Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information
- genetic toxicity in vitro: • FeCl3: no classification, negative for bacterial gene mutation (several studies; key study: Dunkel 1999a), negative (with and without metabolic activation) for in vitro mammalian gene mutation ( 3 studies; key study:Dunkel 1999b), negative for in vitro chromosomal aberration (1 study, key study: Schulz 2009) and weak positive response at cytotoxic concentration with metabolic activation in one in vitro mammalian gene mutation study (Dunkel 1999b) • Fe2(SO4)3: no classification, no studies available, accordingly read across is used from FeCl3 • FeCl2: no classification, negative for bacterial gene mutation (1 study; key study: Kim 2004), data for in vitro mammalian gene mutation (1 study; disregarded study: Shires 1982), read-across to FeCl3 for in vitro chromosomal aberration (1 study, key study: Schulz 2009) • FeSO4: no classification, weak positive response at dose-related cytotoxic concentration with and without metabolic activation in one in vitro mammalian gene mutation study (Dunkel, 1999c) • FeClSO4: no classification, no studies available, accordingly read across is used from FeCl3 - genetic toxicity in vivo: • FeCl3: no classification, no data for in vivo mammalian gene mutation, negative for in vivo mammalian chromosome aberration (several studies; key studies: Bianchini 1988b and Ogawa 1992), • Fe2(SO4)3: no classification, no studies available, accordingly read across is used from FeCl3 • FeCl2: no classification, no reliable data for in vivo mammalian gene mutation (1 study; disregarded study: Shires 1982), negative for in vivo chromosomal aberration (1 study, key study: Ji Yoon 2004) • FeSO4: no classification, no reliable data for in vivo mammalian gene mutation (1 study; supporting study: Lee 1983), negative for in vivo chromosomal aberration (2 studies, key study: Bianchini 1988b) • FeClSO4: no classification, no studies available, accordingly read across is used from FeCl3
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

This endpoint is covered by the category approach for soluble iron salts (please see the section Toxicokinetics, metabolism and distribution for the category justification/report format).

-in vitro

bacterial gene mutation:

• FeCl3 is deemed negative for bacterial gene mutation. One reliable study (Dunkel 1999a) is available, conducted according to OECD 471 using the strains Salmonella typhimurium strains TA97a, TA98, TA100, TA102, TA1535, TA1537 and TA1538 with and without activation in a plate incorporation assay. The test was performed with FeCl3 x 6H2O with concentrations up to 10’000 µg/plate which is equivalent to 6001 µg/plate anhydrous FeCl3.

• Fe2(SO4)3 is deemed negative for bacterial gene mutation. No studies are available for this substance accordingly a read across from FeCl3 is employed.

• FeCl2 is deemed negative for bacterial gene mutation. One reliable study (Kim 2004) is available, conducted according to OECD 471 and GLP using the strains S. typhimurium TA 1535, TA 1537, TA 98 and TA 100 and E. coli WP2 uvr A and concentrations up to 5000 µg/plate in a plate incorporation assay.

• FeSO4 is deemed negative for bacterial gene mutation. No studies are available for this substance accordingly a read across from FeCl2 and FeCl3 is employed.

 • FeClSO4: no classification, no studies available, accordingly read across is used from FeCl3.

 

mammalian gene mutation:

 • FeCl3 is negative for in vitro mammalian gene mutation. Two reliable studies (Dunkel 1999b; McGregor 1988) are available, conducted according to OECD 476 (Dunkel 1999b only) in mouse lymphoma L5178Y cells with cytotoxic concentrations or precipitation as the upper boundaries. In Dunkel,1999b the test was positive with metabolic activation only at cytotoxic concentration and otherwise negative, whereas in the McGregor study the test was negative. This was supported by the study Ohno,1982.

 • FeCl2 is deemed negative for in vitro mammalian gene mutation. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 • FeSO4 is deemed negative for in vitro mammalian gene mutation. One reliable study with mouse lymphoma L5178Y cells

is available (Dunkel 1999c) presenting a negative result in non-cytotoxic concentrations.

 • FeClSO4 is deemed negative for in vitro mammalian gene mutation. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 

mammalian chromosome aberration:

 • FeCl3 is deemed negative for in vitro mammalian chromosome aberration. One reliable OECD 487, GLP study (Schulz 2009) is available, with Chinese hamster lung fibroblasts (V79) up to 1650 µg/mL reporting a negative result.

 • FeCl2 is deemed negative for in vitro mammalian chromosomal aberration. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 • FeSO4 is deemed negative for in vitro mammalian chromosomal aberration. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 • FeClSO4 is deemed negative for in vitro mammalian chromosomal aberration. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 

-in vivo

mammalian gene mutation:

No studies available for any of the members of this iron salt category.

 

mammalian chromosome aberration:

• FeCl3 is deemed negative for in vivo mammalian chromosome aberration. One reliable study (Bianchini 1988a) is available, conducted according to Wargovich et al, J Natl Cancer Inst 71 125-131 1983 analysing micronuclei induction in the GI tract and reporting a negative result. This result is supported by a negative Drosophila wing spot test (Ogawa 1994). All other studies of low reliability except two (Liao, 1988; BASF, 1992) also show negative results. Overall weight of evidence suggests that the substance is negative in chromosomal aberration test.

 • FeCl2 is deemed negative for in vivo mammalian chromosome aberration. One reliable study (Ji Yoon 2004) according to OECD 474/GLP with ICR mice and doses of 2, 5, 10, 20, 50, 100 and 200 mg/ml in the dose range-finder and 1.25, 2.5 and 5 mg/ml in the micronucleus experiment was negative. No further data are available for FeCl2.

 • FeSO4 is deemed negative for in vivo mammalian chromosome aberration. Two reliable studies are available (Bianchini 1988b and Hayashi 1988). Bianchini 1988b analysed micronuclei induction in the GI tract and reported a negative result. Hayashi 1988 a Mammalian Erythrocyte Micronucleus Test according to OECD Guideline 474 using ddy mice treated intraperitoneal with 25, 50, 100, 180 mg/kg bw. The test result was negative. This result is supported by the Drosophila sex linked lethal test (Lee, 1983)

 • FeClSO4 is deemed negative in vivo mammalian chromosome aberration. No studies are available for this substance accordingly a read across from FeCl3 is employed.

 

General:

Human data is not available for genetic toxicity. Both, gene mutation and cytogenicity are cover by a plethora of studies. All relevant studies express that the iron compounds are non-genotoxic. Two short abstracts (Liao 1988 and BASF AG 1992) indicate that FeCl3 might have shown positive results in mammalian chromosomal aberration studies. Nevertheless, these data are considered to be unreliable since insufficiently reported.

In summary, the overwhelming majority of data support the conclusion that iron salts of this category are non-genotoxic. Accordingly, classification for this category is not appropriate or for any of the individual category members.


Justification for selection of genetic toxicity endpoint
Reliable study conducted according to OECD TG 487 and GLP in Chinese hamster lung fibroblasts (V79) using FeCl3

Justification for classification or non-classification

Based on the above stated assessment of the genotoxic potential all members of this iron salt category are deemed non-genotoxic and accordingly do not need to be classified according to Council Directive 2001/59/EC (28th ATP of Directive 67/548/EEC) and according to CLP (5th ATP of Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.