Slags, silicomanganese-manufg.

Toxicity to reproduction

Administrative data

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because (i) the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), (ii) it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and (iii) there is no or no significant human exposure

Justification for type of information:

In accordance with the general rules for adaption set out in Annex XI the registrant justifies that further study of fertility (OECD 433, Extended One Generation Reproductive Toxicity Study) in vertebrates is not appropriate based on a weight of evidence approach, for the following reasons:

1. The substance is of low toxicological activity and there is no systemic exposure. In a 90-day study in rats, plasma samples were analysed to quantify the degree of absorption of four major and representative elements present in the Slags, silicomanganese-manufg.: Mn, Si, Al and Ba. Analysis was conducted using a validated ICP-MS method. Excellent linearity was demonstrated, with Limits of Quantitation (LoQs) at 0.0025 mg/L for Mn, 0.0125 mg/L far Ba, 0.025 mg/L for Al and 5 mg/L for Si. The highest dose administered in the 90-day study was 1000 mg/kg bw/day; blood samples were taken at 1, 4 and 24 hours after dosing during week 7 of the study. Analytical results for all blood samples were below the LoQ. The study provides a clear demonstration that there is no quantifiable systemic absorption of these marker elements even at the upper oral limit dose (1000 mg/kg bw/day). Mn and Al in these blood samples, at these LoQs, appeared comparable or lower than concentrations of these elements monitored in the municipal water supply of the test facility.

2. The substance is UVCB of highly variable composition, being the raw material (ore) for an industrial extraction and refinement process; there is no requirement for quality control other than a high Mn content. Consequently, any given batch cannot be considered toxicologically representative of another. The consequent testing strategy must be either to test multiple batches, or to seek non-animal alternatives. The specified reproductive toxicity study (OECD 433, Extended One-Generation Reproductive Toxicity Study) uses a considerable number of animals, which would be multiplied if several “representative” batches required testing. Commission Implementing Decision of 1.9.2017 requires the information requirement to be fulfilled by vertebrate testing only if no suitable alternative exists. A feasible non-animal alternative is to evaluate the potential for reproductive toxicity from the known components of the mixture; and information for all significant components of this slag are known to be submitted under REACH. The CLH Inventory has been searched for classification of the component metal oxides; none are proposed for classification for fertility (see Table 1). Further, none of the metal cations in isolation (Mn, Fe, Al, Mg, Ti) are classified for fertility. From the 90-day study, there is no demonstration that the components of the slag interact to affect absorption or bioavailability; hence no interference with the extrapolation is evident.

3. A 90-day study of this substance Slags, silicomanganese-manufg. by the oral route in rats conducted to the upper limit dose (1000 mg/kg bw/day) demonstrated no sign of systemic toxicity, including to the reproductive tract of males and females. The study was conducted to modern standards and to GLP, and included weights of testes, epididymides, ovaries and uterus; and histopathological examination of these tissues plus pituitary, prostate, seminal vesicles, and vagina. There were some minor histological lesions in the wall of the stomach, attributed to site-of-contact effects of this granular slag applied by gavage.

4. A modern, guideline and GLP-compliant study of developmental toxicity in the rat is available for a closely analogous material (Slags, ferromanganese-manufg., CAS No 69012-28-8 (EC No 273-728-1), registration number: 01-2119446651-40-0000). The milled slag was administered in corn oil at doses up to 1000 mg/kg bw/day during days 6-19 of pregnancy. There were no signs of maternal toxicity, and no effect on pregnany or the offspring. Fetal survival, growth and development were unaffected by treatment, even at the top limit dose.

5. This Weight of Evidence clearly supports that an EOGRTS study of this systemically unavailable, and toxicologically inert slag is not an appropriate use of animals. It can be safely predicted that no useful information will be obtained despite use of an excessive number of animals.

Existing classification of component chemicals

Substance Classification (CL Inventory)
MnO2 Acute Tox 4 (oral and inhalation)
SiO2 Not classified
CaO Eye damage 1, skin irritation 2, STOT-SE3
Al2O3 No harmonised classification – majority not classified
MgO No harmonised classification – majority not classified
K2O Eye Damage 1, Skin corrosion 1A
BaO Not notified in isolation. Acute Tox 4 (BaO, SiO, MgO2)
S Skin Irritation 2
FeO No harmonised classification – majority not classified
TiO2 Not classified

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified