Reaction products of sodium glucoheptonate with iron sulfate and ammonium hydroxide

Endpoint summary

Description of key information

Skin sensitisation

To address the endpoint skin sensitization, read-across on gluconates and derivatives and iron compounds was performed within the frame of a weight-of-evidence approach.The underlying hypothesis for the read-across is that glucoheptonates and gluconates, structurally similar sugar-like carbohydrate metal-complexes, share the same metabolism pathways in mammals (they are oxidized by pentose phosphate pathway) and that their possible toxicity is a function of the metal cation rather than of the gluconate or glucoheptonate anion.

Overall, according to the CLP criteria, the test material does not meet criteria for classification and labelling as skin sensitizer according to the Regulation (EC) No 1272/2008.

local lymph node assay (LLNA) in mice (iron sulfate) (Ikarashi et al., 1992)

In a dermal sensitization study with 10 % iron (II) sulfate in 20% ethanol solution, 6-8 week old female Balb/c mice (three animals / dose) were tested in the murine local lymph node assay (Ikarashi et al, 1992). The test substance was applied on three consecutive days on the dorsum of each ear, local lymph nodes were isolated on fourth day after application. Isolated cells were cultivated with [3H]methyl thymidine ([3H]TdR) and [3H]TdR incorporation was measured with a scintillation counter.

The stimulation index (SI) was determined to be 1.32 showing that the mice exposed to FeSO₄ did not show an increase in LNC proliferation compared with those exposed to vehicle alone (SI<2).

In this study, FeSO₄ is not a dermal sensitizer. This study is considered to be reliable and to fulfill general scientific requirements.

This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since this iron does not trigger an allergic response in this murine local lymph node assay, iron glucoheptonate is considered to be also non "sensitizing" according to 1272/2008/EC.

patch test in human (iron oxide) (Motolese et al., 1993)

126 enamellers and 64 decorators from 5 factories underwent dermatological and allergiological examination using occupational test series in order to evaluate the prevalence of dermatitis and contact sensitization, and to identify the most important sensitizing substances. 44 workers (corresponding to 25.26% of the study population) were sensitized, with a total of 55 positive patch tests. Dermatitis was present in 22 workers, whereas 44 subjects claimed to have had skin lesions in the past. We found 17 positivities to specific substances: 7 to red iron oxide; 2 to antimony trioxide, manganese dioxide and maleic anhydride; and 1 to red copper oxide, cadmium chloride, vanadium pentoxide and sodium tripolyphospliate.

It is well-known that in the ceramics industry only red and yellow iron oxides are used; however, other industrial processes employ iron salts which are not a frequent cause of eczematous reactions.

This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since iron in red and white iron oxide triggers in only 3.7% (7 of 190 workers) an allergic response in this occupational patch tests, iron glucoheptonate is considered to be "not sensitizing" according to 1272/2008/EC.

opinion on disaccharides (CIR, 2014)

"The Panel acknowledged that sucrose and glucose are used in cosmetics at relatively high concentrations, and that data from irritation and sensitization studies at maximum use concentrations of these ingredients (i.e. calcium gluconate or gluconic acid) are lacking; however, based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers".

These results are also relevant for iron glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, the fact that gluconates are no irritants or sensitisers is important.

Sensitisation data on ferric gluconate complex in sucrose (Ferrlecit) and iron dextran in humans (reference: Sensitisation data (humans)) (sanofi-aventis, 2009)

The estimated usage of ferric gluconate complex in sucrose (Ferrlecit) in Europe is about 2.7 million i. v. doses per year (1992 to 1996). For the same period, Ferrlecit had an allergy event reporting rate of 3.3 allergy episodes per million doses per year compared with a similar rate of 8.7 reported allergy events per million doses per year for iron dextran in the U.S. in 1995.

In a post-market clinical study conducted in North America which included 2,534 Ferrlecit-naive patients who received a single-dose of Ferrlecit in a placebo-controlled, crossover, postmarketing safety study. Undiluted Ferrlecit was administered over ten minutes (125 mg at 12.5 mg/min) during the first hour of hemodialysis. There was no significant difference in the occurrence of suspected hypersensitivity reactions between Ferrlecit and placebo treatment. The study concluded that Ferrlecit is not an allergen.

These results are also relevant for iron glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, ferric gluconate is a good source substance for read across. Thus, iron glucoheptonate is considered to be "not sensitizing" according to 1272/2008/EC.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Rationale for reliability incl. deficiencies:

other:

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
An extended read-across statement is attached under section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Skin sensitisation potential of glucoheptonates is believed to be driven by metal cation bonded to the organic part of the molecule and not by the organic part itself. Glucoheptonates can dissociate on the skin releasing their metals that can further interact with skin proteins, while no skin sensitisation potential can be attributed to the organic part of the molecule. Glucoheptonates are not known to bind to proteins, producing a hapten eliciting a skin sensitisation response.
Therefore, data on skin sensitisation potential of several organic and inorganic compounds have been taken into account to address skin sensitisation potential of iron cation which could be released from the iron glucoheptonate in contact with skin.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Information on purity of the registered substance is provided in the target record under "Test material" as confidential. The iron glucoheptonate content in the registered product is 76 %. Other components are ammonium sulfate and sodium sulfate. Ammonium sulfate and sodium sulfate are considered not to impact sensitization of the target substance to a significant degree. In the HERA risk assessment report on sodium sulfate, sensitizing effects of sodium sulfate are judged to be “highly unlikely based on wide practical experience with sodium sulfate, in combination with the natural occurrence of sulfate in the body” (HERA, 2006). Sensitization data on ammonium is rare. However, ammonium sulfate is not classified as skin sensitizer according to the information of the ECHA homepage. Therefore, the iron ion is the only toxicological relevant component of the registered substance.
There is limited information on purity of the source substance iron sulfate. A purity of 100 % was therefore assumed.

3. ANALOGUE APPROACH JUSTIFICATION
As said before, glucoheptonates can dissociate on the skin releasing their metals that can further interact with skin proteins, while no skin sensitisation potential can be attributed to the organic part of the molecule. Sulphates are endogenous substances and are no skin sensitisers. Therefore, if iron sulphate was a skin sensitiser, the response would entirely belong to iron cation. Thus, results on iron sulphate provide information on the skin sensitising potency of the iron ion of iron Glucoheptonate.

4. DATA MATRIX
please refer to the detailled data matrix attached in section 13.

Reason / purpose for cross-reference:

read-across source

Parameter:

SI

Test group / Remarks:

LLNA performed with 5% FeSO4 in DMSO

Remarks on result:

other: 1.15

Parameter:

SI

Test group / Remarks:

LLNA performed with 10% FeSO4 in 20 % Ethanol solution

Remarks on result:

other: 1.32

Parameter:

SI

Test group / Remarks:

LLNA perfromed with 20% FeSO4 in 70% Ethanol solution

Remarks on result:

other: 1.50

Parameter:

other: disintegrations per minute (DPM)

Test group / Remarks:

LLNA experiments performed with 5% FeSO4 in DMSO

Remarks on result:

other: Mean counts per minute ± SD (x 10E-3): 3.31 ± 0.19

Parameter:

other: disintegrations per minute (DPM)

Test group / Remarks:

LLNA experiments performed with 10% FeSO4 in 20 % Ethanol

Remarks on result:

other: Mean counts per minute ± SD (x 10E-3): 2.03 ± 0.62

Parameter:

other: disintegrations per minute (DPM)

Test group / Remarks:

LLNA experiments performed with 20% FeSO4 in 70% Ethanol

Remarks on result:

other: Mean counts per minute ± SD (x 10E-3): 2.99 ± 0.52

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Although there are some deficiencies in the test conduction, the stimulation index was determined to be 1.32 (10 % FeSO4 in 20 % Ethanol). Hence, it can be concluded that the provided data is sufficient for classification as "not sensitising" according to 1272/2008/EC and further testing would not reveal any other contradicting data. This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since this iron does not trigger an allergic response in this murine local lymph node assay, iron glucoheptonate is considered to be also non "sensitising" according to 1272/2008/EC.

Executive summary:

In a dermal sensitization study with 10 % iron (II) sulfate in 20% ethanol solution, 6-8 week old female Balb/c mice (three animals / dose) were tested in the murine local lymph node assay (Ikarashi, et al., 1992). The test substance was applied on three consecutive days on the dorsum of each ear, local lymph nodes were isolated on fourth day after application. Isolated cells were cultivated with [3H]methyl thymidine ([3H]TdR) and [3H]TdR incorporation was measured with a scintillation counter.

The stimulation index (SI) was determined to be 1.32 (10% FeSO4 in 20 % Ethanol) showing that the mice exposed to FeSO₄ did not show an increase in LNC proliferation compared with those exposed to vehicle alone (SI<2).

In this study, FeSO₄ is not a dermal sensitizer. This study is considered to be reliable and to fulfill general scientific requirements.

This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since this iron does not trigger an allergic response in this murine local lymph node assay, iron glucoheptonate is considered to be also "not sensitising" according to 1272/2008/EC.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
An extended read-across statement is attached under section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Skin sensitisation potential of glucoheptonates is believed to be driven by metal cation bonded to the organic part of the molecule and not by the organic part itself. Glucoheptonates can dissociate on the skin releasing their metals that can further interact with skin proteins, while no skin sensitisation potential can be attributed to the organic part of the molecule. Glucoheptonates are not known to bind to proteins, producing a hapten eliciting a skin sensitisation response.
Therefore, data on skin sensitisation potential of several organic and inorganic compounds have been taken into account to address skin sensitisation potential of iron cation which could be released from the iron glucoheptonate in contact with skin.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Information on purity of the registered substance is provided in the target record under "Test material" as confidential. The content of iron glucoheptonate in the registered product is 76 %. Other components are ammonium sulfate and sodium sulfate. Ammonium sulfate and sodium sulfate are considered not to impact sensitization of the target substance to a significant degree. In the HERA risk assessment report on sodium sulfate, sensitizing effects of sodium sulfate are judged to be “highly unlikely based on wide practical experience with sodium sulfate, in combination with the natural occurrence of sulfate in the body” (HERA, 2006). Sensitization data on ammonium is rare. However, ammonium sulfate is not classified as skin sensitizer according to the information of the ECHA homepage. Therefore, the iron ion is the only toxicological relevant component of the registered substance.
There is limited information on purity of the source substance iron oxide. A purity of 100 % was therefore assumed.

3. ANALOGUE APPROACH JUSTIFICATION
As said before, glucoheptonates can dissociate on the skin releasing their metals that can further interact with skin proteins, while no skin sensitisation potential can be attributed to the organic part of the molecule. Therefore, results on iron oxide provide information on the skin sensitising potency of the iron ion of iron glucoheptonate.

4. DATA MATRIX
please refer to the detailled data matrix attached in section 13.

Reason / purpose for cross-reference:

read-across source

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

2 %

No. with + reactions:

7

Total no. in group:

190

Clinical observations:

the sensitized persons represent 3.7 %

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 2 %. No with. + reactions: 7.0. Total no. in groups: 190.0. Clinical observations: the sensitized persons represent 3.7 %.

Remarks:

iron oxide

Interpretation of results:

ambiguous

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

In this study, 7 out of 190 workers (3.7 %) was positive in patch test to red iron oxide. This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since iron in red and white iron oxide triggers in only 3.7% (7 of 190 workers) an allergic response in this occupational patch tests, iron glucoheptonate is considered to be "not sensitizing" according to 1272/2008/EC.

Executive summary:

126 enamellers and 64 decorators from 5 factories underwent dermaiological and allergological examination using occupational test series in order to evaluate the prevalence of dermatitis and contact sensitization, and to identify the most important sensitizing substances. 44 workers (corresponding to 25.26% of the study population) were sensitized, with a total of 55 positive patch tests. Dermatitis was present in 22 workers, whereas 44 subjects claimed to have had skin lesions in the past. We found 17 positivities to specific substances: 7 to red iron oxide; 2 to antimony trioxide, manganese dioxide and maleic anhydride; and 1 to red copper oxide, cadmium chloride, vanadium pentoxide and sodium tripolyphospliate.

It is well-known that in the ceramics industry only red and yellow iron oxides are used; however, other industrial processes employ iron salts which are not a frequent cause of eczematous reactions.

This result is also applicable to iron glucoheptonate, as the main sensitisation mediating part is the iron. Since iron in red and white iron oxide triggers in only 3.7% (7 of 190 workers) an allergic response in this occupational patch tests, iron glucoheptonate is considered to be "not sensitizing" according to 1272/2008/EC.

Reference 3

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
An extended read-across statement is attached under section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Skin sensitisation potential of gluconates and glucoheptonates is believed to be driven by metal cation bonded to the organic part of the molecule and not by the organic part itself. Gluconates and glucoheptonates can dissociate on the skin releasing their metals that can further interact with skin proteins, while no skin sensitisation potential can be attributed to the organic part of the molecule. This is because gluconates and glucoheptonates are structurally similar sugar-like substances with the same functional groups (sugar backbone), which are not known to bind to proteins, producing a hapten eliciting a skin sensitisation response. So, information on skin sensitisation of gluconate anion allows to strengthen the read-across approach, excluding the skin sensitisation potential of the organic part of the molecule.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Gluconates used in skin sensitisation studies described in this record do not include impurities that are different from those contained in the target substance and which would influence skin sensitisation potential.
Information on purity of the registered substance is provided in the target record under "Test material" as confidential. The iron glucoheptonate content in the registered product is 76 %. Other components are ammonium sulfate and sodium sulfate. Ammonium sulfate and sodium sulfate are considered not to impact sensitization of the target substance to a significant degree. In the HERA risk assessment report on sodium sulfate, sensitizing effects of sodium sulfate are judged to be “highly unlikely based on wide practical experience with sodium sulfate, in combination with the natural occurrence of sulfate in the body” (HERA, 2006). Sensitization data on ammonium is rare. However, ammonium sulfate is not classified as skin sensitizer according to the information of the ECHA homepage. Therefore, the iron ion is the only toxicological relevant component of the registered substance.

3. ANALOGUE APPROACH JUSTIFICATION
Sugars and its salts (Na, Ca, and Mg) are not skin sensitisers. Thus, this study provides information of skin sensitising properties of gluconates, which can be transferred to the glucoheptonate moiety of iron glucoheptonate.

4. DATA MATRIX
please refer to the detailled data matrix attached in section 13.

Reason / purpose for cross-reference:

read-across source

Reading:

other: Mono- and disaccharides did not produce hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs).

Remarks on result:

other: Reading: other: Mono- and disaccharides did not produce hypersensitivity skin reactions when tested in animals and In human repeated insult patch tests (HRIPTs)..

A face and neck formulation containing 2.48% lactose did not produce irritation or hypersensitivity in a 4-wk safety-in use ophthalmological evaluation. Thirty-one subjects participated in the study.

In non-human studies, a 50% aq. solution of gluconic acid was not a dermal irritant and lactitol was not an irritant or sensitizer in rabbits. In human repeated insult patch tests (HRIPTs), formulations containing 10% rhamnose, up to 8% glucose, 5% mannose, 2.48% lactose, and less than 1% isomalt, kefiran, lactitol, sucralose, and xylobiose were not irritants or sensitizers. A formulation containing 10% rhamnose did induce a significant irritation reaction in one subject, and irritation was observed in 16% of the subjects during induction in an HRIPT of a rinse-off hair product containing 29% sucrose (tested as a 50% dilution); no sensitization reactions were reported for this product.

Interpretation of results:

not sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Calcium gluconate and gluconic acid, structurally similar anlogues to glucoheptonates, have been assessed by the Panel as non-sensitizers in cosmetic formulations. These results are also relevant for iron glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, the fact that gluconates are no irritants or sensitisers is important.

Executive summary:

"The Panel acknowledged that sucrose and glucose are used in cosmetics at relatively high concentrations, and that data from irritation and sensitization studies at maximum use concentrations of these ingredients (i.e. calcium gluconate and gluconic acid) are lacking; however, based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers".

These results are also relevant for iron glucoheptonate, as the glucoheptonate-residue is also a derivative of gluconic acid. Therefore, the fact that gluconates are no irritants or sensitisers is important.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

According to the CLP criteria, the test material does not meet criteria for classification and labelling as skin sensitizer according to the Regulation (EC) No 1272/2008.