Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: assessment from available information
Adequacy of study:
key study
Study period:
May 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific methods and is described in sufficient details.

Data source

Reference
Reference Type:
other: final test
Title:
Unnamed
Year:
2013
Report date:
2010

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required

Test material

Constituent 1
Reference substance name:
Dust, steelmaking
EC Number:
266-005-7
EC Name:
Dust, steelmaking
Cas Number:
65996-72-7
IUPAC Name:
Dust steelmaking
Details on test material:
- Physical state: solid
- Composition of test material, percentage of components: Fe total 57.64% (mainly as oxides), CaO 8.89%, Zn 4.16%, MgO 3.64%, C 0.69%, SiO2 1.56%, Mn 0.57 %, K2O 0.281%, Na2O 0.251%, Al2O3 0.18%
- Lot/batch No.: 21.10.2009
- Expiration date of the lot/batch: unlimited
- Storage condition of test material: stored in PE container at room temperature

Results and discussion

Any other information on results incl. tables

Acute studies

The substance, Dust, steelmaking, was applied to laboratory animals (rat, mouse, and rabbit) during studies with different way of entry into organism (e.g. stomach, respiratory tract - nose, skin and eye).

Only mild systemic effects – piloerection only 3 hours after application in all animals were described after single oral application of the dose level 2000 mg/kg of the substance to rats. Observed changes faded away till 24 hours after application of the test substance.

Common clinical abnormalities (increased respiratory rate, hunched posture, piloerection and wet fur - till the 7th day after exposure) were noted after 4-hour nose exposure of the substance at the concentration of 5.15 mg/L.

After single application on skin of rabbit, no irritant or corrosive effects were observed. The substance is not irritant. No symptoms of systemic toxicity were observed in rabbits after application on skin.

Examination of eye after single application of substance to the conjunctival sac demonstrated, that Dust, steelmaking, is irritating for eye of rabbit; the changes observed were reversible (redness and chemosis of conjunctivae and lacrimation – these changes faded away till the 8th day of study). No corrosive effects were observed on eyes of rabbit and no clinical signs of systemic intoxication were detected. 

The substance, Dust, steelmaking, elicited positive response after topical application to the mouse ear in LLNA; so the test substance may cause skin sensitisation by skin contact. No clinical signs of systemic intoxication were detected in study of sensitization.

    

Long-term studies

The oral administration of the substance, Dust, steelmaking, to rats by gavage for a period of 28 consecutive days at dose levels 120, 300 and 750 mg/kg/day did not cause mortality.      

The haematology examination showed an effect on total leucocyte count (statistically significant increase) in males of middle dose level with irreversible effect.  

Only one statistically significant effect, which was manifested in results of biochemical examination was the increase of calcium and phosphorus ions concentrations in peripheral blood. Values of these ions were increased at the highest dose level in both sexes (in females statistically significant). This symptom had delayed character in males and irreversible effect in females. During biochemical examination also the changes of values of liver enzymes were detected - an insignificantly decreased activity of AST, ALT, ALP at the highest dose was recorded in both sexes. These changes have had irreversible character in all treated animals. Decreased value of creatinine with dose-dependent manner was recorded in females. All these changes together with increase of weight of liver (with dependence on dose level in males) can be indications of affection of liver metabolism but during histopathological investigation no changes of hepatocytes morphology were observed.

In Reproduction/Developmental Toxicity Screening Test the following dose levels: 100, 300 and 900 mg/kg/day were administered.

The application of the test substance did not cause the death of any female or male.

The test substance affected reproductive system of parental males. Histopathological examination of reproductive system of parental males showed vacuolation of cytoplasm of spermatogonia in testes in majority males of treated groups and lymphocyte infiltration in epididymides of all males. Also atrophy and degeneration of germ epithelium in testes and lymphocyte infiltration in interstitium of prostate gland was diagnosed at all groups. The test substance had probably injurious effect on sperm quality of treated males. Markedly increased impaired sperm motility was recorded at the lowest and middle dose levels.

At the highest dose level slightly increased sperm motility was recorded on the contrary. The effect of the test substance on sperm motility declined with the dose level. Increased percentage of affected sperms was recorded at all treated groups. Mainly damages of sperm head and sperm neck were diagnosed.

The number of pups, sex ratio, average weight of litter, average body weight of pups and postnatal development of pups were unaffected by the test substance treatment.

In Prenatal Developmental Toxicity Study the following dose levels: 1000, 400 and 160 mg/kg/day were administered.

The application of the test substance did not cause the death of pregnant females. No effect of the test substance on maternal animals was observed.

Test substance application did not induce external and/or visceral malformations of foetuses (permanent structural change that may adversely affect survival).

Delayed development of foetuses - delayed ossification of cranial, sternum skeleton and sacral vertebrae, was detected at all dose levels. These findings related with decreased individual body weights of some foetuses. The test substance treatment evoked occurrence of variations – wavy ribs in all treated groups, so it indicates teratogenic properties of the test substance (it did cause morphologic changes of skeleton) on early prenatal development of organism in uterus.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: see Conclusions
The systemic effect (disappeared shortly after administration) was described after single oral administration of the substance Dust, steelmaking to rats. It is not possible to confirm absorption of the test substance from digestive tract after single administration of the test substance. The clinical symptoms found (piloerection) could be related with total reaction of organism to application of the test substance.
After single application of test substance to the skin of rabbits, systemic toxic effects were not detected – the substance obviously does not penetrate through the skin after acute exposure. The test substance is not a skin sensitizer.
Sensitisation potential was found out after application on ears of mice – the test substance may cause skin sensitisation by the skin contact.
After single application of the substance to conjunctival sac of the rabbit eye the local reversible effects (redness, chemosis and lacrimation) appeared. These changes persisted till 7th day after application of the test substance – the substance is irritating to the eye. Systemic toxic effects were not detected – the test substance does not penetrate to the body after acute eye exposure.
Based on results of repeating administration of the test substance - 28-day study in rats, 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 (what is demonstrated by the effects on blood haematological and biochemical parameters).
The test substance Dust, steelmaking, has negative effect mainly on the white component part of blood - irreversible effect on white blood cells parameters in males at the middle dose level (increase of value of total leucocyte count) was recorded.
According to evaluation of the biochemical parameters it could be deducted, that the test substance affected liver metabolism. During biochemical examination the changes of values of liver enzymes were detected at the all dose level: decreased value of ALT, AST and ALP in both sexes. These changes have had irreversible character.
It is evident, that application of the test substance caused temporary colouring of the chyme and had not harmful effect on digestive tract (no histopathological changes in stomach or intestine mucosa). Colouration of stomach contents by the test substance which was observed in all treated animals during necropsy at the end of application period demonstrated slow absorption of the test substance - still 24 hours after administration the test substance was situated in application site.
Results of Reproduction/Developmental study in rats revealed that the test substance Dust, steelmaking had negative influence on reproduction parameters of parental males – the test substance had probably injurious effect on sperm quality of treated males. Markedly increased impaired sperm motility was recorded. Histopathological examination of reproductive system of parental males showed vacuolation of cytoplasm of spermatogonia in testes, lymphocyte infiltration in epididymides, atrophy and degeneration of germ epithelium in testes and lymphocyte infiltration in interstitium of prostate gland.
Based on this study there was no evidence that development of pups was affected.
Result of Prenatal Developmental Toxicity Study in rats revealed that the test substance treatment evoked delayed development of foetuses and occurrence of variations – wavy ribs. It indicates teratogenic properties of the test substance on early prenatal development of organism in uterus.
Above-mentioned results raise suspicion that the substance probably could get through placenta and affect foetus development.
Absorption of Dust, steelmaking from the digestive system and their distribution throughout the body of experimental animals to relatively distant compartments (liver, testes) was confirmed during oral repeated dose studies, but it could be presumed, that the substance is not able to get through placenta and affect the embryo or foetus.
No information was found about the excretion of Dust, steelmaking.
Executive summary:

Evaluation of toxicokinetics of the substance Dust, steelmaking was performed. Evaluation of toxicokinetics of the substance is required according to the 8.8.1 of Annex VII to the Directive (EC) No. 1907/2006 (REACH).

Dust, steelmaking is the complex product of oxides and elements. The main components of the test substance are the following: Fe total 57.64 % (mainly as oxides) and CaO (8.89 %).

The evaluation of toxicokinetics of above mentioned substance was performed according to experimental data from the testing of Dust, steelmaking at CETA - VUOS.

The data used for the evaluation originated from three sources:

- Experimental data of toxicological tests (unpublished)

- Literature data obtained from internet

- Data from toxicological databases - free and commercial