Slags, ferronickel-manufg.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via inhalation route

Dose descriptor:

NOAEC

650 mg/m³

Additional information

No study on the effects of slags, ferronickel-manufg on fertility and the development are available. In order to avoid testing on live animals it was decided to assess the toxicity to reproduction of the slags based on the toxicological profile of the individual constituents, supplemented by data collected from findings of other toxicological experiments performed on the substance.

Iron:

Iron is an essential element for humans and as such has been extensively studied. The toxicity of iron overload on successive generations was tested in female rats from generation 1 to generation 5 included. Mothers and offspring were examined for iron body burden, litter size and litter postnatal development. Mother weight was higher in the iron-treated females but no differences in litter size (viability of offspring) were noted. It can be concluded that iron overload did not affect fertility of female rats in subsequent generations.

Calcium Oxide:

No animal studies of calcium oxide on reproduction were available. The toxicity of CaO is directly related to its irritating potential. CaO damages mucous membranes by generating heat and dehydrating the tissues as the particles react with the moisture in the skin, and by the alkalinity of Ca(OH)2 that is formed in this process (Swed Occup Standards 1999; US Dept Health CaO). However, CaO in Ferronickel slags is chelated with the rest of the non-irritant constituents of the slag matrix which renders invalid its inherent irritation potential. This has been verified in the acute oral and inhalation toxicity experiments of Ferronickel slags (see relative endpoints) as well as in the skin and eye irritation experiments (see relative endpoints). It is thus concluded that CaO is of negligible toxicity in ferronickel slags.

Trivalent Chromium:

Cr(III) has been proven to be of low toxicity (see repeated dose toxicity endpoint) and genotoxicity therefore reproductive toxicity is not an issue for this substance. No systemic effects relevant to reproductive toxicity were observed in any of the chronic toxicity tests performed with chromium. The Cr content is proven to be trivalent, since no hexavalent Cr was detected (up to the detection limit of the method) in representative samples of various grades of Ferronickel Slags, which were analysed using alkaline digestion and colorimetry (EPA 3060A and EPA7196A respectively).

Nickel:

Concern has risen over the reproductive toxicity of Ni, Ni oxides and salts, given the possible or probable carcinogenicity of many of these substances. A detailed 13 week study on NiO inhalation on female and male rats revealed no effects on estrous cycle length (days) and estrous stages for females and no effects on sperm morphology and motility for males. A NOEC of 3.9 mg Ni/m3 was noted for sperm count, corresponding to 650mg/m3 of Ferronickel slags (based on a worst case scenario Ni concentration of 0.6%), (endpoint: Concentration 106/g cauda epididymal tissue). Ni metal which is even more insoluble than NiO is expected to have even less bioavailability thus to exhibit a higher NOEC for rats. It can be deduced that insoluble Ni compounds are of limited toxicological effect on mammalian fertility.

Aluminium Oxide:

No studies of aluminium oxide on reproductive and developmental toxicity are available. However, reproductive toxicity is not an issue for this substance because:

-toxicokinetic data revealed a low bioavailability potential of aluminium following chronic inhalation exposure. In case it becomes systemically available, no detectable levels were found in reproductive organs. Furthermore, it is believed that circulating aluminium is bound to transferrin which has a low absorption in the placenta.

- aluminium oxide (CAS: 1344-28-1) has been characterized as a non-hazardous nuisance dust; the higher the concentration of dust the greater the risk of irritation to the respiratory system and mechanical irritation to the eyes. As a result aluminium oxide should be addressed as a benign dust (poorly soluble dust with low toxicity).

-read across to the equally insoluble aluminium hydroxide (alumina hydrate) (CAS:21645-51-2)shows that Al(OH)3 is an inert dust which is extensively used in pharmaceuticals, personal care products and foodstuffs, thus its safety has been verified. Aluminium hydroxide is purchased as an antacid drug or against hyperphosphataemia under a variety of brand names in Europe and US (Alamag®, Maalox®, Mylanta® Alternagel®, Alu-Cap®, Dialume®, Amphojel®, Alu-Tab®, Aloh-Gel® etc). Aluminium hydroxide is also used as an adjuvant to the diphtheria and pertussis toxoid for infant immunization. In Europe, aluminium hydroxide is an approved colour additive (CI 77002) that may be used in all types of cosmetics and personal care products (Annex IV of Cosmetics Directive 76/768/EEC). FDA also permits aluminium hydroxide to be used as anindirect food additive. For example, it may be used as a defoaming agent in the manufacture of paper and paperboard used to package food (see alsohttp://www.cosmeticsinfo.org). The wide use of aluminium hydroxide even in injecting preparations verifies its high safety profile.

The other ingredients of Ferronickel slag (SiO2 and MgO) are of proved insignificant toxicological profile (in regards to reproduction) and are insufficient to trigger relevant classification for the whole mixture. Especially for silicon dioxide, XRD analysis with application of Rietveld quantitative phase analysis, showed no detectable quantities of crystalline silica in both the total substance and in the respirable fraction of various grades. Therefore, Ferronickel Slags contain no Respirable Crystalline Silica in quantities potentially dangerous to life.

Overall the data on effects on fertility are sufficient and allow for robust risk characterization of ferronickel slags. No classification in regards to reproductive toxicity is justified.

Short description of key information:
Data from fertility studies on the individual components of ferronickel slags showed no significant adverse effects, with the exception of a detailed 13 week study on NiO inhalation on female and male rats that revealed no effects on estrous cycle length (days) and estrous stages for females and no effects on sperm morphology and motility for males. Based on this study an inhalation NOAEC of 3.9 mg Ni/m3 was determined which corresponds to 650mg Ferronickel slag/m3 (in a worst case scenario of 0.6% Ni content of the slag). Based on these, and on the fact that all of the constituents are chemically bound in the matrix of the ferronickel slags having low solubility (with the exception of sulfur, that poses no problem whatsoever), no classification in regards to reproductive toxicity is justified.

Effects on developmental toxicity

Description of key information

Data from studies on the toxicological properties of the individual components of ferronickel slags on development and teratogenesis, showed no significant adverse effects. The studies included both animal studies and human epidemiological data. Based on these, and on the fact that all of the constituents are chemically bound in the matrix of the ferronickel slags having low solubility (with the exception of sulfur, that poses no problem whatsoever), no classification in regards to developmental toxicity is justified.

Additional information

No study on the effects of slags, ferronickel-manufg on the developmental toxicity/teratogenicity are available.In order to avoid testing on live animals it was decided to assess the toxicity to reproduction and to development of the slags based on the toxicological profile of theindividual constituents, supplemented by data collected from findings of other toxicological experiments performed on the substance.

Iron is an essential element for humans and as such has been extensively studied. The toxicity of iron overload on successive generations was tested in female rats from generation 1 to generation 5 included. Test group received a total amount of 62-72 mg/animal during a 6 week period of dosing parenterally. This route was chosen because iron given orally is absorbed in limited quantities. When the offspring was 6 weeks old random separation and repetition of the experiment until fourth generation was performed. Mothers and offspring were examined for iron body burden, litter size and litter postnatal development. No differences in litter size (viability of offspring), litter weight, litter iron body burden and litter rate of growth was noted. It can be concluded that iron overload did not affect embryo rat development in subsequent generations.

No animal studies of calcium oxide on reproduction are available. The toxicity of CaO is directly related to its irritating potential. CaO damages mucous membranes by generating heat and dehydrating the tissues as the particles react with the moisture in the skin, and by the alkalinity of Ca(OH)2 that is formed in this process. However, CaO in ferronickel slags is chelated with the rest of the non-irritant constituents of the slag matrix which renders invalid its inherent irritation potential. This has been verified in the acute oral and inhalation toxicity experiments of ferronickel slags (see relevant endpoints) as well as in the skin and eye irritation experiments (see relevant endpoints). It is concluded that CaO is of negligible toxicity in ferronickel slags.

Cr(III) has been proven to be of low toxicity (see repeated dose toxicity endpoint) and genotoxicity therefore reproductive toxicity is not an issue for this substance. No systemic effects relevant to reproductive or developmental toxicity were observed in any of the chronic toxicity tests performed with chromium.

The toxicity of inhalation of water-soluble Ni salts (which are more bioavailable than Ni metal) on embryonic developmental parameters has been extensively studied on a population of female workers in a Ni refinery.The odds ratio (OR) of delivering a newborn with a genital malformation (undescended testes or hypospadias) for the women working in nickel exposed areas did not reveal a difference between these groups and the general population of the town of the Ni refinery. Furthermorethere was no adverse effect of maternal occupational exposure to water-soluble Ni in the first part of pregnancy on the risk of delivering a chromosomally normal SGA (small for gestational age) new born.There was also no adverse effect of maternal exposure during the periconception period and early pregnancy to water-soluble Ni on the risk of delivering a newborn with musculoskeletal deformities and malformations. Finally, another study on this population did not reveal a statistical association between maternal exposure to water-soluble Ni in early pregnancy and the risk of self-reported spontaneous abortion

No studies of aluminium oxide of developmental toxicity are available. However, developmental toxicity is not an issue for this substance because:

-toxicokinetic data revealed a low bioavailability potential of aluminium following chronic inhalation exposure. In case it becomes systemically available, no detectable levels were found in reproductive organs. Furthermore, it is believed that circulating aluminium is bound to transferrin which has a low absorption in the placenta (regarding developmental toxicity).

- aluminium oxide (CAS: 1344-28-1) has been characterized as a non-hazardous nuisance dust; the higher the concentration of dust the greater the risk of irritation to the respiratory system and mechanical irritation to the eyes. As a result aluminium oxide should be addressed as a benign dust (poorly soluble dust with low toxicity).

-read across to the equally insoluble aluminium hydroxide (alumina hydrate) (CAS:21645-51-2) shows that Al(OH)3 is an inert dust which is extensively used in pharmaceuticals, personal care products and foodstuffs, thus its safety has been verified. Aluminium hydroxide is purchased as an antacid drug or against hyperphosphataemia under a variety of brand names in Europe and US (Alamag®, Maalox®, Mylanta® Alternagel®, Alu-Cap®, Dialume®, Amphojel®, Alu-Tab®, Aloh-Gel® etc). Aluminium hydroxide is also used as an adjuvant to the diphtheria and pertussis toxoid for infant immunization (see also Butler et al, 1969). In Europe, aluminium hydroxide is an approved colour additive (CI 77002) that may be used in all types of cosmetics and personal care products (Annex IV of Cosmetics Directive 76/768/EEC). FDA also permits aluminium hydroxide to be used as anindirect food additive. For example, it may be used as a defoaming agent in the manufacture of paper and paperboard used to package food (see alsohttp://www.cosmeticsinfo.org). The wide use of aluminium hydroxide even in injecting preparations verifies its high safety profile.

The other ingredients of Ferronickel slags (SiO2 and MgO) are of proved insignificant toxicological profile (in regards to developmental toxicity/teratogenicity) and are insufficient to trigger relevant classification for the whole mixture.

Overall the data on effects on embryo development are sufficient and allow for robust risk characterization of ferronickel slags and point to no classification.

Justification for classification or non-classification

Data from fertility studies on the individual components of ferronickel slags showed no significant adverse effects, with the exception of a detailed 13 week study on NiO inhalation on female and male rats that revealed no effects on estrous cycle length (days) and estrous stages for females and no effects on sperm morphology and motility for males. Based on this study an inhalation NOAEC of 3.9 mg Ni/m3 was determined which corresponds to 650mg Ferronickel slag/m3 (in a worst case scenario of 0.6% Ni content of the slag). Based on these, and on the fact that all of the constituents are chemically bound in the matrix of the ferronickel slags having low solubility (with the exception of sulfur, that poses no problem whatsoever), no classification in regards to reproductive toxicity is justified.

Data from studies on the toxicological properties of the individual components of ferronickel slags on development and teratogenesis, showed no significant adverse effects. The studies included both animal studies and human epidemiological data. Based on these, and on the fact that all of the constituents are chemically bound in the matrix of the ferronickel slags having low solubility (with the exception of sulfur, that poses no problem whatsoever), no classification in regards to developmental toxicity is justified.