Registration Dossier

Administrative data

Description of key information

No acute toxicity of any slag
Basis for this conclusion
Oral
ABS, GBS, EAF C: OECD TG 401, rats: LD50 > 2000 mg/kg bw
BOS, SMS: OECD TG 423, rats: LD50 > 2000 mg/kg bw
Inhalation
GGBS: OECD 403, rats: 4 h-LC50 >5235 mg/m3
Skin
BOS, SMS: rats OECD 402, rats: LD50 > 4000 mg/kg

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Doses:
In the case of products mortality was not observed with the minimum dosage DL50 will be considered as higher than 2000 mg/kg.
No. of animals per sex per dose:
3
Control animals:
not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: highest and only concentration tested
Mortality:
none observed
Clinical signs:
none reported
Body weight:
not reported
Gross pathology:
not reported
Other findings:
none reported

SMS: LD50> 2000 mg/kg

Crushed stone: LD50> 2000 mg/kg

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
SMS: LD50 > 2000 mg/kg
Crushed stone: LD50 > 2000 mg/kg
Executive summary:

To examine the oral toxicity of slags, steelmaking (SMS), and crushed stone from a quarry in the vicinity of Serra, Brasilia, tests were performed following OECD guideline 423 in Wistar rats. Fine-ground BOS, SMS and crushed stone were dosed by gavage, in their original form, at 2 g/kg bw (body weight). After dosing, the animals were observed for a post exposure period of 14 days. The LD50 was > 2000 mg/kg bw for each test material.

Slags, steelmaking (SMS), and natural stone from a quarry in Serra, Brasilia, are not toxic via the oral route,and do not need to be classified as oral toxicants. No signal word and no hazard statement is required.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
animals kept at 12 h light /dark cycle at 22+/-3 °C
Route of administration:
oral: unspecified
Vehicle:
unchanged (no vehicle)
Doses:
>2000 mg/kg bw
No. of animals per sex per dose:
not reported
Control animals:
not specified
Details on study design:
Observation period of 14 d after incubation
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no effects on all test animals
Mortality:
no mortality
Clinical signs:
no clinical signs
Body weight:
no efffect on body weight
Gross pathology:
none reported

In an acute toxicity test according to OECD TG 401 with Wistar rats, no effect of SMS (ladle slag) was observed in a limit test at 2000 mg/kg bw

Interpretation of results:
practically nontoxic
Remarks:
Migrated information not toxic Criteria used for interpretation of results: EU
Conclusions:
SMS rat LD50 >2000 mg/kg bw
Executive summary:

To examine the oral toxicity of slags, steelmaking (SMS, ladle slag), a test was performed following OECD guideline 401 in Wistar rats. Fine-ground SMS was dosed at 2 g/kg bw (body weight). After dosing, the animals were observed for a post exposure period of 14 days. The LD50 was > 2000 mg/kg bw.

Slags, steelmaking (SMS) are not toxic via the oral route, and do not need to be classified as oral toxicants. Neither a signal word nor a hazard statement is required.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
animals kept at 12 h light /dark cycle at 22+/-3 °C
Route of administration:
oral: unspecified
Vehicle:
unchanged (no vehicle)
Doses:
>2000 mg/kg bw
No. of animals per sex per dose:
not reported
Control animals:
not specified
Details on study design:
Observation period of 14 d after incubation
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no effects on all test animals
Mortality:
no mortality
Clinical signs:
no clinical signs
Body weight:
no efffect on body weight
Gross pathology:
none reported

In an acute toxicity test according to OECD TG 401 with Wistar rats, no effect of SMS (desulfurization slag) was observed in a limit test at 2000 mg/kg bw

Interpretation of results:
practically nontoxic
Remarks:
Migrated information not toxic Criteria used for interpretation of results: EU
Conclusions:
SMS rat LD50 >2000 mg/kg bw
Executive summary:

To examine the oral toxicity of slags, steelmaking (SMS, desulfurization slags), a test was performed following OECD guideline 401 in Wistar rats. Fine-ground SMS was dosed at 2 g/kg bw (body weight). After dosing, the animals were observed for a post exposure period of 14 days. The LD50 was > 2000 mg/kg bw.

Slags, steelmaking (SMS) are not toxic via the oral route, and do not need to be classified as oral toxicants. Neither a signal word nor a hazard statement is required.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
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
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Species: SPF-bred Wistar rats of the strain HsdCpb:WU from Laboratory animal breeder Harlan Nederland (NL), Kreuzelweg 53, 5960 AD Horst.
Acclimatization: at least 5 days before use. Acclimatization to the restraining tubes at least 1 x 2h, 2 x 4h).
Health status: Historical data is available. The breeding colony is routinely spot-checked for the main specific pathogens.Only healthy rats free of pathological signs will be used. Animals are not vaccinated or treated with anti-infective agents either before their arrival or during the acclimatization
or study periods. The females are nulliparous and not pregnant.
Age and weight: 2-3 months old. Weight range at the exposure day – males: 160 – 210 gram; - females: 150 – 200 gram
Number and groups: 6 animals will be used at each dose (3 animals/sex/group). When the test article is diluted, it may be necessary to use generic control animals (5 animals/sex) to identify exposure related effects
Identification: individual colour-marking and cage-labels.
Randomization: Prior to exposure, standard randomization procedure applied (computerized list of random numbers serves to assign animals at random to the treatment groups)
Animal housing: singly in Makrolon® Type IIIH cages (based on A. Spiegel and R. Gönnert, Zschr. Versuchstierkunde, 1, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)). Cages are changed twice a week while unconsumed feed and water bottles are changed once per
week. The legal requirements of Directive 86/609 EEC were followed.
Bedding: Bedding consisted of type Lignocel BK 8-15 low-dust wood granulate from Rettenmaier. The wood granulate is randomly checked for harmful constituents at the request of the Laboratory Animal Services, Bayer HealthCare AG.
Temperature: 22 ± 3 °C
Relative humidity: 40 - 60 %,
Dark/light cycle : 12 h/12 h; artificial light from 6.00 a.m. to 6.00 p.m., light intensity: maximum 200 Lux
Ventilation: at least 10 air changes/h
Cleaning, disinfection, and pest control: The animal room is regularly cleaned and disinfected once a week with an aqueous solution of TEGOÒ 2000 VT25.
Pest control measures: Cleaning. Cockroach traps
Feeding: Ration consist of a standard fixed-formula diet (KLIBA 3883 = NAFAG 9441) pellets; PROVIMI KLIBA SA, 4303 Kaiseraugst, Switzerland) and tap water (drinking bottles). Both food and water is available ad libitum. The pelletized feed is contained in a rack in the stainless-steel wire cage
cover. Specification of ingredients and contaminants according to recommendations of GV SOLAS (August, 2001).
Water: Drinking quality municipality tap-water (current version of the Drinking Water Decree) is provided ad libitum in polycarbonate bottles containing approximately 300 ml (based on A. Spiegel and R. Gönnert, Zschr. Versuchstierkunde, 1, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)).
Body weights: Body weights are recorded before exposure and 1, 3, 7, and 14 days (or similar time increments, if applicable) after exposure. Individual weights are also recorded at death, if applicable (onset of mortality ³ first postexposure day). As a rule, for data evaluation, the exposure day is
defined as day 0 (relative).
Clinical observations: The appearance and behaviour of each rat are examined carefully several times on the day of exposure and at least once daily thereafter. Weekend assessments are made once a day (morning). Assessments from restraining tubes are made only if unequivocal signs occur (e.g.
spasms, abnormal movements, and severe respiratory signs). Following exposure, observations are made and recorded systematically; individual records are maintained for each animal. Cage-side observations included, but are not limited to, changes in the skin and fur, eyes, mucous membranes,
respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particular attention is directed to observation of tremors, convulsions, salivation, diarrhea, lethargy, somnolence and prostration. The time of death is recorded as precisely as
possible, if applicable. Since these signs can only be assessed adequately from freely moving animals, no specific assessment is performed during exposure while animals are restrained.
On the first postexposure day, each rat is first observed in its home cage and then individually examined. The following reflexes are examined, based on recommendations made by Irwin (Comprehensive Observational Assessment: Ia: A Systematic, Quantitative Procedure for Assessing the Behavioral and Physiologic State of the rats. Psychopharmacologica 13, pp. 222-257 (1968)):
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
Inhalation Chamber: An aluminium inhalation chamber with the following dimensions has to be used: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume = about 3.8 l). If feasible, multiple segments of this chamber can be used, however, the respective air-flows have to be adapted to the larger chamber volume.
Optimization of respirability of aerosol (if applicable): In order to increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the inhalation chamber, a pre-separator/baffle and/or elutriator/cyclone systems which favours the formation of fine particles is used.
Conditioning the compressed air: Compressed air is supplied by Boge compressors and is conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer.
Inhalation chamber steady-state concentration: The test atmosphere generation conditions provide an adequate number of air exchanges per hour (approximately 200-times or more). Under such test conditions steady state is commonly attained within the first minute of exposure (t99% = 4.6 x
chamber volume/flow rate). The ratio between the air supplied and exhausted is chosen so that approximately 80-90% of the supplied air is removed via the exhaust system. The remainder provides adequate dead-space ventilation for the exposure tubes. At each exposure port a minimal air flow rate of 0.75 L/min must be provided.
Air flows: During the exposure period air-flows are monitored continuously and, if necessary, readjusted to the conditions required. Air-flows are measured with calibrated flow-meters and/or soap bubble meter (Gilibrator) and are checked for correct performance at regular intervals by other
equipment (e.g., spirometer).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Remarks on duration:
2 weeks post exposure observation
Concentrations:
5235 mg/m3
No. of animals per sex per dose:
3 female and 3 males in exposure groups, 5 males in control group
Control animals:
yes
Details on study design:
Analysis of particle-size distributions:
Sampling in the vicinity of the breathing zone, two samples per exposure.
ANDERSEN- or an AERAS low-pressure critical orifice cascade impactor. The individual impactor stages are covered by an adhesive stage coating (silicone spray) in order to prevent particle bounce and re-entrainment. If not advisable due to the specific conditions of the test coating can be omitted, or other measures may be taken.
Determined Mass Median Aerodynamic Diameter (MMAD)
Calculation of Geometric Standard Deviation (GSD): GSD = 84.1% mark / 50% mark.
To verify graphically that the aerosol is in fact unimodal and log-normally distributed the normalized mass per stage (fH') is evaluated as a histogram. Calculate the histogram
Calculate the log-normal mass distribution y'(Dae) = 1/Nf x y(Dae) as a function of the aerodynamic diameter
Statistics:
Necropsy findings: Fisher test after the R x C chi-squared test if required
Body weights: Means and single standard deviations, one-way ANOVA (vide infra)
Physiological data: ANOVA procedure (vide infra).
Calculation of the LC50: according to the method of Rosiello ROSIELLO, A.P., ESSIGMANN, J.M., and WOGAN, G.N. (1977). Rapid and Accurate Determination of the Median Lethal Dose (LD50) and its Error with Small Computer. J. Tox. and Environ. Health 3, pp. 797-809).
Analysis of variance (ANOVA): Checks for normal distribution of data by comparing the median and mean. The groups are compared at a confidence level of (1-a) = 95% (p = 0.05). The test for the between-group homogeneity of the variance employed Box's test if more than 2 study groups are compared with each other. If the above F-test shows a difference then a pair-wise post-hoc comparison is conducted (1- and 2-sided) using the Games and Howell modification of the Tukey-Kramer significance test.
Preliminary study:
as no mortality occured at the highest technically attainable concentration, no other test was done
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 235 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC0
Effect level:
>= 5 235 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Mortality:
No mortality occurred and the 4 h-LC50 inhalation (powder, aerosol) was > 5235 mg/m3.
Clinical signs:
other: The following clinical signs were observed, some of them up to the sixth (females; males forth) postexposure day: labored breathing patterns, irregular breathing patterns, hair coat ungroomed, piloerection, motility reduced, limp, high-legged gait, nasal
Body weight:
means of control males: d 0 (postexposure day 0): 183.2 g/animal, d 1: 181.4 g/animal, d 3: 200.0 g/animal, d 7: 230.4 g/animal, d 14: 285.2 g/animal
means of exposure group males: d 0 (postexposure day 0): 169.3 g/animal, d 1: 155.0 g/animal, d 3: 174.0 g/animal, d 7: 206.0 g/animal, d 14: 248.7 g/animal
means of control females: d 0 (postexposure day 0): 180.0 g/animal, d 1: 176.8 g/animal, d 3: 187.6 g/animal, d 7: 197.6 g/animal, d 14: 211.6 g/animal
means of exposure group females: d 0 (postexposure day 0): 168.3 g/animal, d 1: 152.7 g/animal, d 3: 171.7 g/animal, d 7: 188.0 g/animal, d 14: 206.3 g/animal
Gross pathology:
Macroscopic findings of animals sacrificed at the end of the observation period were essentially indistinguishable amongst exposure and control groups apart from lungs with gray areas
Other findings:
Hyperthermia: rectal temperatures were decreased from mean 37.9 °C to 34.3 °C in males and 38.4 °C to 32.7 °C in females as typical for "overloading" of the upper airways with dry, respirable dust
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
no classification required
Executive summary:

To determine the acute inhalation toxicity of slags, ferrous metal, blast furnace (ground, granulated – GGBS), a test was conducted with rats in accordance to OECD Technical Guideline 403 (2009) and Directive 92/69/EEC. Annex V Method B.2. GGBS was applied as a powder aerosol nose-only to one group of rats for an exposure duration of 4 hours at a concentration of 5235 mg/m3 which was also the maximum technically attainable concentration. The aerosol was respirable, i.e. the mass median aerodynamic diameter (MMAD) was 3.1 µm, and the geometric standard deviation was 1.8 µm. The exposure was followed by a postexposure observation period of 2 weeks.

No mortality occurred and the 4 h-LC50 inhalation (powder, aerosol) was > 5235 mg/m3. The following clinical signs were observed, some of them up to the sixth postexposure day: labored breathing patterns, irregular breathing patterns, hair coat ungroomed, piloerection, motility reduced, limp, high-legged gait, nasal discharge (serous), hypothermia, and decreased body weights. The 4 h-NO(A)EL was < 5235 mg/m3.

Slags, ferrous metal, blast furnace (ground, granulated – GGBS) are not toxic to rats via the inhalation route.

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
other: OECD 403, OECD 39 and 92/69/EEC
Deviations:
no
Principles of method if other than guideline:
This pilot study was carried out in accordance with OECD Guideline No. 403 (2009) {in regard to the exposure methodology and the criteria for dose selection}. More general procedures were considered in the study design as called for by OECD Guideline#39 (2009), and Directive 92/69/EEC testing guidelnes.
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
Species: SPF-bred Wistar rats of the strain HsdCpb:WU from Laboratory animal breeder Harlan Nederland (NL), Kreuzelweg 53, 5960 AD Horst.
Acclimatization: at least 5 days before use.
Health status: Historical data is available. The breeding colony is routinely spot-checked for the main specific pathogens.Only healthy rats free of pathological signs will be used. Animals are not vaccinated or treated with anti-infective agents either before their arrival or during the acclimatization
or study periods.
Age and weight: approx. 2 months old. Weight range at the exposure day – males: 210 – 250 gram
Number and groups: 6 animals will be used in each group. There are for each concentration (0, 10, 250 mg/m³) and each postexposure day (1, 7, 28, 90) 2 groups, one for BAL & histopathology and one for kinetics.
Identification: individual color-marking and cage-labels.
Randomization: Prior to exposure, standard randomization procedure applied (computerized list of random numbers serves to assign animals at random to the treatment groups)
Animal housing: singly in Makrolon® Type IIIH cages (based on A. Spiegel and R. Gönnert, Zschr. Versuchstierkunde, 1, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)). Cages are changed twice a week while unconsumed feed and water bottles are changed once per
week. The legal requirements of Directive 86/609 EEC were followed.
Bedding: Bedding consisted of type Lignocel BK 8-15 low-dust wood granulate from Rettenmaier. The wood granulate is randomly checked for harmful constituents at the request of the Laboratory Animal Services, Bayer HealthCare AG.
Temperature: 22 ± 3 °C
Relative humidity: 40 - 60 %,
Dark/light cycle : 12 h/12 h; artificial light from 6.00 a.m. to 6.00 p.m., light intensity: maximum 200 Lux
Ventilation: at least 10 air changes/h
Cleaning, disinfection, and pest control: The animal room is regularly cleaned and disinfected once a week with an aqueous solution of TEGOÒ 2000 VT25.
Pest control measures: Cleaning. Cockroach traps
Feeding: Ration consist of a standard fixed-formula diet (KLIBA 3883 = NAFAG 9441) pellets; PROVIMI KLIBA SA, 4303 Kaiseraugst, Switzerland) and tap water (drinking bottles). Both food and water is available ad libitum. The pelletized feed is contained in a rack in the stainless-steel wire cage
cover. Specification of ingredients and contaminants according to recommendations of GV SOLAS (August, 2001).
Water: Drinking quality municipality tap-water (current version of the Drinking Water Decree) is provided ad libitum in polycarbonate bottles containing approximately 300 ml (based on A. Spiegel and R. Gönnert, Zschr. Versuchstierkunde, 1, 38 (1961) and G. Meister, Zschr. Versuchstierkunde, 7, 144-153 (1965)).
Body weights: Body weights are recorded before exposure and 1, 3, 7 days and weekly thereafter. As a rule, for data evaluation, the exposure day is
defined as day 0 (relative).
Clinical observations: The appearance and behavior of each rat are examined carefully several times on the day of exposure and at least once daily thereafter. During the recovery period, if free from specific symptoms, the results of clinical observations were recorded once per week. Assessments from restraining tubes are made only if unequivocal signs occur (e.g. spasms, abnormal movements, and severe respiratory signs). Following exposure, observations are made and recorded systematically; individual records are maintained for each animal. Cage-side observations included, but are not limited to, changes in the skin and fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behavior pattern. Particular attention is directed to observation of tremors, convulsions, salivation, diarrhea, lethargy, somnolence and prostration. The time of death is recorded as precisely as possible, if applicable. Since these signs can only be assessed adequately from freely moving animals, no specific assessment is performed during exposure while animals are restrained.
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
Animal exposure and postexposure period: The test article will be dosed by inhalation. The exposure duration is 1 x 6 hours. The post exposure period is up to 13 weeks (depending on the timing of taking the bronchoalveolar lavage samples). Following time points: day(s) 1 (+/- 0), 7 (+/- 1), 28 (+/-3), 90 (+/-7 days tolerance)
Inhalation Chamber: An aluminum inhalation chamber with the following dimensions has to be used: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume = about 3.8 l). If feasible, multiple segments of this chamber can be used, however, the respective air-flows have to be adapted to the larger chamber volume.
Optimization of respirability of aerosol (if applicable): In order to increase the efficiency of the generation of respirable particles and to prevent larger particles from entering the inhalation chamber, a pre-separator/baffle and/or elutriator/cyclone systems which favors the formation of fine particles is used.
Conditioning the compressed air: Compressed air is supplied by Boge compressors and is conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer.
Inhalation chamber steady-state concentration: The test atmosphere generation conditions provide an adequate number of air exchanges per hour (approximately 200-times or more). Under such test conditions steady state is commonly attained within the first minute of exposure (t99% = 4.6 x
chamber volume/flow rate). The ratio between the air supplied and exhausted is chosen so that approximately 80-90% of the supplied air is removed via the exhaust system. The remainder provides adequate dead-space ventilation for the exposure tubes. At each exposure port a minimal air flow rate of 0.75 L/min must be provided.
Air flows: During the exposure period air-flows are monitored continuously and, if necessary, readjusted to the conditions required. Air-flows are measured with calibrated flow-meters and/or soap bubble meter (Gilibrator) and are checked for correct performance at regular intervals by other
equipment (e.g., spirometer).
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
6 h
Remarks on duration:
90 days post exposure observation
Concentrations:
Study groups
targeted concentration: animal-numbers
0 mg/m3: 1 - 48
10 mg/m3: 49 - 96
250 mg/m3: 97 - 144
No. of animals per sex per dose:
male: 48
female: 0
Control animals:
yes
Details on study design:
Analysis of particle-size distributions:
Sampling in the vicinity of the breathing zone, two samples per exposure.
ANDERSEN- or an AERAS low-pressure critical orifice cascade impactor. The individual impactor stages are covered by an adhesive stage coating (silicone spray) in order to prevent particle bounce and re-entrainment. If not advisable due to the specific conditions of the test coating can be omitted, or other measures may be taken.
Determined Mass Median Aerodynamic Diameter (MMAD)
Calculation of Geometric Standard Deviation (GSD): GSD = 84.1% mark / 50% mark.
To verify graphically that the aerosol is in fact unimodal and log-normally distributed the normalized mass per stage (fH') is evaluated as a histogram. Calculate the histogram
Calculate the log-normal mass distribution y'(Dae) = 1/Nf x y(Dae) as a function of the aerodynamic diameter
Statistics:
Necropsy findings: Fisher test after the R x C chi-squared test if required
Body weights: Means and single standard deviations, one-way ANOVA (vide infra)
Physiological data: ANOVA procedure (vide infra).
Calculation of the LC50: according to the method of Rosiello ROSIELLO, A.P., ESSIGMANN, J.M., and WOGAN, G.N. (1977). Rapid and Accurate Determination of the Median Lethal Dose (LD50) and its Error with Small Computer. J. Tox. and Environ. Health 3, pp. 797-809).
Analysis of variance (ANOVA): Checks for normal distribution of data by comparing the median and mean. The groups are compared at a confidence level of (1-a) = 95% (p = 0.05). The test for the between-group homogeneity of the variance employed Box's test if more than 2 study groups are compared with each other. If the above F-test shows a difference then a pair-wise post-hoc comparison is conducted (1- and 2-sided) using the Games and Howell modification of the Tukey-Kramer significance test.
Sex:
male
Dose descriptor:
LC50
Effect level:
> 230.1 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
6 h
Mortality:
Substance-induced mortality did not occur at any exposure level.
Clinical signs:
other: All rats tolerated the exposure without effects considered to be test substance-induced.
Body weight:
Concentration-dependent effects on body weight were not observed.
Gross pathology:
No evidence of specific lung injury. Minor unspecific morphological changes in the lung at 230.1 mg/m³.
Other findings:
Biokinetics for metal tracer was determined in the lung. At the concentration of 230.1 mg/m³ and 10 mg'/m³ the amounts of silicon, vanadium and chromium were increased. The concentrations decreased over time, suggesting that these trace metals were pregressively eliminated from the lung. The elimination half-lives are comparable to clearance kinetics via alveolar marcophages known for inorganic dust having low solubility. There can be found no translocation to liver and kidneys.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
no classification required
Executive summary:

Overall, data suggests that there is no likely acute inhalation hazard due to GGBS. There were no deaths or clinical signs. No evidence of lung injury was seen. Minor reversible changes noted in BAL fluid indicative of macrophage-mediated particle clearance, increased organ weights of lung / in lung-associated lymph nodes and minor unspecific landings in lungs reflect the time-dependent physiological response of the body to inhaled mineral particulates of low solubility.

Endpoint:
acute toxicity: inhalation
Remarks:
EXPERT TOXICOLOGICAL REVIEW
Type of information:
other: EXPERT TOXICOLOGICAL REVIEW OF AN INHALATION PULMONARY TOXICITY AND KINETICS STUDY OF GGBS (SLAGS, FERROUS METAL, BLAST FURNACE, GROUND GRANULATED) IN RATS
Adequacy of study:
supporting study
Study period:
2012
Reliability:
1 (reliable without restriction)
Reason / purpose:
reference to other study
Interpretation of results:
other: Expert toxicological review of 90 days after single short-term inhalation exposure to GGBS.
Conclusions:
In conclusion, certain lesions or changes in the respiratory tract are to be expected from the concentration of materials given, or the experimental design of a study. It should be noted that the occurrence of particle-loaded macrophages of different morphological appearance after inhalation of respirable particles is generally considered an adaptive rather than a toxic response. Furthermore, no evidence of lung injury was seen in rats exposed to 10.3 and 230.1 mg/m³ GGBS (solid aerosol). It is of note that results obtained in the pilot rat study of GGBS are dissimilar to results obtained with quartz in rats.
Executive summary:

This rat experiment investigated the concentration- and time-related onset of lung changes up to 90 days after a single short-term exposure to GGBS. Male rats were exposed to solid GGBS aerosol at concentrations of 0 (air), 10.3 or 230.1 mg/m³ for 6 hours. Particle size distribution measurements indicated that the test aerosol particles were within the respirable range for rats and thus the experiment could be considered valid. The review has not identified major deficiencies.

Overall, data suggests that there is no likely acute inhalation hazard due to GGBS. There were no deaths or clinical signs. No evidence of lung injury was seen. Minor reversible changes noted in BAL fluid indicative of macrophage-mediated particle clearance, increased organ weights of lung / lung-associated lymph nodes, enlarged lung-associated lymph nodes, and minor unspecific findings in lungs reflect the time-dependent physiological response of the body to inhaled mineral particulates of low solubility.

At 230.1 mg/m³ these changes resembled particle overload in which deficient pulmonary macrophage clearance is thought to play a role. It is suggested that the inhaled particulate accumulates in the alveolar macrophages that become overloaded with inhaled material at the high test concentration.

In addition, concentration-dependent lung burdens were reported for the persistent trace metals chromium, silicon and vanadium. Long elimination half-lives for chromium and silicon at 230.1 mg/m³ appears consistent with the anticipated slow elimination of low soluble particles from the lung. A translocation to liver and kidneys could not be seen.

Particles deposited in the lungs can translocate to the pulmonary interstitium and further via the pulmonary lymph flow to the hilar lymph nodes. It is also known from several animal studies that with increased lung burden and reduced elimination of particles from lung, e.g. approaching particle overload thresholds, the amount of particles escaping the clearance by alveolar macrophages increases, and hence the lymph node content is elevated. As anticipated for GGBS, enlargement of lung-associated lymph nodes was noted at 230.1 mg/m³ (on Days 28 and 90) that correlated well with elevated organ weights. However, metal burden of the lung-associated lymph nodes (and urine) could not be determined in this pilot study due to some inconsistencies of data. Nonetheless, lung-associated lymph nodes are known to participate in the physiological lung defense against inhaled particles and it is thus reasonable to assume from organ weights and gross pathology (enlargement of lung-associated lymph nodes) that the lymphatic system was an additional pathway for clearance of alveolar GGBS particles at the high test concentration.

The macrophage response to inhaled inorganic dust can range from simple phagocytosis and clearance with minimal inflammation to abundant production of inflammatory cytokines and other potent mediators, depending on the nature of particulate involved. These endogenous substances have cytotoxic, pro- and anti-inflammatory, angiogenic, fibrogenic, and mitogenic activities and hence, pathogenic potential. Pro-inflammatory cytokines directly promote the accumulation of inflammatory cells. Resulting acute and chronic inflammatory processes might then be associated with transient or chronic occurrences of high neutrophil concentrations on the alveolar surfaces and the increase of the alveolar macrophage population which can be determined by BAL or on histological slide of lung tissue; an overview on lung changes due to cytotoxic particles is given elsewhere (Jochims 2012)

Hence, depending on the particulate deposited in the alveolar space, alveolar macrophages as well as interstitial macrophages can become hyperresponsive by mounting an inflammatory response and releasing the mediators aimed at protecting the host.Review of the report on potential acute inhalation toxicity revealed that results after GGBS exposure of rats are dissimilar to results obtained in inhalation toxicity studies of dust with established cytotoxic lung injury, such as quartz.

Quartz given at a concentration of about 250 mg/m³ once to rats (single exposure, 90-day follow-up period) produced a high acute inflammatory change. The contribution of neutrophil leukocytes to clearance is especially typical for the response to cytotoxic particles, in particular for the response to inhaled quartz in lung tissue. The fibrogenic properties of quartz particles are also considered to be due to its direct toxicity to cell and lysosomal membranes and / or the continuing secretion of fibroblast proliferating factors by alveolar macrophages. Furthermore, responses to quartz increased with increased post-exposure period (Pauluhn 2009), whereas there was no exacerbation after inhalative exposure to GGBS (solid aerosol) in the pilot study reviewed herein.

The ability of the rat lung to recover post-exposure was low after exposure to quartz. Particulates such as quartz among others, have been shown to induce enhanced or prolonged production and release of radical oxygen and nitrogen species from alveolar macrophages. Ultimately, the release of mediators from alveolar macrophages leads to direct lung tissue damage. In addition, radical oxygen and nitrogen species can indirectly activate signal transduction pathways via kinases and transcription factors that also may contribute to lung diseases. These alterations described for quartz

toxicity were not seen in the acute inhalation study of GGBS and the results of the pilot study do not indicate that phagocytosis of GGBS particulates induced an activation of signal transduction pathways in alveolar macrophages, or an excessive and persistent release of effector molecules by alveolar macrophages. Hence, the available data demonstrated no relevant acute inhalation effect of aerosolised GGBS.

Endpoint:
acute toxicity: inhalation
Remarks:
The biological response of alveolar macrophage to inorganic mineral dust/particulates
Type of information:
other: Expert Opinion
Adequacy of study:
supporting study
Reason / purpose:
reference to other study
Conclusions:
The biological response of alveolar macrophages to inorganic dust depends on several factors. These are chemical durability and biopersistence as well as reactivity of the surface of particulates, as well as the availability of iron or other transition metals at the surface of fibres and particles. An increased number of alveolar macrophages is generally considered an adaptive rather than a toxic response of a biological system to inhaled inorganic particulates. However, phagocytosis of particulates may be followed by activation of signal transduction pathways in alveolar macrophages, such as second messengers and transcription factors that lead to the production of potent mediators, including ROS, RNS, cytokines, growth factors, eicosanoids, and several other factors. The excessive and persistent release of these effector molecules by alveolar macrophages can cause tissue damage and organ dysfunction and may contribute to the pathogenesis of inorganic particulate-induced pulmonary diseases as noted after crystalline silica for example.

Therefore, careful case-by-case analysis of the response of a biological system to inhaled inorganic dust i.e., assessment of morphological changes in the lungs and BAL findings in an experimental study, is deemed necessary in order to properly describe inhalation effects as adaptive physiological processes or as dust-induced lung toxicity. It should also be noted that structural and anatomic pulmonary disparities between rodents and humans exist and that significant species differences in the way species respond to inhaled particulates have been described in the literature. Thus, variations in deposition patterns and airway cell morphology and distribution that account for deposition / clearance differences among species should also be carefully considered in a toxicological assessment on inhaled inorganic dust.
Executive summary:

Ferrous slags are produced in steel mills as essential by-products of iron and steel manufacturing and consist of the following 5 slag types:

1. ABS/GBS: Slag, ferrous metal, blast furnace (air cooled or granulated), EINECS No. 266-002-0

2. BOS Slag, steelmaking, converter (converter slag), EINECS No.: 294-409-3

3. EAF C Slag, steelmaking, elec. furnace (carbon steel production), EINECS No.: 932-275-6

4. EAF S Slag, steelmaking, elec. furnace (stainless/high alloy steel production), EINECS No.: 932-476-9

5. SMS Slag, steelmaking, EINECS No.: 266-004-1

The physicochemical, toxicological and ecotoxicological properties are similar and follow a regular pattern. Similarities comprise also the composition of the slags. Therefore, the category approach was applied to efficiently fulfil REACH1 Registration requirements for these slags. A Chemical Safety Report (CSR) was submitted in 2011 (CSR 2011) by ThyssenKrupp Steel Europe AG, Duisburg (Germany) which was the lead registrant for the slag types 1, 2 and 5.

One of the possible risks to human health presented by ferrous slags is a formation of fine dust. The inhalation of mineral particulates may occur during manufacture and processing because fine particles with a size of 1 – 5 μm have the potential for aerial transport and inhalative exposure; thus fine particles may enter the alveoli of the lungs.

Steelmaking slags (categories 2 to 5) are generated as by-products of the steel production process. They arise e.g. from the conversion of hot metal to steel, from melting scrap in an electric arc furnace or from the subsequent treatment of crude steel. The composition of the slags varies depending on the process step in which they are produced. The molten slag which has tapping temperatures of around 1600°C is cooled under controlled conditions and solidifies to provide an artificial aggregate having a crystalline structure. The majority of steelmaking slags is used as aggregates for road construction, earth works or water engineering. These slowly cooled mainly coarse grained crystalline slags only have a low risk what concerns dust formation.

Blast furnace slag (category 1) is a by-product of the manufacture of iron by thermochemical reduction in a blast furnace. It is formed in a continuous process by the fusion of limestone (and / or dolomite) and other fluxes with the residues from the carbon source and the non-metallic components of the iron bearing materials (e.g. iron ore, iron sinter). Blast furnace slag is generated at temperatures above 1500°C. Dependent on the way of cooling of the liquid slag it can be distinguished between crystalline air-cooled blast furnace slag (ABS) and glassy granulated blast furnace slag (GBS).

In contrast to steelmaking slags, the vast majority of blast furnace slag is rapidly quenched forming a glassy material for the use in cement production. GBS is almost exclusively finely crushed (< 100 μm) to ground granulated blast furnace slag (GGBS). For this GGBS a possible risk concerning the formation of inhalable dust has to be considered. On the other hand slowly air

cooled blast furnace slag is a mostly coarse grained crystalline material – comparable to steelmaking slag. Also for granulated blast furnace slag (not ground) the risk of dust formation is negligible. Therefore from the toxicological point of view GGBS is considered to cover the worst-case of “slags, ferrous metal, blast furnace” as the marketed products of other slags only contain far smaller proportions of fine particles.

The question arose how biological systems, i.e. alveolar macrophages, deal with such inorganic dust. Therefore, a literature search was performed in April 2012 at Deutsches Institut für Medizinische Dokumentation und Information (DIMDI) on ′slags, ferrous metal, blast furnace′, CAS-RN 65996-69-2, GGBS, blast furnace slag, (ferrous) slag, inorganic dust, natural rock, particulate matter, coal mining, silicosis, and in combination with (alveolar) macrophage, inhalation, toxicity, inhalation toxicity, macrophage / alveolar clearance, or (lung) persistence in at least the following databases: Adis Newsletters, AnimAlt-ZEBET, CAB Abstracts, CCRIS, ChemIDPlus, Chemicals and Contact Allergy, Derwent Drug Backfile, Derwent Drug File, EMBASE, EMBASE Alert, GLOBAL Health, HSDB, IPA, ISTP + ISTP/ISSHP, MEDLINE, SciSearch, SOMED, TOXBIO, XTOXLINE, RTECS, and various databases from publishers like Kluwer and Thieme, from 1966 (MEDLINE) or 1974 (EMBASE) to 2012. In addition, the service of the United States National Library of Medicine (PubMed) that includes over 16 million citations from MEDLINE and other life science journals for biomedical articles, back to the 1950s, was used. To identify more recent studies, the search strategy was supplemented by the reference lists in the most recently published papers.

According to the fibre definitions of the Organisation for Economic Co-operation and Development and the World Health Organisation ferrous slags are virtually free of fibres and virtually free of asbestos. Thus, the clearance kinetic of inhaled fibrous particles like asbestos from the respiratory tract was not considered in the review of the scientific literature. Moreover, potential inhalation toxicity data of black carbon, cigarette smoke and diesel soot are largely disregarded in this Expert Opinion as data on these substances are considered to be of limited value when attempting to answer the basic question how alveolar macrophage deal with GGBS.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 235 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
water
Duration of exposure:
24 h, consecutive observation period 14 d
Doses:
their skin treated with the maximum dosage recommended for each product (4000 mg/kg)
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
The animals were individually observed with special attention during the first 24 h after the administration of the test substance and for a period of 14 d when they were observed 7 d a week if evident signs were found, or 5 d a week when toxicity signs were not evident. The symptoms to be observed were alterations in the skin, fur, eyes and mucous membranes, dyspnoea, behaviour alterations, tremors, convulsions, salivation, diarrhea, lethargy, sleepiness, coma and death. In the case of mortality, the records include the approximate time of death.
Preliminary study:
As it was known that there is no evidence of dermal toxicity, main test was made with maximum possible concentration of slags and crushed natural stone
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 4 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortality reported
Clinical signs:
no clinical signs reported
Body weight:
no data
Gross pathology:
no data
Other findings:
The monitoring of the animals included observation for alternations in the skin, fur, eyes and mucous membranes dyspnoea, behaviour alternations, tremors, convulsions, salivation, diarrhoea, lethargy, sleepiness, coma, and death. In case of death, the time of death would have been reported.

SMS LD50 > 4000 mg/kg

Crushed stone: LD50 > 4000 mg/kg

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
SMS: rats OECD 402: LD50 > 4000 mg/kg
Crushed natural stone: rats OECD 402: LD50 > 4000 mg/kg
Executive summary:

To test the dermal toxicity of slags, steelmaking (SMS), and crushed stone from a quarry in the vicinity of Serra, Brasilia, tests were performed following OECD guideline 402 in Wistar rats. Fine-ground SMS and crushed stone were dosed, in their original form, at 4 g/kg bw (body weight) under semi-occlusive dressing for 24 h. After dosing, the patches were removed and the animals were observed for a post exposure period of 14 days. The LD50 was > 4000 mg/kg bw for each test material.

Slags, steelmaking (SMS), and natural stone from a quarry in Serra, Brasilia, are not toxic via the dermal route, and do not need to be classified as dermal toxicants. No signal word and no hazard statement is required.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
4 000 mg/kg bw

Additional information

Oral

10 reports were identified that provided information on the acute oral toxicity of ferrous slags.

7 of these studies followed the method described in OECD TG 401. The following slags were tested:

·       Slags, ferrous metal, blast furnace (air cooled – ABS)

·       Slags, ferrous metal, blast furnace (granulated – GBS)

·       Slags, steelmaking, converter (BOS, 2 studies)

·       Slags, steelmaking, elec. furnace (carbon steel production - EAF C)

·       Slags, steelmaking (SMS; 2 studies; ladle slag and desulfurization slag)

A single dose of at least 2000 mg/kg bw was applied orally to Wistar rats. No mortalities or abnormalities were observed in these studies.

3 reports were published on the data of an exhaustive project on health and environmental safety of steelmaking slags. This project comprised 2 studies performed according to OECD TG 423 on slags, steelmaking, converter (BOS) and on slags, steelmaking (SMS), respectively, applying a dose of 2000 mg/kg bw by gavage. No mortalities or abnormalities were observed in these studies.

Slags, steelmaking, elec. furnace (stainless/high alloy steel production - EAF S) were not tested. Since the major difference between EAF S and EAF C is their content in iron (compounds), data on EAF C are equally valid for EAF S, and almost identical leaching properties, there was no need for additional testing also in regard to animal welfare.

In the rat, all oral LD50values for ABS/GBS, BOS, EAF C, and SMS are higher than 2000 mg/kg bw, which is the maximum LD50requiring classification and labelling. No classification and labelling for acute oral toxicity are required for all ferrous slags.

 

Inhalation

There is one study available on the inhalation toxicity of ferrous slags. As test material slags, ferrous metal, blast furnace (ground, granulated – GGBS) were selected because the majority of blast furnace slag is produced as GBS, which is almost exclusively fine-ground (< 100 µm) for use in cement production. As the marketed products of other slags contain only far smaller proportions of fine particles than GGBS, the testing of GGBS served to cover the worst-case.

To determine the acute inhalation toxicity of GGBS, a test was conducted with rats in accordance to OECD Technical Guideline 403 (2009) and Directive 92/69/EEC. Annex V Method B.2. GGBS was applied as a powder aerosol nose-only to one group of rats for an exposure duration of 4 hours at a concentration of 5235 mg/m3which was also the maximum technically attainable concentration. The aerosol was respirable, i.e. the mass median aerodynamic diameter (MMAD) was 3.1 µm, and the geometric standard deviation was 1.8 µm. The exposure was followed by a postexposure observation period of 2 weeks.

No mortality occurred and the 4 h-LC50 inhalation (powder, aerosol)was > 5235 mg/m3. The following clinical signs were observed, some of them up to the sixth postexposure day: labored breathing patterns, irregular breathing patterns, hair coat ungroomed, piloerection, motility reduced, limp, high-legged gait, nasal discharge (serous), hypothermia, and decreased body weights. The 4 h-NO(A)EL was < 5235 mg/m3.

Slags, ferrous metal, blast furnace (ground, granulated – GGBS) do not exert acute inhalation toxicity in rats.

Results of the study: “Inhalation pulmonary toxicity and kinetics in rats” have been reviewed. Dose dependent reduction in alveolar macrophage count has been found. A cytotoxic potential of biologically available parts of GGBS under overload conditionscannot be excluded and needs clarification. The origin of trace elements and Si in different tissues and urine of control animals first needs clarification to explain the extraordinary huge interindividual variance related to some analytical parameters in control rats. Therefore, the toxicological significance of findings cannot be conclusively judged without further investigations.

Dermal

3 reports were published using the data of an exhaustive project on health and environmental safety of steelmaking slags. This project comprised 3 studies performed according to OECD TG 402 on slags, steelmaking, converter (BOS) and slags, steelmaking (SMS), and crushed stone from a quarry in the vicinity of Serra (), respectively. Fine-ground BOS, SMS and crushed stone were dosed, in their original form, at 4 g/kg bw under semi-occlusive dressing for 24 h to Wistar rats. After dosing, the patches were removed and the animals were observed for a post exposure period of 14 days. The LD50was > 4000 mg/kg bw for each test material.

BOS, SMS, and the natural stone are not toxic via the dermal route. Due to the similarity of all ferrous slags, the LD50can be read across to the other slags. All ferrous slags do not need to be classified as dermal toxicants. No signal word and no hazard statement are required for any ferrous slag.

Ferrous slags are almost insoluble in water and lipid phases. As a consequence, they cannot pass through the skin. The aqueous layer of the skin is not acidic enough to enable the release and uptake of ions of toxicological relevance. Systemic exposure appears to be negligible and toxicologically insignificant. Furthermore, dermal contact with natural rock - which is similar in chemical and mineral composition to slags - is a common feature of everyday life of humans. No acute toxicity as a result of dermal contact has been reported. Based on these facts, the requirement for additional tests on the dermal acute toxicity of ferrous slags is waived also in regard to animal welfare.

 

Justification for classification or non-classification

At any concentration tested, no significant toxic effect of ferrous slags on test organisms occurred, and no classification is required for acute toxicity after oral, dermal and respiratory exposure.