Draize
Conclusions:
No specific findings. On the basis of the results, obtained after a single dermal administration of the test article "LITHARGE lead oxide" to Wistar rats, the LD50 values after 24 h and 14 days were as follows: Male and Female > 2000 mg/kg. This value is higher than the limit specified as harmful by the EEC Directive 2001/59/EEC of 6 August 2001 and the Gefahrstoffverordnung (GefStoffV) of 15 November 1999 (BGB1.I, p. 2233). When administered by the dermal route, the test article "Litharge lead oxide" may be classified as "non-toxic".
Executive summary:

The acute dermal toxicity of LITHARGE lead oxide was investigated in one group of rats comprising 5 males and 5 females. On the basis of the range finding test, the animals were given a single dermal administration of LITHARGE lead oxide at the dose of 2000 mg/kg. The skin was exposed to the test articles for 24 hours. Clinical observations were carried out at regular intervals during the 14 -day observation period. Signs of erythema and oedema were evaluated once daily for 14 days. Body weights were determoned immediately before treatment and on days 7 and 14 p.a. Gross pathological examinations were carried out at study termination on all animals. The following results were obtained:

- No animal died during the 14 -day observation period.

- No abnormal clinical signs were observed.

- No signs of or skin iiritation were observed.

- The body weight development was slightly influenced in most animals during the first week after treatment, possibly due to the administration procedure as such. At the end of the study, 14 days after treatment, the body weights were in the normal range

-Gross pathological examinations on day 14 p.a. did not reveal any findings in the rats.

Since no deaths were caused in Wistar rats after dermal treatment with the test article LITHARGE lead oxide of 2000mg/kg, the LD50 values after 24h and 14 days were as follows: Male and Female >2000 mg/kg

The above value is higher than the limit specified as harmful by the EEC Directive 2001/59/EEC of 6 August 2001 and the Gefahstoffverordnung (GedStoffV) of 15 November 1999 (BGB1.I, p. 2233). When administered by the dermal route, the test article LITHARGE lead oxide may therefore be classified as "non-toxic".

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 001 mg/kg bw

Additional information

Although lead can exert toxic effects upon multiple organ systems and body functions, this toxicity manifests under conditions of

Although lead can exert toxic effects upon multiple organ systems and body functions, this toxicity manifests under conditions of sub-chronic to chronic exposure that can range from months to years in duration. Acute toxicity is not observed in animals after oral or inhalation exposures up to the limit values of acute toxicity testing. Similarly, toxicity in humans after true acute exposures is limited and, when documented, is generally under conditions that yield sub-chronic or chronic exposures. This finding is not unexpected given the pharmacokinetics of lead uptake into the body. Lead uptake is generally quite low and heavily reliant upon easily saturable active transport mechanisms. Once saturation of these uptake mechanisms has occurred, uptake proceeds by inefficient passive diffusion. The uptake of lead is thus highly non-linear as a function of dose with uptake efficiency declining with the amount of lead administered to a test animal or an exposed human. Although toxic under chronic exposure situations, the acute toxicity of lead and inorganic lead compounds appears to be quite low.

These results can be assigned to lead titanium zirconium oxide applying a read across based on a grouping of substances (Lead compounds).


Justification for selection of acute toxicity – oral endpoint
Study is done according to OECD guideline 423.

Justification for selection of acute toxicity – inhalation endpoint
Well-documented and corresponded to the requirements of the recommended Annex V test guidelines.

Justification for selection of acute toxicity – dermal endpoint
Well-documented and corresponded to the requirements of the recommended Annex V test guidelines.

Justification for classification or non-classification

Acute toxicity is not observed in animals after oral, inhalation or dermal exposures up to the limit values of acute toxicity testing. Similarly, toxicity in humans after true acute exposures is limited and, when documented, is generally under conditions that yield sub-chronic or chronic exposures. This finding is not unexpected given the pharmacokinetics of lead uptake into the body. Lead uptake is generally quite low and heavily reliant upon easily saturable active transport mechanisms. Once saturation of these uptake mechanisms has occurred, uptake proceeds by inefficient passive diffusion. The uptake of lead is thus highly non-linear as a function of dose with uptake efficiency declining with the amount of lead administered to a test animal or an exposed human. Although toxic under chronic exposure situations, the acute toxicity of lead and inorganic lead compounds appears to be quite low and does not require classification.