Concentrates of lead and zinc compounds with sulfur resulting from hydrometallurgy (hot acid leaching, super-hot acid leaching and flotation)

Carcinogenicity

Description of key information

According to transformation/dissolution study (OECD guidance 29) conducted for the substance, the most critical constituents leachable to water from this UVCB substance are lead and zinc compounds. Therefore, the chemical safety assessment focuses on the properties of these constituents and the key values for CSA are selected based on the read-across data on the most bioavailable compounds of Pb and Zn.
Evidence from studies with rats, and to a lesser extent mice, provide consistent evidence that soluble lead compounds administered via oral or inhalation routes 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. 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. Human epidemiology study data do not support studies with experimental animals. 
No adequate experimental animal studies are available to evaluate the carcinogenicity of zinc compounds in humans. In a recent critical assessment of epidemiology studies regarding dietary/supplemental zinc and prostate cancer risk, it was concluded that epidemiological studies have not provided an established relationship of dietary/supplemental zinc on the risk of prostate cancer (Costello L. C. et al., 2008).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

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.Read-across justification:Read-across from the most critical and bioavailable constituents (lead and its compounds):Based on the mineralogical composition, lead is the main constituent in the target substance and appears in sulphate form. The target substance is a solid inorganic UVCB substance and insoluble in water. Therefore, the transformation/dissolution study (OECD guidance 29) was conducted for the target substance to focus on the most critical bioavailable constituents of the substance. According to the T/D study results, the readily soluble constituent is lead. Based on the hazard profile of lead it is also the most hazardous constituent of this substance. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from the most critical constituent is used to evaluate the short-term and long-term toxicological adverse effects of the target substance. The read-across data focuses on the properties of lead sulphate and other bioavailable forms of lead.

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)

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 (ppm^1)	Male Rats^2	Female Rats^2	Dosing^3mg/kg/day	Total Pb^3
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.

 

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.

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

Reference

Endpoint:

carcinogenicity: inhalation

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

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.Read-across justification:Read-across from the most critical and bioavailable constituents (lead and its compounds):Based on the mineralogical composition, lead is the main constituent in the target substance and appears in sulphate form. The target substance is a solid inorganic UVCB substance and insoluble in water. Therefore, the transformation/dissolution study (OECD guidance 29) was conducted for the target substance to focus on the most critical bioavailable constituents of the substance. According to the T/D study results, the readily soluble constituent is lead. Based on the hazard profile of lead it is also the most hazardous constituent of this substance. Therefore, and in order to avoid the unnecessary animal testing, the read-across data from the most critical constituent is used to evaluate the short-term and long-term toxicological adverse effects of the target substance. The read-across data focuses on the properties of lead sulphate and other bioavailable forms of lead.

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:

Route of administration:

inhalation

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 determinedGroup 3: 50 rats exposed to lead oxide by inhalation for 1 yearGroup 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 sessionsIn 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 determinedGroup 3: 50 rats exposed to lead oxide by inhalation for 1 yearGroup 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 dataFOOD 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: NoWATER 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 MORTALITYBODY WEIGHT AND WEIGHT GAINFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)FOOD EFFICIENCYWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)OPHTHALMOSCOPIC EXAMINATIONHAEMATOLOGYCLINICAL CHEMISTRYURINALYSISNEUROBEHAVIOURORGAN WEIGHTSGROSS 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)

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

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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

5 mg/m³

Study duration:

chronic

Species:

rat

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based upon the overall weight of the evidence from read across lead and zinc compounds permit the conclusion to be drawn that the substance need to be classified for carcinogenicity. The classification for Carc 2 H351 according to CLP Regulation 1272/2008 and for Carc. Cat. 3; R40 according to the Directive 67/548/EEC is warranted .

Additional information

The health hazard assessment was conducted based on the most critical constituents of the substance. This substance is an UVCB substance and can be described as a moist solid powder which is insoluble to water. Therefore, the transformation/dissolution study (OECD guidance 29) was conducted for the substance and the results of this study were used for the chemical safety assessment.

According to the chemical composition analysis, the main phases of the substance are lead sulphate and zinc sulphide. The product consists primarily of sulphur (ca. 35 %), lead (ca. 25 %) and zinc (ca. 17 %) together with minor trace elements such as silver, silicon, aluminium, calcium and iron.

The transformation and dissolution study (OECD guidance 29) results indicated that the release at pH 6 was higher for all studied elements compared to release at pH 8. Therefore the following 7 and 28 day studies were conducted at pH 6. Based on the screening test results (loading rate 100 mg/L), the most critical components for the assessment were lead and zinc, with releases of 8282 µg/L and 75.4 µg/L, respectively. The other minor leachable metals were silver (34.7 µg/L), cadmium (0.48 µg/L) and copper (17.2 µg/L).

Results from the 7 day T/D test (loading rate 100 mg/L, pH 6) showed similar trend in release rates: 12333 µg/L (Pb), 91.4 µg/L (Zn), 15.6 µg/L (Cu), 31.4 µg/L (Ag) and 0.056 µg/L (Cd). In the 28 day test with lower loading rate (1 mg/L, pH 6), only concentrations of Pb (362.4 µg/L) and Zn (3.2 µg/L) were over the detection limits or blank sample values.

According to T/D study results, the most soluble and critical components of this substance are lead and zinc. Therefore, the studies for this endpoint have been selected as a read-across data for the critical constituents. The read-across justification is presented in CSR annex I. All read-across data for toxicology are based on test data using either soluble Pb or Zn salts or measured (dissolved) Pb or Zn concentrations. The weight of evidence approach was used to make conclusions on the key value for CSA. Conclusion for this endpoint is based on read-across data from zinc and lead compounds.

Lead compounds

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 epiedemiology 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.     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.

Zinc compounds

There are a range of epidemiological studies that investigated the association between zinc exposure either through occupational activities or food supplementation and increased cancer risks. While no associations were found between occupational zinc exposure and excess cancer risk, the main association that has been made in this context is related to dietary/supplemental zinc and prostate cancer risk.

In contrast to established clinical and experimental evidence that prostate cancer is associated with a decrease in the zinc uptake, numerous epidemiology studies and reports of the effect of dietary and supplemental zinc on the incidence of prostate cancer have provided divergent, inconsistent and inconclusive results which range from adverse effects of zinc, protective effects of zinc and no effect of zinc on the risk of prostate cancer. Clinical and experimental studies have established that zinc levels are decreased in prostate cancer and support a role of zinc as a tumour suppressor agent. Malignant prostate cells in situ are incapable of accumulating high zinc levels from circulation (Franklin R. B. et al.,2005; Costello L. C, and Franklin R. B., 2006; Franklin R. B. and Costello L. C, 2007).

In a recent critical assessment of epidemiology studies regarding dietary/supplemental zinc and prostate cancer risk, Costello et al., concluded that epidemiological studies have not provided an established relationship for any effect or lack thereof of dietary/supplemental zinc on the risk of prostate cancer. Proclamations of an association of dietary/supplemental zinc and increased prostate cancer are based on inconclusive and uncorroborated reports (Costello L. C. et al.,2008).

Conclusions

The read-across studies with rats, and in lesser extent mice, provide consistent evidence that soluble lead compounds administered via oral or inhalation routes are carcinogenic in laboratory animals. Human epidemiology study data of lead do not support studies with experimental animals. Thus, the classification for Carc. 2; H351: Suspected of causing cancer according to CLP and Carc. Cat. 3; R40: Limited evidence of a carcinogenic effect under DSD has been given to the substance.

On the basis of the existing information it can be concluded that there is no conclusive evidence for carcinogenic activity of any of the read-across zinc compounds considered in this chemical safety report.

Justification for selection of carcinogenicity via oral route endpoint:
No study conducted for the target UVCB substance. The selected study was conducted for the most critical read-across substance (ie. bioavailable lead) with respect to carcinogenicity.

Justification for selection of carcinogenicity via inhalation route endpoint:
No study conducted for the target UVCB substance. The selected study was conducted for the most critical read-across substance (ie. bioavailable lead) with respect to carcinogenicity.

Justification for selection of carcinogenicity via dermal route endpoint:
No dermal studies available for the substance itself or the most critical constituents in the target substance i.e. lead and zinc compounds.

Carcinogenicity: via oral route (target organ): urogenital: kidneys