Hydrogen (glycinato-N,O)[sulphato(2-)-O,O']ferrate(1-)

Endpoint summary

Description of key information

There are no data regarding the skin sensitzing potential of ferrous monoglycinate sulfate. Based on its ionic structure, ferrous monoglycinate sulfate is considered to dissociate into its ions namely, glycine and ferrous sulfate and the cells are predominantly exposed to the single constituents of the salt.

There are information about the skin sensitizing potential of ferrous sulfate and glycine.

- publication, 1992, test similar to LLNA conducted in F344 rats, the animals were exposed for 3 consecutive days with 0, 0.5, 1.0, 2.5, and 5.0% FeSO4 in DMSO:water (9:1). 24h after the last application the animals were sacrificed and the draining lymphnodes were collected and evaluated, based on an overall SI < 3, FeSO4 is not considered to be a dermal sensitizer.

- QSAR estimation using VEGA-QSAR platform, the prediction clearly showed no sensitizing potential for glycine. The substance lies within the applicability domain of the model thus the result is regarded reliable.

- QSAR Toolbox request, a request of the QSAR Toolbox database revealed reliable data (LLNA, according to OECD guideline 429, 2012, in mice) proving that glycine is not a dermal sensitizer.

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:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

The test was performed in 3 animals instead of 4 and the test was performed in rats.

GLP compliance:

no

Type of study:

mouse local lymph node assay (LLNA)

Species:

other: rat

Strain:

other: F344

Sex:

not specified

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Japan Charles River Breeding Laboratories, Inc.
- Females (if applicable) nulliparous and non-pregnant: not specified
- Microbiological status of animals, when known:
- Age at study initiation: 6-8 weeks
- Housing: 3 per cage

Vehicle:

other: Iron sulfate was dissolved in DMSO:water (4:1)

Concentration:

Iron sulphate was applied at concentrations of 0 (vehicle alone), 0.5, 1.0, 2.5, and 5.0% (w/v)

No. of animals per dose:

3 animals were used per group

Details on study design:

MAIN STUDY
Rats received 100µL and guinea pigs received 200 µL of chemicals or vehicle. Animals were sacrificed 24 h following the final exposure. The draining auricular lymph nodes were excised and pooled and weighed for each experimental group. A single suspension of LNC was prepared by mechanical disaggregation through sterile 200-mesh stainless steel gauze. Cell suspensions were washed once in phosphate-buffered saline (pH 7.2) and resuspended in RPMI-1640 culture medium supplemented with 10% FCS, 25 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 100 µg/mL penicillin, 100 units/ml streptomycin (FCS-RPMI). Total LNC number was determined using an automated cell counter. Cell suspensions (1E+06 cells/200µL) were seeded into 96-well tissue culture plate (5 wells per group) and cultured at 37°C in a humidified atmosphere of 5% CO2 in air with 0.5/µCi [methyl-3H]thymidine (3HTdR). After 18 h culture, LNC were harvested with an automatic cell harvester and 3HTdR incorporation was determined by liquid scintillation counting. A stimulation index (SI), the increase in 3HTdR incorporation relative to vehicle-treated controls, was derived for each experimental group.

Positive control substance(s):

other: nickel sulfate, potassium dichromate and cobalt chloride were also tested in this publication and are well known metall allergens.

Positive control results:

K2Cr2O7, CoCl2 and NiSO4 are known metal allergens. K2Cr2O7 and CoCl2 revealed a SI of > 3 in at least two concentrations. For K2Cr2O7 the SI was 6.64 at 1%, 10.94 at 2.5% and 5.44 at 5%. For CoCl2 the SI was 3.82 at 2.5% and 3.57 at 5%. Both Substances were tested in rats.

Key result

Parameter:

SI

Value:

1.28

Test group / Remarks:

0.5%

Key result

Parameter:

SI

Value:

0.61

Test group / Remarks:

1.0%

Key result

Parameter:

SI

Value:

1.64

Test group / Remarks:

2.5%

Key result

Parameter:

SI

Value:

1.12

Test group / Remarks:

5.0%

Cellular proliferation data / Observations:

CELLULAR PROLIFERATION DATA
Exposure to 2.5% K2Cr20 7 induced a strong proliferative response (10.9-fold increase in 3HTdR incorporation) compared with the vehicle-treated control group. However, LNC proliferation was decreased in the 5% K2Cr2O7 group compared with the 2.5% K2Cr2O7 group. In the case of CoCI 2, SI of 3.82 was maximum in the 2.5% group. Lymph node weight and total LNC number increased following exposure to K2Cr2O7 and CoCI 2 but, compared with in vitro LNC proliferation, were less sensitively correlated to lymph node activation. Exposure to NiSO4 and FeSO4 failed to induce significant lymph node responses at all concentrations.

CLINICAL OBSERVATIONS:
Not reported
BODY WEIGHTS
Not reported

Chemical	Concentration (w/v%)	LNC proliferation 3HTdR incorporation (mean cpm±SD x E-03)	SI	Total LNC number (E+06/group)	Lymph node weight (mg/group)
FeSO4	0	2.35±0.18	-	25.68	61.8
	0.5	3.02± 0.32	1.28	23.71	65.0
	1.0	1.42± 0.16	0.61	26.20	59.5
	2.5	3.87± 0.23	1.64	20.52	48.4
	5.0	2.63± 0.17	1.12	26.86	54.3
K2Cr2O7	0	1.71± 0.06	-	27.86	59.3
	0.5	3.43± 0.11	2.00	28.74	67.0
	1.0	11.39± 0.33	6.64	58.72	85.6
	2.5	18.76± 0.36	10.94	92.28	114.3
	5.0	9.33± 0.26	5.44	60.86	114.4
CoCl2	0	1.95± 0.17	-	23.26	54.7
	0.5	1.71± 0.21	0.88	21.35	51.1
	1	1.95± 0.10	1.00	29.72	52.0
	2.5	7.45± 0.65	3.82	70.70	71.5
	5	6.95± 0.69	3.57	38.81	59.2

Interpretation of results:

GHS criteria not met

Conclusions:

In a dermal sensitization study conducted similar to OECD guideline 429 with FeSO4 in DMSO:water; 4:1, young adult F344 rats (4/group) were tested using the method of Kimber et al., 1989. As positive control substances in this case can be regarded K2Cr2O7 and CoCl2 which are known metal allergens. No clinical signs were observed for in the rats treated with FeSO4 at any concentration, no mortality occurred nor any pathological change was detected at necropsy. Furthermore, there was no indication for skin sensitisation after treatement with FeSO4.                                                 
 
The test was conducted for 24h after initial treatment for three consecutive days. In this study, FeSO4 is not a dermal sensitizer and thus does not need to be classified according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).

Executive summary:

In a dermal sensitization study conducted similar to OECD guideline 429 with FeSO4 in DMSO:water; 4:1, young adult F344 rats (4/group) were tested using the method of Kimber et al., 1989. As positive control substances in this case can be regarded K2Cr2O7 and CoCl2 which are known metal allergens No clinical signs were observed for in the rats treated with FeSO4 at any concentration, no mortality occurred nor any pathological change was detected at necropsy. Furthermore, there was no indication for skin sensitisation after treatement with FeSO4.                                                 

 

The test was conducted for 24h after initial treatment for three consecutive days. In this study, FeSO4 is not a dermal sensitizer and thus does not need to be classified according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).

Reference 2

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

other: Information from the QSAR Toolbox database

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study without detailed documentation

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

not specified

Vehicle:

not specified

Key result

Parameter:

EC3

Remarks on result:

other: Value not reported in QSAR Toolbox

Key result

Parameter:

SI

Value:

< 3

Test group / Remarks:

mean of all tested groups

Remarks on result:

other:

Remarks:

The LLNA test referred to in the QSAR Toolbox revealed no SI value above 3, thus the substance was considered negative

Interpretation of results:

GHS criteria not met

Conclusions:

The QSAR Toolbox was used in order to gather all available information about the skin sensitizing potential of glycine. The QSAR Toolbox revealed two identical entries exhibiting the same result from a test conducted accoding to OECD guideline 429 (LLNA). Glycine does not meet the classification criteria of Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemcials (GHS) and is therefore no classified as dermal sensitizer.

Executive summary:

Using the OECD QSAR Toolbox all available information about the skin sensitizing potential of glycine was gathered.

The QSAR Toolbox revealed two identical entries exhibiting the same result from a test conducted accoding to OECD guideline 429 (LLNA). Glycine does not meet the classification criteria of Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemcials (GHS) and is therefore no classified as dermal sensitizer.

Reference 3

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE
VEGA-QSAR:AI inside a platform for predictive toxicology
2. MODEL (incl. version number)
1.1.5
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
O=C(O)CN
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
For more detailed information please refer to the 'attached justification' section

5. APPLICABILITY DOMAIN
For more detailed information please refer to the 'attached justification' section

6. ADEQUACY OF THE RESULT
For more detailed information please refer to the 'attached justification' section

Qualifier:

no guideline followed

Principles of method if other than guideline:

Result of a QSAR prediction using VEGA-QSAR platform Skin Sensitization model (CAESAR) 2.1.6.

GLP compliance:

no

Species:

other: not applicable for an in silico system

Strain:

other: not applicable for an in silico system

Details on test animals and environmental conditions:

not applicalbe for an in silico system

Vehicle:

other: not applicable for an in silico system

Concentration:

not applicable for an in silico system

No. of animals per dose:

not applicable for an in silico system

Details on study design:

not applicable for an in silico system

Key result

Parameter:

other: not applicable for an in silico system

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Interpretation of results:

study cannot be used for classification

Conclusions:

In the present QSAR calculation using VEGA-QSAR platform and its Skin Sensitization model (CAESAR) 2.1.6. the skin sensitizing potential of Glycine was estimated. There are no indications for skin sensitisation by appliying this QSAR prediction method. The results are considered to be reliable because the substance falls in the applicability domain of the used model. Glycine is not a sensitizier according to this prediction.

Executive summary:

There are no experimental data available regarding the skin sensitizing potential of glycine. Therefore, a QSAR estimation was performed using the VEGA_QSAR platform. There are no indications for skin sensitisation by appliying this QSAR prediction method. The results are considered to be reliable because the substance falls in the applicability domain of the used model. Glycine is not a sensitizier according to this prediction.

Reference 4

Endpoint:

skin sensitisation: in vitro

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
A study for sensitisation is scientifically not necessary. For detailed information please refer to the attached justification below.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There are no data regarding the skin sensitzing potential of ferrous monoglycinate sulfate. Based on its ionic structure, ferrous monoglycinate sulfate is considered to dissociate into its ions namely, glycine and ferrous sulfate and the cells are predominantly exposed to the single constituents of the salt. Both constituents are not considered to be dermal sensitizer. Hence, there was no hazard identified for both constituents of the salt the parent substance as well is not considered to be a sensitizer.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

There are no data about the skin sensitization potential of ferrous monoglycinate sulfate. Based on the read-across hypothesis that the test item dissociates/is hydrolyzed into common break down products, data from the main constituents, namely ferrous sulfate and glycine were used to determine the skin sensitizing properties of ferrous monoglycinate sulfate.

In the study of Ikarashi (1992) the skin sensitizing potential of FeSO₄was determined according to OECD guideline 429 (LLNA). FeSO₄dissolved in water was applied to the dorsum of the ear of three animals per group for four groups with the concentrations 0.5, 1.0, 2.5 and 5.0% (w/v). The test item was applied for three consecutive days, animals were sacrificed after 24h after the last application and the draining lymph nodes were isolated and cultured for 18h with³HTdR. Adjacently, the incorporation of³HTdR was measured and FeSO₄did not result in an SI of ≥ 3, thus FeSO₄is not a skin sensitizer under the conditions of the test.

Testing of glycine, the smallest amino acid, was omitted because in vitro test systems are not considered to be suitable for the determination of a skin sensitizing potential of glycine. For registrations according to Annex VII in vivo testing is not foreseen. However, also in vivo tests are not considered to be the appropriate test method for the determination of skin senitization as described in the justification for waiving testing of skin sensitization attached in 7.4.1.

Based on the available information the target substance ferrous monoglycinate sulfate is not callsified as skin sensitizer according to Regulation (EU) No. 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).