Ashes (residues), nonhazardous municipal solid waste

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

December 2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study, tested with the source substance. According to the ECHA guidance the reliability was changed to RL2 to reflect the fact that this study was conducted on a read-across substance.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
See attached document in IUCLID Section 13 – Read across document

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attached document in IUCLID Section 13 - Read across document

3. ANALOGUE APPROACH JUSTIFICATION
See attached document in IUCLID Section 13 - Read across document

4. DATA MATRIX
See attached document in IUCLID Section 13 - Read across document

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Assessment from available information

Adequacy of study:

key study

Study period:

December 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific method and is described in sufficient detail.

Objective of study:

toxicokinetics

Qualifier:

no guideline required

TOXICOKINETICS EVALUATION

According to the experimental data

Acute studies

The test substance, Ashes (residues), was applied to laboratory animals (rat, mouse, and rabbit) during studies with different way of entry into organism (e.g. skin, stomach, and eye).

According to the results of acute studies it is not possible to determine if the substance does not penetrate into the organism at all or if it is absorbed without detrimental effect to treated animals.

The substance when applied to the skin of the rabbit or mouse or to the mucous membrane (conjunctivae) elicited only slight effects at the site of application that disappeared quickly. The substance is not irritant nor sensitizer.

After the acute exposition through the stomach of rats (high single exposure doses, up to 2000 mg/kg of body weight) no digestive tract irritation or other clinical or pathological symptoms were observed. This experiment did not allow the estimation if the substance is absorbed during such an exposition design.

Long-term studies

The oral administration of the test substance, Ashes (residues), to rats by gavage for a period of 28 consecutive days at dose level 250, 500 and 1000 mg/kg/day produced generally no toxicologically significant changes in the parameters measured with one exception: histopathological examination induced slight pathological changes in males (oedema in prostate gland), which could be related to the administration of test substance.

In Reproduction/Developmental Toxicity Screening Test the following dose levels: 1000 mg/kg/day, 400 mg/kg/day, 160 mg/kg/day were administered. Statistically significant effects of the test substance manifested in: decrease of male body weight (1000 mg/kg/day), decrease in the weight of male pituitary gland (1000 mg/kg/day), and increased weight of mothers uterus (400 mg/kg/day). Also the negative effects on fertility indices were observed: increased post-implantation loss at a dose level of 400 mg/kg/day and decrease of number of pups at a dose level of 1000 mg/kg/day. Based on these results it could be deduced that the test substance is absorbed from gastrointestinal tract and it is distributed throughout the body of experimental animals to relatively distant compartments, e.g. influence to pituitary gland, prostate gland and uterus.

According to the databases data

In the introduction it should be noted that the information found in STN and Chemdrug databases overlaps, so the following review does not specify the source of the information.

Among the literature sources dealing with the effect of fly ash on laboratory animals after inhalation only two papers were found which revealed some indices of fly ash absorption through the lung and its transfer to other tissues.

One of them studied the effect of fly ash using whole body inhalation exposure for 28 days in laboratory rats on the deposition of metal ions and histopathological changes in the liver and serum clinical enzymes has been studied. The results showed an increase in the concentration of metals such as cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), and lead (Pb) in the tissues of exposed rats. The level of metals varied from metal to metal and from organ to organ. Level of serum enzymes such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, and alkaline phosphatase were increased in fly ash exposed rats as compared to sham controls.

Histopathological studies of rat liver exposed to fly ash revealed infiltration of mononuclear cells in and around the portal triads, which seems to be laden with fly ash particles. Hepatocytes showed necrotic changes such as pyknotic nuclei, karyorrhexis, and karyolytic. 

These findings demonstrate that the toxic metals of inhaled fly ash in rats may get translocated into extrapulmonary organs, become deposited and hence may manifest their toxic effects on different tissues.

Another study showed that exposure of rats to fly ash for 15 days, 6 hours daily, inhibited pulmonary and hepatic NADH-oxidase activity, so that the toxic components of the fly ash have been transported to the liver cells.

 

Other studies resulted generally in the local effect of inhalation exposure of rats or guinea pigs by ash particles of different origin such as:

- mild neutrophilic inflammation in the lung and blood following short-term exposure at levels that could be occupationally relevant 

- a toxic effects of the fly ash inhalation with the damage, local inflammation and remodelling of lung as indicated by hypertrophy and hyperplasia

- fly ash burden of lungs resulting in an impairment of the local immune response of the lungs without an associated effect on the systemic immunity

 - heavy metals, cadmium, lead, zinc, and mercury were elevated in the lungs of guinea pigs. histologic evaluation of pulmonary tissue revealed multifocal pneumoconiosis.

- elevation of plasma fibrinogen levels and modulation of bone marrow and pulmonary inflammatory changes

Special information is given by Chemdrug database about the reproduction effects. After tracheal instillation of fly ash to the rats the Specific Developmental Abnormalities of cardiovascular (circulatory) system and urogenital system were observed. On the other hand no such an effect was revealed in the CETA reproduction study at comparable level of dosing. But there was a difference in the way of exposure.

Conclusions:

Interpretation of results (migrated information): other: See conclusions
The substance when applied to the skin or to the mucous membrane (conjunctivae) of experimental animals elicited only slight effects at the site of application that disappeared quickly. The substance is not irritant nor sensitizer. Presumably the substance does not enter the body through these routes.
After the acute exposition through the stomach of rats (2000 mg/kg) no digestive tract irritation or other clinical or pathological symptoms were observed. This experiment did not allow the estimation if the substance is absorbed during such an exposition design.
After repeated per oral exposure there is some evidence in favour of the substance penetration through stomach mucosa and entering distant compartment of the body a as to pituitary gland, prostate gland or uterus. In reproduction study the effect on fertility indices was detected (increased post-implantation loss and decrease in the number of pups in litter).
The substance could penetrate the body more readily during the inhalation or intratracheal instillation. But also the effects observed in these studies were mostly local influencing the histological structure of pulmonary tissue and the local immune response. The substance is absorbed into blood circulation and influences the blood biochemical and/or haematological parameters. Scarcely the distant effects are reported as those in the bone marrow or the liver. These distant effects are dependent on the physical and chemical constitution of the particulate matter and on the conditions of exposure. But at the optimal conditions the substance could reach also the uterus and elicit negative influence on the foetus development.
No information was found about the excretion of the fly ash, but it could be further searched for single components of ash materials as the heavy metals

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Test material

Test material information

Constituent 1

Reference substance name:

Ashes (residues), nonhazardous municipal solid waste

EC Number:

937-417-0

Molecular formula:

not applicable

IUPAC Name:

Ashes (residues), nonhazardous municipal solid waste

Test material form:

solid: bulk

Details on test material:

- Name of test material (as cited in study report): Ashes (residues), nonhazardous municipal solid waste
- Substance type: UVCB (inorganic oxides)
- Physical state: solid
- Composition of test material, percentage of components: SiO2 47.71 %; Al2O3 12.24 %; Fe2O3 9.62 %; CaO 15.80 %; Na2O 3.93 %; MgO 1.98 %; SO3 (total) 1.73 %; K2O 1.46 %; TiO2 1.22 %;
- Lot/batch No.: SPRUK-pololetí II/2010

Results and discussion

Any other information on results incl. tables

TOXICOKINETICS EVALUATION

According to the experimental data

Acute studies

The test substance, Ashes (residues), was applied to laboratory animals (rat, mouse, and rabbit) during studies with different way of entry into organism (e.g. skin, stomach, and eye).

According to the results of acute studies it is not possible to determine if the substance does not penetrate into the organism at all or if it is absorbed without detrimental effect to treated animals.

The substance when applied to the skin of the rabbit or mouse or to the mucous membrane (conjunctivae) elicited only slight effects at the site of application that disappeared quickly. The substance is not irritant nor sensitizer.

After the acute exposition through the stomach of rats (high single exposure doses, up to 2000 mg/kg of body weight) no digestive tract irritation or other clinical or pathological symptoms were observed. This experiment did not allow the estimation if the substance is absorbed during such an exposition design.

Long-term studies

The oral administration of the test substance, Ashes (residues), to rats by gavage for a period of 28 consecutive days at dose level 250, 500 and 1000 mg/kg/day produced generally no toxicologically significant changes in the parameters measured with one exception: histopathological examination induced slight pathological changes in males (oedema in prostate gland), which could be related to the administration of test substance.

In Reproduction/Developmental Toxicity Screening Test the following dose levels: 1000 mg/kg/day, 400 mg/kg/day, 160 mg/kg/day were administered. Statistically significant effects of the test substance manifested in: decrease of male body weight (1000 mg/kg/day), decrease in the weight of male pituitary gland (1000 mg/kg/day), and increased weight of mothers uterus (400 mg/kg/day). Also the negative effects on fertility indices were observed: increased post-implantation loss at a dose level of 400 mg/kg/day and decrease of number of pups at a dose level of 1000 mg/kg/day. Based on these results it could be deduced that the test substance is absorbed from gastrointestinal tract and it is distributed throughout the body of experimental animals to relatively distant compartments, e.g. influence to pituitary gland, prostate gland and uterus.

According to the databases data

In the introduction it should be noted that the information found in STN and Chemdrug databases overlaps, so the following review does not specify the source of the information.

Among the literature sources dealing with the effect of fly ash on laboratory animals after inhalation only two papers were found which revealed some indices of fly ash absorption through the lung and its transfer to other tissues.

One of them studied the effect of fly ash using whole body inhalation exposure for 28 days in laboratory rats on the deposition of metal ions and histopathological changes in the liver and serum clinical enzymes has been studied. The results showed an increase in the concentration of metals such as cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), and lead (Pb) in the tissues of exposed rats. The level of metals varied from metal to metal and from organ to organ. Level of serum enzymes such as serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, and alkaline phosphatase were increased in fly ash exposed rats as compared to sham controls.

Histopathological studies of rat liver exposed to fly ash revealed infiltration of mononuclear cells in and around the portal triads, which seems to be laden with fly ash particles. Hepatocytes showed necrotic changes such as pyknotic nuclei, karyorrhexis, and karyolytic. 

These findings demonstrate that the toxic metals of inhaled fly ash in rats may get translocated into extrapulmonary organs, become deposited and hence may manifest their toxic effects on different tissues.

Another study showed that exposure of rats to fly ash for 15 days, 6 hours daily, inhibited pulmonary and hepatic NADH-oxidase activity, so that the toxic components of the fly ash have been transported to the liver cells.

 

Other studies resulted generally in the local effect of inhalation exposure of rats or guinea pigs by ash particles of different origin such as:

- mild neutrophilic inflammation in the lung and blood following short-term exposure at levels that could be occupationally relevant 

- a toxic effects of the fly ash inhalation with the damage, local inflammation and remodelling of lung as indicated by hypertrophy and hyperplasia

- fly ash burden of lungs resulting in an impairment of the local immune response of the lungs without an associated effect on the systemic immunity

 - heavy metals, cadmium, lead, zinc, and mercury were elevated in the lungs of guinea pigs. histologic evaluation of pulmonary tissue revealed multifocal pneumoconiosis.

- elevation of plasma fibrinogen levels and modulation of bone marrow and pulmonary inflammatory changes

Special information is given by Chemdrug database about the reproduction effects. After tracheal instillation of fly ash to the rats the Specific Developmental Abnormalities of cardiovascular (circulatory) system and urogenital system were observed. On the other hand no such an effect was revealed in the CETA reproduction study at comparable level of dosing. But there was a difference in the way of exposure.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: See conclusions
The source substance Ashes (residues) when applied to the skin or to the mucous membrane (conjunctivae) of experimental animals elicited only slight effects at the site of application that disappeared quickly. The substance is not irritant nor sensitizer. Presumably the substance does not enter the body through these routes.
After the acute exposition through the stomach of rats (2000 mg/kg) no digestive tract irritation or other clinical or pathological symptoms were observed. This experiment did not allow the estimation if the substance is absorbed during such an exposition design.
After repeated per oral exposure there is some evidence in favour of the substance penetration through stomach mucosa and entering distant compartment of the body a as to pituitary gland, prostate gland or uterus. In reproduction study the effect on fertility indices was detected (increased post-implantation loss and decrease in the number of pups in litter).
The source substance Ashes (residues) could penetrate the body more readily during the inhalation or intratracheal instillation. But also the effects observed in these studies were mostly local influencing the histological structure of pulmonary tissue and the local immune response. The substance is absorbed into blood circulation and influences the blood biochemical and/or haematological parameters. Scarcely the distant effects are reported as those in the bone marrow or the liver. These distant effects are dependent on the physical and chemical constitution of the particulate matter and on the conditions of exposure. But at the optimal conditions the substance could reach also the uterus and elicit negative influence on the foetus development.

Executive summary:

Short description of toxicokinetic behaviour of the source substance Ash (residues) was carried out (see conclusions). Based on the similarity of the source material, Ashes (residues), and the target material, Ashes (residues), nonhazardous municipal solid waste, may be assumed identical or similar toxicokinetic behaviour both materials.