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EC number: 235-252-2 | CAS number: 12141-20-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
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- Nanomaterial pour density
- Nanomaterial photocatalytic activity
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- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://echa.europa.eu./o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Carcinogenicity
Administrative data
Description of key information
Evidence from studies with rats, and to a lesser extent mice, provide consistent evidence that soluble lead compounds are carcinogenic in laboratoryanimals. Renal tumours, most often in the male rat, have been reproducibly induced by high-level lead administration in water or food. Limited data suggest that other tissue sites (e.g., the brain) might be impacted. The mechanism by which lead induces tumours in rodents has been actively researched and may entail mechanisms that are both indirect (nongenotoxic) and of uncertain relevance to humans. A number of studies have suggested carcinogenesis in the kidney is secondary to nephropathy and the induction of sustained compensatory cell proliferation.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Well-documented and corresponded to the criteria set for assessing animal studies in (Klimisch, et. al. 1996)- A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data, giving due consideration to the published data quality criteria in place at the time the study was conducted.
- Qualifier:
- no guideline available
- GLP compliance:
- no
- Species:
- rat
- Sex:
- male/female
- Route of administration:
- oral: feed
- Details on exposure:
- of lead added to the laboratory diest was 0, 10, 50, 100, 500, 1000 and 2000 ppm.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Measured concentration of lead in the diet: 5 ppm, 18 ppm, 62 ppm, 141 ppm, 548 ppm, and 3 ppm, 1130 ppm and 2102 ppm.
- Duration of treatment / exposure:
- Two years
- Frequency of treatment:
- Daily in food
- No. of animals per sex per dose:
- 50 male and 50 female rats per dose level and 100 male and 100 female control rats receiving the basal laboratory diet. After the study was in effect for several months, a second two-year feeding study was initiated in rats to provide dietary lead levels of 0, 1000 and 2000 ppm added lead. In the latter study, only 20 male and female rats were used per dose level.
- Details on study design:
- In order to provide additional information on the effects of the long-term ingestion of lead, our laboratory fed diets containing lead acetate to rats and dogs for two years. The concentration of lead added was 0, 10, 50, 100 and 500 ppm. There were 50 male and 50 female rats per dose level and 100 male and female control rats receiving basal laboratory diet. Four male and four female beagle dogs were used at each dose level. After the studywas in effect for several months, a second two-year feeding study was initiated in rats to provide dietary lead levels of 0, 1000 and 2000 ppm added lead. in the latter study, only 20 male and 20 female rats were used per dose level.
- Observations and examinations performed and frequency:
- During the study, the clinical appearance and behavior of the animals was observed. A neurologic examination was done on the dogs by a recognized authority in veterinary neurology from the University of Pennsylvania. Food consumption, growth and mortality were recorded. Periodic blood, urine, fecal and tissue lead analyses were done using atomic absorption spectrophotometry. A complete blood count, hemoglobin, hematocrit, stippled cell count, prothrombin time, alkaline phosphatase, urea nitrogen, glutamic-pyruvic transaminase, cholesterol, and all albumin microscopic urinalyses were performed. The activity of the enzyme delta-aminolevulinic acid dehydrase (ALAD) in the blood and the excretion of its substrate, deltaaminolevulinic acid (DALA) in the urine were also determined.
- Sacrifice and pathology:
- A thorough necropsy including both gross and histologic examination was done on all animals that died, survived or were sacrificed during the two-year period.
- Other examinations:
- A three-generation, six litter, reproduction study was done using the rats fed 0, 10, 50, 100, 1000 and 2000 ppm lead.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Details on results:
- There were no significant effects on the appearance, behavior, weight gain, mortality or neurologic examination of dogs receiving as much as 500 ppm Pb in their diet. The clinical appearance and behavior of the rats receiving as much as 2000 ppm Pb was normal; however, the rate of weight gain was depressed in both male and female rats ingesting diets containing 1000 and 2000 ppm Pb. Male rats fed 500 and 2000 ppm Pb had an increased mortality; however, the mortality at the 1000 ppm Pb level was not different from the control. The reason for this discrepancy is not known.It is also apparent that kidney tumors were seen in male rats at the 500 ppm Pb level and above. These were not seen in the females until the 2000 ppm Pb level. Most of the tumors were adenomas derived from the tubular epithelium. There were no pathologic changes seen in the rats fed up to and including 100 ppm lead in their diet. With the dogs, there were no pathologic effects of dietary lead on any of the organ systems in the females. A slight degree of cytomegaly was found in the proximal convoluted tubule of the kidney in two of four male dogs fed 500 ppm Pb.
- Dose descriptor:
- LOAEC
- Effect level:
- >= 500 ppm
- Sex:
- male
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Conclusions:
- There were no significant effects on the appearance, behavior, weight gain, mortality or neurologic examination of dogs receiving as much as 500 ppm Pb in their diet. The clinical appearance and behavior of the rats receiving as much as 2000 ppm Pb was normal; however, the rate of weight gain was depressed in both male and female rats ingesting diets containing 1000 and 2000 ppm Pb. Male rats fed 500 and 2000 ppm Pb had an increased mortality; however, the mortality at the 1000 ppm Pb level was not different from the control. The reason for this discrepancy is not known. It is also apparent that kidney tumors were seen in male rats at the 500 ppm Pb level and above. These were not seen in the females until the 2000 ppm Pb level. Most of the tumors were adenomas derived from the tubular epithelium. There were no pathologic changes seen in the rats fed up to and including 100 ppm lead in their diet. With the dogs, there were no pathologic effects of dietary lead on any of the organ systems in the females. A slight degree of cytomegaly was found in the proximal convoluted tubule of the kidney in two of four male dogs fed 500 ppm Pb.
- Executive summary:
In order to provide additional information on the effects of long-term ingestion of lead, the Haskell laboratory fed diets containing lead acetate to rats and dogs for two years. The concentration of lead added was 0, 10, 50, 100 and 500 ppm. There were 50 male and 50 female rats per dose level and 100 male and 100 female control rats receiving the basal laboratory diet. Four male and four female beagle dogs were used at each dose level. After the study was in effect for several months, a second two-year feeding study was initiated in rats to provide dietary lead levels of 0, 1000 and 2000 ppm added lead. In the latter study, only 20 male and 20 female rats were used per dose level.
There were no significant effects on the appearance, behavior, weight gain, mortality or neurologic examination of dogs receiving as much as 500 ppm Pb in their diet. The clinical appearance and behavior of the rats receiving as much as 2000 ppm Pb was normal; however, the rate of weight gain was depressed in both male and female rats ingesting diets containing 1000 and 2000 ppm Pb. Male rats fed 500 and 2000 ppm Pb had an increased mortality; however, the mortality at the 1000 ppm Pb level was not different from the control. The reason for this discrepancy is not known. It is also apparent that kidney tumors were seen in male rats at the 500 ppm Pb level and above. These were not seen in the females until the 2000 ppm Pb level. Most of the tumors were adenomas derived from the tubular epithelium. There were no pathologic changes seen in the rats fed up to and including 100 ppm lead in their diet. With the dogs, there were no pathologic effects of dietary lead on any of the organ systems in the females. A slight degree of cytomegaly was found in the proximal convoluted tubule of the kidney in two of four male dogs fed 500 ppm Pb.
Reference
In this study, the major finding in animals fed dietary Pb levels at or below 100 ppm for two years was inhibition of ALA-dehydrase. 100 ppm resulted in a blood Pb concentration of 31.5 in the dog and 35.2 in the rat and was not associated with any significant clinical, histopathologic, neurologic, reproductive, or mortality effects. Similarly, adult humans generally begin to show clinical signs of lead poisoning at blood Pb values above 80 ug/100gm. In this study, a dietary Pb level of 500 ppm produced a blood Pb concentration in both species of about 80 ug/100 ml which was associated with an increase in DALA excretion. At this level and higher, increased mortality and renal changes were observed in the rats. The latter may be attributable to the very high concentration of lead found in the kidney of the rat compared to man and the dog.
A high degree of correlation was found between blood Pb concentration and concentrations of lead found in the kidney, bone, liver and brain of both rats and dogs. Thus, blood Pb concentration appears to be a good index of tissue Pb deposition as well as exposure to Pb.
Table 1: Kidney Tumour Incidence in the Azar et al. Bioassay
Pb Dose (ppm1) |
Male Rats2 |
Female Rats2 |
Dosing3mg/kg/day |
Total Pb3 |
3 |
0/120 |
0/120 |
0.23 |
0.06 |
18 |
0/50 |
0/50 |
0.78 |
0.2 |
62 |
0/50 |
0/50 |
3.1 |
0.8 |
141 |
0/50 |
0/50 |
7.8 |
2 |
548 |
5/50 (10%) |
0/50 |
27 |
7 |
1130 |
10/20 (50%) |
0/20 |
55 |
14 |
2102 |
16/20 (80%) |
7/20 (35%) |
103 |
26 |
1Dosage expressed as Pb content of food.
2Results given as number of animals with tumours/number of
animals per treatment group %. Animals at 7 tumours given in parenthesis.
3Calculated on the assumption of 350 g adult weight and that
daily food consumption is 5% of body weight.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 7.8 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Carcinogenicity: via inhalation route
Link to relevant study records
- Endpoint:
- carcinogenicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Well-documented and corresponded to the criteria set for assessing animal studies in (Klimisch, et. al. 1996)- A Systematic Approach for Evaluating the Quality of Experimental Toxicological and Ecotoxicological Data, giving due consideration to the published data quality criteria in place at the time the study was completed.
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: French Atomic Energy Commission
- GLP compliance:
- yes
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF outbred OFA
- Age at study initiation: 10 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: After exposure all rats were housed throughout their life-span in the same animal house.
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period: After their arrival in the laboratory, the animals were kept in quarantine for 1 week before any treatment and acclimated to inhalation exposure chambers for 1 week before the beginning of inhalation exposure.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): Animals were maintained on a 12 hour light cycle.
IN-LIFE DATES: From: To:
TEST ANIMALS
- Source: SPF outbred OFA
- Age at study initiation: 10 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: After exposure all rats were housed throughout their life-span in the same animal house.
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period: After arrival in the laboratory, the animals were kept in quarantine for 1 week before any treatment and acclimated to inhalation exposure chambers for 1 week before the beginning if inhalation exposure.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): The animals were maintained a 12 hour light cycle.
IN-LIFE DATES: From: To:
TEST ANIMALS
- Source: SPF outbred OFA
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):
IN-LIFE DATES: From: To:- Details on exposure:
- The experiments were carried out on 10-week old male SPF outbred OFA Sprague-Dawley rats. After their arrival in the laboratory, the animals were kept in quarantine for 1 week before any treatment and acclimated to inhalation exposure chambers for 1 week before the beginning of inhalation exposure. After exposure all rats were housed throughout their life-span in the same animal house, maintained on a 12 hour light cycle.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The aerodynamic size measurement of aerosolized particles was determined using an Andersen 1 ACFM Non-Viable Ambient Particle Sizing Sampler (Cascade Impactor). The actual diameter of aerosolized particles was determined on 50.1 aliquot air samples taken from the exposure chamber and collected on 0.2 um pore size Millipore filters. The actual diameter of particles was determined by light microscopy using a Carl Zeiss Photomicroscope coupled with a video computerized image analysis system. The mean particle diameter was 0.69 um (og= 1.74).
- Duration of treatment / exposure:
- Group 1: 63 rats exposed to 0.6 Gy fission neutrons. In the author's series, this dose has been shown to result in a 10% incidence of lung cancers and a 3% incidence of kidney cancers (Morin and Lafuma, 1990).
Group 2: 50 rats exposed to 0.6 Gy fission neutrons and 2 months later, exposure to lead oxide by inhalation for 1 year as previously determined
Group 3: 50 rats exposed to lead oxide by inhalation for 1 year
Group 4: 25 rats exposed to lead oxide by inhalation for 1 year and 1 month after the end of exposure treated with six intramuscular injection of 5-6 benzoflavone - Frequency of treatment:
- The number of fissions was 4.88 10E16.
There were 240 inhalations sessions
In the group treated with 5-6 benzoflavone, 1 month after the end of the inhalation exposure, the rats recieved six intramuscular injections of 25 mg kgE-1 of 5-6 benzoflavone at fortnightly intervals. - Post exposure period:
- All animals were kept until moribund except those of the 5-6 benzoflavone group which were killed 100 days after the last injection of 5-6 benzoflavone
- No. of animals per sex per dose:
- See duration of treatment and exposure.
- Details on study design:
- The long-term inhalation carcinogenesis study was carried out on four experimental groups of Sprague-Dawley male rats.
Group 1: 63 rats exposed to 0.6 Gy fission neutrons. In the author's series, this dose has been shown to result in a 10% incidence of lung cancers and a 3% incidence of kidney cancers (Morin and Lafuma, 1990).
Group 2: 50 rats exposed to 0.6 Gy fission neutrons and 2 months later, exposure to lead oxide by inhalation for 1 year as previously determined
Group 3: 50 rats exposed to lead oxide by inhalation for 1 year
Group 4: 25 rats exposed to lead oxide by inhalation for 1 year and 1 month after the end of exposure treated with six intramuscular injection of 5-6 benzoflavone - Positive control:
- Tumour incidence and survival time were compared with those observed in a group of 785 untreated control rats, housed simultaneously in the same animal house and with those observed in three historical groups of rats exposed to fission neutrons in the Silene reactor.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: No
- Time schedule:
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: No
- Time schedule:
DERMAL IRRITATION (if dermal study): No
- Time schedule for examinations:
BODY WEIGHT: No
- Time schedule for examinations:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: No
- Time schedule for collection of blood:
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.
CLINICAL CHEMISTRY: No
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:
- Parameters checked in table [No.?] were examined.
URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
OTHER: - Sacrifice and pathology:
- GROSS PATHOLOGY: A full necropsy was performed in every animal. Liver, spleen, kidney, lungs and brain, and all organs, exhibiting macroscopic lesions were taken ssystematically.
HISTOPATHOLOGY: Histologic samples were fixed with Bouin-Hollande fixative solution. The entire lungs were fixed by intratracheal instillation of the fixative solution. Tissue samples were prepared in the form of 5um paraffin sections stained with haematoxylin-eosin-saffron for histopathological examination. - Other examinations:
- Tumour incidence and survival times
- Clinical signs:
- not examined
- Mortality:
- not examined
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Details on results:
- CLINICAL SIGNS AND MORTALITY
BODY WEIGHT AND WEIGHT GAIN
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
FOOD EFFICIENCY
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
OPHTHALMOSCOPIC EXAMINATION
HAEMATOLOGY
CLINICAL CHEMISTRY
URINALYSIS
NEUROBEHAVIOUR
ORGAN WEIGHTS
GROSS PATHOLOGY: A full necropsy was performed in every animal. Liver, spleen, kidney, lungs, and brain and all organs exhibiting macroscopic lesions nwere taken systematically.
HISTOPATHOLOGY: NON-NEOPLASTIC
HISTOPATHOLOGY: NEOPLASTIC (if applicable): Malignant tumors were differentiated into carcinomas and sarcomas. In control male rats, the spontaneous incidence of kidney and lung carcinomas was very low, 0.64%. The global incidence of cancers, including both carcinomas and sarcomas was increased in all groups exposed to fission neutrons but this increased incidence of cancers was higher in the group exposed to fission neutrons 1.15 Gy than in the other groups. In this group the incidence of lung carcinomas was multiplied by a factor of about 40 and the incidence of kidney carcinomas by a factor of about 20 compared with controls. The global incidence of cancers was lower in group 2 exposed to fission neutrons and lead oxide combined (34%) than in group 1 exposed to fission neutrons 0.6 Gy alone (47.9%). The incidence of lung carcinomas was also lower in group 2 than in group 1. In this group, only one rat had two primitive lung carcinomas, a squamous cell carcinoma and a bronchioloalveolar adenocarcinoma, as compared with four lung carcinomas, two bronchogenic adenocarcinomas and two bronchioloalveolar carcinomas, observed in group 1.
HISTORICAL CONTROL DATA (if applicable)
OTHER FINDINGS No significant survival time shortening was observed for the group exposed to lead oxide after previous irradiation by fission neutrons compared with that exposed to fission neutrons only, nor for the group exposed to lead oxide alone compared with untreated controls. - Dose descriptor:
- NOEL
- Effect level:
- ca. 5 mg/m³ air
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Conclusions:
- These results did not show a direct carcinogenic effect of inhaled lead oxide in rats, nor did they show a co-carcinogenic effect of lead oxide under the experimental conditions used.
- Executive summary:
The aim of this work was to ascertain whether lead oxide acts as a complete lung carcinogen when inhaled alone, or as a lung co-carcinogen in rats previously exposed to fission neutrons, irradiation acting then as an initiator; or a lung co-carcinogen in rats exposed first to lead oxide by inhalation and by the end of the inhalation period to intramuscular injections of 5 -6 benzoflavone (5 -6 benaoflavone), which has been previously demonstrated to be a specific promotor of experimentally induced squamous cell carcinoma in Spragur-Dawley rats.
The results of this study did not show any excess of cancers and especially no excess of lung or kidney cancer in the groups exposed to lead oxide by inhalation as compared with unexposed control rats or with groups irradiated by fission neutrons. They did not show a clear carcinogenic or co-carcinogenic effect of inhaled lead oxide under the different experimental conditions used.
Reference
Proportion if canceers (%) observed in the organs of exposed rats |
ORGAN | Group 1Fission neutrons (0.6 Gy) only(63 rats) | Group2Fission neutrons (0.6 Gy) + PbO(50 rats) | Group 3PbO alone(50 rats) | Group 4PbO + 5-6 Benzopyrene(25 rats) |
Lung | 6.4 | 4 | -- | -- |
Salivary Glands | -- | 2 | -- | -- |
Intestines | 3.2 | -- | -- | -- |
Liver | 1.6 | -- | -- | -- |
Pancreas | 3.2 | -- | -- | -- |
Skin | -- | 2 | 2 | -- |
Mammary tissues | 1.6 | 2 | -- | -- |
Testes | -- | -- | -- | -- |
Seminal vesicle | 1.6 | -- | -- | -- |
Kidneys and Bladder | 1.6 | 4 | 2 | 8 |
Adrenals | 1.6 | -- | 2 | -- |
Pituitary | -- | -- | 2 | 4 |
Thyroid | -- | -- | 2 | -- |
Carcinomas | 20.8 | 14 | 10 | 12 |
Nervous system | 6.4 | 2 | 2 | -- |
Brain | -- | -- | -- | 4 |
Bone | -- | -- | -- | -- |
Leukemia | 3.2 | 4 | -- | 4 |
Spleen Sarcoma | 1.6 | 2 | -- | -- |
Angiosarcoma | 3.2 | 2 | -- | -- |
Soft tissue sarcoma | 11.1 | 6 | 6 | 4 |
Deep tissue sarcoma | 1.6 | 4 | 2 | -- |
Mesothelioma | -- | -- | -- | -- |
Sarcomas | 27.1 | 20 | 10 | 4 |
TOTAL | 47.9 | 34 | 20 | 4 |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- chronic
- Species:
- rat
Carcinogenicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
EU carcinogenicity classification under the Dangerous Substances Directive applied to only lead acetate (Category 3 R40) indicating adequate evidence for animals but not for humans. The existing classification for lead acetate is supported by this evaluation but does not at this time extend to other inorganic lead compounds or lead metal.
Lead monoxide is included in Regulation (EC) No 1272/2008 Annex VI Table 3.1 under the entry “lead compounds with the exception of those specified elsewhere in this Annex (Index No 082-001-00-6). No classification for the carcinogenicity endpoint is included
Soluble lead compounds have caused cancer in rats and/or mice by a variety of exposure routes, including oral, subcutaneous, intramuscular, transdermal, and transplacental, and translactational. However, a number of human epiddemiological studies have been conducted there remains no consistent observation between occupational lead exposure and cancer. IARC (2006) concluded that most of the epidemiological literature is not consistent with a causal relatuonship between human lead exposure with only a modest increase in stomach cancer being judged to be of potential significance. Based upon anticipated oral bioavailability it is expected that information on soluble lead compounds such as lead acetate can be read across and that the currentt CLP classification of this substance be applied to lead monoxide.
Thus lead monoxide is also proposed to be classified as Carc. 2; H351: Suspected of causing cancer according to CLP.
Additional information
Lead has been evaluated for carcinogenicity in multiple animal species, oftentimes producing positive results. A number of epidemiology studies have further documented the mortality experience of general population and occupationally exposed cohorts. Human epiedmiology study data (described in section 7.10.2) do not support studies with experimental animals. The following conclusions are drawn from an evaluation of these studies:
1. Although a number of human epidemiology studies have been conducted or updated over the past several decades, there remains no consistent observation of a relationship between occupational lead exposure and cancer. Sporadic increases of lung, kidney, stomach, brain and bladder cancer have been reported. However, the findings between studies are disparate and fail to provide a consistent pattern of elevated cancer mortality. Increases in cancer for lung, kidney and stomach are modest and within the range of that which might be attributed to uncontrolled confounding. Registry-based suggestions of a linkage to brain cancer are of interest, but have not been verified by cohort studies. Studies of general population exposures are both limited in number and contradictory in outcome. Given the findings from the study of occupationally exposed cohorts, risk at general population exposure levels would not be expected. There is thus insufficient epidemiology evidence to indicate that inorganic lead or lead compounds pose human cancer risk at most tissue sites studied.
2. IARC has recently affirmed that most of the epidemiological literature is not consistent with a causal relationship between human lead exposure and cancer at most tissue sites (i.e. studies are not adequate to support classification in Category 1 or known human carcinogen). Sites of initial concern (brain, lung and kidney) were ultimately judged to be the likely result of confounding. Only a modest excess observed in stomach cancer was judged to be of potential significance. Although impacts of co-exposures and other confounding factors (e.g. ethnicity, particulate matter and H. pylori infection)seemed to explain a proportion of the cancer excess observed in some studies, some impact of lead exposure could not be precluded. A limited association was thus judged to exist, but was inadequate for classification as a known human carcinogen. In accordance with the IARC preamble, the observation of cancer in animals results in a default classification of category 2B (possible human carcinogen) that is elevated to category 2A (probable human carcinogen) based upon limited epidemiological findings for stomach cancer for inorganic lead compounds.
3. Evidence from studies with rats, and to a lesser extent mice, provide consistent evidence that soluble lead compounds are carcinogenic in laboratory animals. Renal tumours, most often in the male rat, have been reproducibly induced by high-level lead administration in water or food. Limited data suggest that other tissue sites (e.g., the brain) might be impacted. Carcinogenicity from a poorly soluble lead compound (lead phosphate) has been demonstrated following subcutaneous and i.p. injection. However, the relevance of this route of administration is questionable. Overall, animal evidence for the carcinogenicity of most lead compounds in animals is adequate.
4. Rodent inhalation studies with lead oxide have been negative - but the intensity and duration of exposure was not sufficient to attribute significance to this negative finding.
5. The mechanism by which lead induces tumours in rodents has been actively researched and may entail mechanisms that are of uncertain relevance to humans. A number of studies have suggested carcinogenesis in the kidney is secondary to nephropathy and the induction of sustained compensatory cell proliferation. However, tumours have also been induced in the absence of detected degenerative changes in a single study of intrauterine exposure. Given the weak and conflicting nature of genotoxicity studies, indirect mechanisms of carcinogenesis remain the most probable mode of action have been hypothesised. However, until such time as such hypotheses have been validated, mechanistic information based upon effects in the rodent kidney are difficult to apply to an assessment of risk for humans. Mechanistic inferences are even more difficult in consideration of human cancer at tissue sites (e.g. stomach) that are not sites affected by lead in animals.
Justification for selection of carcinogenicity via oral route
endpoint:
Key study
Carcinogenicity: via oral route (target organ): urogenital:
kidneys
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