Reaction products of sodium glucoheptonate with copper sulfate and ammonium hydroxide

Endpoint summary

Description of key information

A weight of evidence approach was followed to address the endpoint of skin sensitisation as there is no skin sensitisation study available for Copper glucoheptonate. Therefore, medical and scientific literature data on skin sensitisation potential of glucoheptonate ion, its structurally related analogue gluconate, and copper as well as inorganic copper compounds have been taken into account to evaluate skin sensitisation potential of copper glucoheptonate.  No skin sensitisation potential can be attributed to glucoheptonate moiety. Calcium glucoheptonate has been used for decades in both human and veterinary medicine for treatment of hypocalcaemia to correct calcium deficiency states (EMEA, 1998) (for reference please see section: acute toxicity: oral; Drop and Cullen, 1980, cited in the read-across statement). In human medicine, the normal dose is intended to provide 50 mmol of calcium daily (equivalent to 25 g/day of calcium glucoheptonate). In cases of hypocalcaemia, parenteral administration of 2.25 to 4.5 nmol calcium (equivalent to 1.125 to 2.25 g/day of calcium glucoheptonate) may be given and repeated as necessary (EMEA, 1998).There is no maximum residue limit established for calcium glucoheptonate in foodstuff of animal origin (Commission Regulation, 2009, No. 37/2010).  No cases of delayed contact hypersensitivity associated with glucoheptonates have been found in the literature (literature search of Chemservice SA in 2017). Glucoheptonates are widely used as imaging agents in nuclear medicine (please refer to read-across statement). No skin sensitisation or other types of allergic reactions due to the use of glucoheptonates are reported. Glucoheptonic acid is a structural sugar like analogue of an endogenous substance gluconic acid. Calcium gluconate and gluconic acid have been assessed for their safe use in cosmetics (CIR, 2014a). "The 2014 Cosmetic Ingredient Review Expert Panel acknowledged that the group of monosaccharides, disaccharides, and their related Ingredients, including calcium gluconate and gluconic acid, are safe for humans at concentrations as used in cosmetics. Based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers.” Furthermore, Calcium gluconate is listed by the Food and Drug Administration (FDA) as GRAS for food additives and is approved as a direct food additive (CIR, 2014).  Similarly, a copper containing organic substance Tripeptide-Copper Complex Glycyl-L-Histidyl-L-Lysine-Cu2+ (CAS 89030-95-5) was also evaluated as safe for the use in cosmetics as a skin condition agent (CIR, 2014b). Moreover, copper showed wound healing effect in in vivo and in in vitro studies (Simeon et al., 1999; McCormack et al., 2001).  There are only few reports of sensitisation to copper with an immunological aetiology (SCOEL, 2013). Most of the documented cases were regarded as either unspecific or cross reactions to nickel allergy (ATSDR 2004, Greim 2004, cited in SCOEL, 2013). With regard to the extensive use of copper and its compounds and the small number of case reports, there is little concern about the sensitising properties of copper. The few cases of skin sensitisation from exposure to copper or its compounds reported in the literature are restricted to clinical case reports involving small numbers of patients, and in evaluation of a case-series of patients from dermatology clinics (EU VRAR, 2007).  Inorganic copper compounds may evoke allergic contact dermatitis in susceptible individuals (WHO, 1998; WHO, 2002). Testing of patients with contact eczema or of workers occupationally exposed to copper dust or fumes provoked dermal reactions following testing with copper sulphate in concentrations up to 5 % copper sulphate. However, the number of reported cases with a clear copper induced sensitisation is very low and was observed only at high concentrations of 5 % of copper salts (Walton et al., 1983a; Walton, 1983b, cited in SCOEL, 2013). The observed dermal reactions were mostly either unspecific or cross reactions to a nickel allergy. In some cases, they may have been provoked by nickel contaminations of the copper (Greim 2004, cited in SCOEL, 2013). A single case of occupational respiratory sensitisation is reported. A worker in the galvanic industry showed a 30 % decline of the forced expiratory volume after provocation with 1 mg copper sulphate/m3 (Cirla 1985, cited in SCOEL, 2013). To evaluate the prevalence of skin sensitisation to a range of metals encountered in the ceramics industry, Motolese and co-workers (1993) assessed 190 enamellers and decorators by patch tests.  While the patch tests showed several cases positive to other metals, there was only a single case (out of 190 workers) of a positive patch test to red copper oxide in the group. Routine patch testing with 2% copper sulphate assessing 1190 eczema patients over a three-year period did not reveal any conclusive case of contact sensitivity. Several concomitant reactions, especially to cobalt, nickel, and eliminate were seen in the 13 patients and the results of the serial dilution tests did not support the existence of a true sensitivity to copper. Serial dilution tests with nickel and cobalt demonstrated that impurities of the metals are possible explanations for some of the initial test reactions (Karlberg et al., 1983). The largest investigation of women using copper containing intrauterine devices who reported side effects including skin reactions found that none reacted positively to copper in patch tests. This finding suggests that copper was not responsible for their symptoms (EU VRAR, 2007). These findings indicate the relative rarity of copper compounds in comparison to other metals as a cause of allergic contact dermatitis.  Among publically available animal studies, two maximisation tests in guinea pigs with the pentahydrate of copper sulphate in petrolatum yielded conflicting results (Boman et al., 1979, Karlberg et al., 1983). At the challenge concentration 1%, two (24 h) and seven (48 h) animals out of 20 each reacted positive compared to none (24 & 48 h) among the controls (Boman et al., 1979). The difference was statistically significant at the 48-h reading. On the contrary, no difference between copper-exposed and control animals was observed in any of the 3 test series at challenge exposures (Karlberg et al., 1983). As these studies were done by the same working group at similar conditions, the reason for this discrepancy is unknown (SCOEL, 2013). One Local Lymph Node Assay (LLNA) in mice with 10 % copper sulphate pentahydrate in ethanol failed to show a positive reaction (Ikarashi et al 1992). Another LLNA with copper chloride (1–5 % in DMSO) exhibited a strong lymphocytic proliferation, but this was attributed to the local necrotic action of the compound (Basketter et al 1999). In unpublished animal studies made available for the preparation of voluntary Risk Assessment Report (EU VRAR, 2007) none of the inorganic copper compounds was positive in either GPMT or in Buehler Test. According to EU VRAR (2007), the available animal and human data on the skin sensitisation properties of copper (I) oxide, copper (II) oxide, copper carbonate, copper sulphate, copper oxychloride and copper powder have been considered against EU classification criteria as contained in Annex VI of Directive 67/548/EEC.   The available animal data do not meet the criteria requiring these substances to be classified for skin sensitisation.  Human data on skin sensitisation properties of copper or its compounds are insufficient to require classification for skin sensitisation. Copper and copper compounds are not listed as known skin sensitizers (German MAK List, 2015).  Based on this information no skin sensitisation potential can be expected for Copper glucoheptonate. The substance does not need to be classified and labelled as skin 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:

other: Acceptable well documented publication which meets basic scientific principles.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

not specified

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA

Sex:

not specified

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Harlan Olac, Bicester, United Kingdom
- Age at study initiation: 7-12 weeks

Vehicle:

dimethyl sulphoxide

Concentration:

1.0, 2.5 and 5.0%

No. of animals per dose:

4

Positive control substance(s):

other: In these investigations, the LLNA was used to determine the skin sensitization potential of 13 metal salts, 8 of which were considered to possess a significant ability to sensitize man, whereas the remaining 5 were judged to lack such potential.

Statistics:

A substance was regarded as a skin sensitizer if, at any test concentration, the proliferation in treated lymph nodes was threefold or greater than that in the concurrent vehicle treated controls.

Positive control results:

Of the 13 metals considered here, 8 (Au, Be, Co, Cr, Hg, Ni, Pt, and Sn) were judged to possess significant ability to cause ACD. Nickel showed evidence of a positive dose-response trend, but could not be tested at higher application concentrations to determine whether it might reach a threshold positive level. In the LLNA, 7 of these 8 sensitizing metals were identified correctly, with nickel being the only allergen that was missed. At first sight, this might seem to be an important predictive error, because, as mentioned above, nickel is a very frequent cause of ACD in humans.

Parameter:

SI

Remarks on result:

other: see Remark

Remarks:

Copper was found, at 1 or more test concentrations, to stimulate lymph node cell proliferation at least threefold greater than that observed in concurrent vehicle-treated control, although in this series of experiments the substance was not found to display convincing dose-responses. Stimulation index (SI) was as follows: 1 % : 8.1; 2.5 %: 13.8; 5.0 %: 13.6% Copper elicited a marked proliferative response (SI > 5). However, it caused substantial local adverse effects, with necrosis at the higher test concentrations. Therefore, Copper was not considered to possess significant ability to sensitize the skin. When compared with the classification that was based on substantial human experience, the LLNA result for copper in this test was considered to be false positive.

Interpretation of results:

not sensitising

Conclusions:

Cu was not considered to possess, to any significant degree, the ability to cause skin sensitization in humans, and, thus, would not be classified and labeled as sensitizer.

Executive summary:

Among the metals tested, 5 metals evaluated (Al, Cu, Mn, Pb, and Zn) were not considered to possess, to any significant degree, the ability to cause skin sensitization in humans, and, thus, would not be classified and labeled as sensitizers. In the present LLNA, 4 of the 5 were correctly identified, the false positive being Cu. This material is a very rare human skin sensitizer, and it would not be expected to yield positive results in a hazard identification method such as the LLNA. However, it was noted that at the concentrations used, the copper (II) chloride salt in dimethyl sulfoxide (DMSO) was extremely irritant, and this may have contributed to relatively high stimulation indices observed. Although it is clear that, in this case, Cu is a true false positive (the stimulation indices obtained are higher than seen with the significant skin irritant, sodium dodecyl sulfate, which at most are typically in the range of 4 to 5) the data obtained nevertheless emphasize the need for scientific evaluation of the results of skin sensitization testing rather than prescriptive evaluation in terms of a simple regulatory model.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: A short communication report. A lot of details missing.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Two groups of 20 animals were used. One group was actively sensitized and the other group (control) was treated in the same way as the experimental group (Freund's complete adjuvant, petrolatum occlusion, etc.) except for the test compound.
Concentrations for induction were 0.01 % (intradermal) and 25 % (epicutaneous). The animals were challenged by 0.1, 0.5 and 1.0 % CuSO4 x 5 H2O in petrolatum. Statistical method was the chi-square test (two-way tables).

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

data from old study

Species:

guinea pig

Strain:

other: not reported

Sex:

not specified

Route:

intradermal and epicutaneous

Vehicle:

petrolatum

Concentration / amount:

Intradermal induction: 0.01;
Epicutaneous induction: 25 %;
Challenge. 0.1, 0.5 and 1.0 %

Route:

other: not reported

Vehicle:

petrolatum

Concentration / amount:

Intradermal induction: 0.01;
Epicutaneous induction: 25 %;
Challenge. 0.1, 0.5 and 1.0 %

No. of animals per dose:

20

Positive control substance(s):

no

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1 %

No. with + reactions:

2

Total no. in group:

20

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1 %

No. with + reactions:

7

Total no. in group:

20

Clinical observations:

statistically significant

Interpretation of results:

sensitising

Conclusions:

No definite conclusion about skin sensitisation potential of copper sulphate pentahydrate can be made based on this study result.

Executive summary:

There are several case reports concerning copper sensitivity in humans (for a review see Forstrom et al. 1977), but the incidence has not been documented. In order to attempt to elucidate this question, copper sulfate has been included in a routine patch test series (Wahlberg, unpublished). Two groups of 20 animals were used. One group was actively sensitized and the other group (control) was treated in the same way as the experimental group (Freund's complete adjuvant, petrolatum occlusion, etc.) except for the test compound. Concentrations for induction were 0.01 % (intradermal) and 25 % (epicutaneous). The animals were challenged by 0.1, 0.5 and 1.0 % CuSO4 x 5 H2O in petrolatum). Statistical method was the chi-square test (two-way tables).

At the challenge concentration 1%, two (24 h) and seven (48 h) animals reacted compared to none (24 & 48 h) among the controls. The difference was statistically significant at the 48-h reading.

Reference 3

Endpoint:

skin sensitisation, other

Remarks:

in vitro and in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented publications which meet basic scientific principles.

Qualifier:

no guideline followed

Principles of method if other than guideline:

-In vitro assay for determining effect on normal and keloid-producing human dermal fibroblasts: Copper tripeptide-1 (1 x 10E-9 mol/L) is added to fibroblast cultures. Cellular response is described in terms of secretion of transforming growth factor-β1(TGF-β1).
-Assay for evaluating expression of matrix metalloproteinases in experimental wound healing model: Wound chambers are inserted under skin of male Sprague-Dawley rats, and copper tripeptide-1 (2 mg in 0.2 ml phosphate-buffered saline) injected serially into the chambers. Animals are killed up to day 22 after chamber implantation. Wound fluid and connective tissue in chamber is analyzed for enzyme expression. The contents are also subjected to biochemical analysis and examined histologically.

GLP compliance:

no

Type of study:

other: In vitro assay for determining the effect on normal and keloid-producing human dermal fibroblasts. Assay for evaluating the expression of matrix metalloproteinases in experimental wound healing model.

Justification for non-LLNA method:

review data

Parameter:

other: The CIR Expert Panel concluded that copper tripeptide, a skin conditioning agent, is safe in the present practices of use and concentration in cosmetics.

Remarks on result:

no indication of skin sensitisation

In the Assay for evaluating expression of matrix metalloproteinases in experimental wound healing model copper tripeptide increased expression/activity of the following enzymes: interstitial collagenase, matrix metalloproteinase-9 (gelatinase B), matrix metalloproteinase-2 (gelatinase A), and pro-matrix metalloproteinase-2. Copper tripeptide-1 also increased cell invasion and extracellular matrix deposition in chambers.

In the vitro assay, at 24 h, treated normal and keloid-producing fibroblasts secreted less TGF-β1, compared to phosphate-buffered saline controls (p < 0.05), suggesting possible clinical use for decreasing excessive scar formation.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: other: Cosmetic Ingredient Review Panel

Conclusions:

The CIR Expert Panel concluded that copper tripeptide, a skin conditioning agent, is safe in the present practices of use and concentration in cosmetics.

Executive summary:

In an Assay for evaluating expression of matrix metalloproteinases in experimental wound healing model, wound chambers were inserted under the skin of Sprague-Dawley rats and received serial injections of either 2 mg glycyl-L-histidyl-L-lysine-Cu(II) or the same volume of saline. The wound fluid and the neosynthetized connective tissue deposited in the chambers were collected and analyzed for matrix metalloproteinase expression and/or activity. Copper tripeptide increased expression/activity of the following enzymes: interstitial collagenase, matrix metalloproteinase-9 (gelatinase B), matrix metalloproteinase-2 (gelatinase A), and pro-matrix metalloproteinase-2. Copper tripeptide-1 also increased cell invasion and extracellular matrix deposition in chambers.

In an in vitro test, the effect of copper tripeptide on normal and keloid-producing dermal fibroblasts in a serum-free in vitro model was evaluated. The cellular response was described in terms of viability and secretion of basic fibroblast growth factor (bFGF) and transforming growth factor-β1 (TGF-β1). Primary cell lines were established from patient facial skin samples obtained during surgery and plated in serum-free media. At 0 hour, copper tripeptide (1x10E-9 mol/L), or appropriate control vehicle was added. Cell counts and viability were established at 24, 72, and 120 hours. Supernatants were collected at the same intervals and were assessed for bFGF and TGF-β1 concentrations using the enzyme-linked immunosorbent assay technique.

Cell lines showed viability between 86% and 96% (mean, 92%) throughout the experiment. Normal and keloid-producing dermal fibroblasts treated with copper tripeptide secreted less TGF-β1 than did controls, suggesting a possible clinical use for decreasing excessive scar formation.

Reference 4

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well-documented peer-reviewed reports.

Qualifier:

no guideline available

Principles of method if other than guideline:

Summary of sensitization study results (non-human and human) conducted with monosaccharides, disaccharides, and related Ingredients as used in cosmetics.

GLP compliance:

not specified

Type of study:

patch test

Justification for non-LLNA method:

review data

Reading:

other: Mono- and disaccharides did not produe 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 produe 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

Conclusions:

Calcium gluconate and gluconic acid, structurally similar anlogues to glucoheptonates, have been assessed by the Panel as non-sensitizers in cosmetic formulations.

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 are lacking; however, based on the clinical experience of the Panel, there is little concern that these ingredients are irritants or sensitizers".

Reference 5

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented (peer-reviewed) report.

Qualifier:

according to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.6 (Skin Sensitisation)

Deviations:

no

Principles of method if other than guideline:

Summary of unpublished reports.

GLP compliance:

not specified

Type of study:

other: summary of unpublished reports

Justification for non-LLNA method:

reviewed data serve as weight of evidence

Reading:

other: Available data provide no evidence that copper (I) oxide, copper (II) oxide, copper oxychloride, copper sulphate or copper powder cause skin sensitisation.

Remarks on result:

other: Available data provide no evidence that copper (I) oxide, copper (II) oxide, copper oxychloride, copper sulphate or copper powder cause skin sensitisation..

Table 1. Summary of skin sensitisation studies in animals

Reference	Substance			Reported Test Guideline^a	Vehicle		Skin response after challenge	Study rating^b
	Identity	Purity (%)	Cu content (% w/w)		Induction	Challenge
Bien (1993)^c	Copper (I) oxide	NR	88	Annex V B.6 (GPMT)	CMCand/or FCA^d	Vaseline	None	2^e
Driscoll (1999e)^c	Copper (I) oxide	NR	NR	Annex V B.6; OECD 406 (GPMT)	Water/FCA	Water	None	1^e
Smith (1986)^c	Copper (I) oxide	NR	NR	EPA guidelines (1982; modification of Buehler)	Moistened with propylene glycol	Moistened with propylene glycol	Very slight erythema at 24h (3/10 animals) and 48h (1/10 animals)	2
Sanders (2002e)^c	Copper (II) oxide	97.7	NR	Annex V B.6 (GPMT)	Arachis oil	Arachis oil	Mild skin response (4/10 animals) at 24h; no response at 48h.	1
Mercier (1994a)^c	Copper sulphate pentahydrate	NR	NR	Annex V B.6 (GPMT)	FCA and/or water	Water	Slight skin response (1 animal) at 24h; no response at 48h	1^e
Walker(1990)^c	Copper oxychloride	NR	NR	JMAFF; equivalent to Annex V B.6 (Buehler)	Water	Water	None	1^e
Sanders (2001d)^c	Copper powder	NR	NR	Annex V B.6 (GPMT)	Arachis oil	Arachis oil	None	1^e

NR not reported                    a GPMT – guinea pig maximisation test

b based on evaluation criteria developed by Klimischet al(1997)

c unpublished report

d - carboxymethyl cellulose; FCA - Freunds Complete Adjuvant.

e a study rating of ‘1’ was considered appropriate for this study, even though purity data were not provided.

Interpretation of results:

not sensitising

Conclusions:

Available data provide no evidence that copper (I) oxide, copper (II) oxide, copper oxychloride, copper sulphate or copper powder cause skin sensitisation.

Executive summary:

No published studies are available which report on the potential of copper or its compounds to cause skin sensitisation in animals.  

Several unpublished studies have been made available, using the guinea pig maximisation test of Magnusson and Kligman or the Buehler test and all have been conducted according to EU Annex V or OECD guidelines.  These studies have investigated the skin sensitising potential of copper (I) oxide, copper (II) oxide, copper sulphate pentahydrate, copper oxychloride and copper powder. In these tests, none of the substances investigated have demonstrated potential to cause skin sensitisation in guinea pigs.

There have been several reports in humans of skin reactions to copper either as the metal, principally from jewellery and intra-uterine devices (IUDs), or in copper salts, principally from the use of copper sulphate as a pesticide. Positive reactions from patch tests have been reported following challenge with 1-5% solutions of copper sulphate and, in a single case, with copper oxide. The possibility of cross-reactivity to salts of potent sensitisers exists. The prevalence of sensitisation to copper sulphate among patients with pre-existing skin conditions are reported to be of the order of 1% but is unknown among asymptomatic individuals. The largest investigation of women using copper containing IUDs (n=37) who reported side effects including skin reactions (n=10) found that none reacted positively to copper in patch tests. This finding suggests that copper was not responsible for their symptoms.

The following clinical criteria should be satisfied to accept a reported case of skin sensitisation as likely to be caused by copper or its compounds:

- a clear history of significant dermal exposure to the copper species, followed by

- experience of skin rashes, and

- a positive reaction on patch testing

Using the above criteria resulted in very few documented cases of copper and/or its compounds as a cause of skin sensitisation in humans in the medical and scientific literature. Given the extensive use of copper, and the potential for continuous and/or intermittent skin contact, human case-reports of skin sensitisation due to copper or its compounds are rare.

No information is available from animal or human studies concerning the potential of copper substances covered by this Risk Assessment to cause respiratory sensitisation. In the absence of any relevant data, the potential to cause respiratory sensitisation cannot be assessed. 

Classification for sensitisation

Current classification of copper (I) oxide, copper (II) oxide, copper sulphate, copper oxychloride and copper powder for sensitisation: none

Available animal and human data on the skin sensitisation properties of copper (I) oxide, copper (II) oxide, copper carbonate, copper sulphate, copper oxychloride and copper powder have been considered against EU classification criteria as contained in Annex VI of Directive 67/548/EEC.  The available animal data do not meet the criteria requiring these substances to be classified for skin sensitisation. Human data on skin sensitisation properties of copper or its compounds are insufficient to require classification for skin sensitisation.

With regard to sensitisation by inhalation, in the absence of relevant human or animal data, there is no basis for classification of copper substances covered by this Risk Assessment for respiratory sensitisation.

Data to be carried forward to ‘Risk Characterisation’:

Available data provide no evidence that copper (I) oxide, copper (II) oxide, copper oxychloride, copper sulphate or copper powder cause skin sensitisation. Consequently, no data on skin sensitisation are carried forward to ‘Risk Characterisation’. 

In the absence of data on the potential of copper or copper compounds to cause respiratory sensitisation in animals or humans, no data on respiratory sensitisation are to be carried forward to ‘Risk Characterisation’.

Reference 6

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:

other: Performed similar to guideline EU B.42

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Deviations:

yes

Remarks:

Only one concentration tested, three instead of four animals used, animals were sacrificed on day 4

Principles of method if other than guideline:

Application of the test substance on three consecutive days on the dorsum of each ear, local lymph node isolation on fourth day after application, cultivation of isolated cells with [3H]methyl thymidine ([3H]TdR), measurement of [3H]TdR incorporation with scintillation counter.

GLP compliance:

not specified

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

Balb/c

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Japan SLC Inc., Shizuoka, Japan
- Age at study initiation: 6-8 weeks
No further data on test animals is given.

Vehicle:

other: 20% ethanol solution

Concentration:

10%

No. of animals per dose:

3

Details on study design:

RANGE FINDING TESTS:
No details on range finding test are given.

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Local Lymph Node Assay
- Criteria used to consider a positive response: Stimulation index > 2 (SI, ratio of incorporated [3H]TdR after treatment with test material to treatment with vehicle only)

TREATMENT PREPARATION AND ADMINISTRATION:
No details on treatment preparation are given.
25 µL of test solution (10 % CuSO4 in 20% ethanol solution) were applied on the dorsum of each ear of three mice. The dorsal surface was gently abraded by lightly dragging a 19-g needle across the dorsal surface of each ear five times (without causing bleeding) just prior to the application of test chemical.

Positive control substance(s):

other: nickel sulphate

Statistics:

Incorporation of [3H]TdR is given as mean cpm +/- standard deviation (SD) per node of three mice per group.

Positive control results:

No data on positive control given.

Parameter:

SI

Remarks on result:

other: 2.67

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Mean counts per minute ± SD (x 10E-3): 4.08 ± 1.20

Mean counts per minute (vehicle 20% Ethanol solution): 1.52 x 10E-3 +/- 0.67 x 10E-3

Interpretation of results:

sensitising

Conclusions:

In this study, the stimulation index for copper sulphate pentahydrate was determined to be 2.67 compared with the vehicle treated group.

Executive summary:

In a dermal sensitization study with Copper sulphate pentahydrate in 20% ethanol solution, 6-8 week old female Balb/c mice (three animals / dose) were tested in the murine local lymph node assay. 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 2.67. In this study, Copper sulphate pentahydrate is considered to be a dermal sensitizer.

Reference 7

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

GPMT and in human patch test

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented publication which meets basic scientific principles.

Qualifier:

no guideline followed

Principles of method if other than guideline:

During a period of 3 years a total of 1190 eczema patients were tested in routine patch test series. 2.0% copper sulphate (CuSO4 x 5H2O) in pet. was included in the routine patch test series together with about 30 well-known contact allergens.
In addition, 3 GPMT studies with varying concentrations of copper sulphate at intradermal induction (0.1 %, 0.05 % and 0.01 %) were carried out. At epicuianeous induction of 25% of the salt in pet. was used in all series. Challenge testing was performed on day 21 with 1.0, 0.5 and 0.1 % of the salt in pet. The animals exposed to 0.1% copper sulphate at intradermal induction were also challenged with nickel sulphate (NiSO4 x 6H2O) (0.5. 0.25. and 0.05% in pet.).

GLP compliance:

no

Type of study:

other: human patch test and GPMT

Justification for non-LLNA method:

data from old study

Species:

guinea pig

Strain:

not specified

Sex:

not specified

Route:

epicutaneous, open

Vehicle:

petrolatum

Remarks:

human patch test

Concentration / amount:

2 % in petrolatum

Adequacy of induction:

not specified

Route:

intradermal and epicutaneous

Vehicle:

petrolatum

Concentration / amount:

epicutaneous: 2 5% in petrolatum
intradermal: 0.1 %

Day(s)/duration:

21 days

No.:

#1

Route:

intradermal and epicutaneous

Vehicle:

petrolatum

Remarks:

GPMT

Concentration / amount:

1 %, 0.5 % and 0.1 % in petrolatum

Adequacy of challenge:

not specified

No. of animals per dose:

human patch test: 1190 eczema patients
GPMT: 19 animals

Positive control substance(s):

no

Positive control results:

In series 1 (the animals were exposed to 0.1 % copper sulphate at intradermal induction) the tests with nickel sulphate were negative.

Reading:

1st reading

Group:

test chemical

Dose level:

intradermal: 0.1 %; epicutane: 25 %

No. with + reactions:

0

Total no. in group:

19

Remarks on result:

no indication of skin sensitisation

Remarks:

GPMT

Reading:

1st reading

Group:

test chemical

Dose level:

intradermal: 0.05 %; epicutane: 25 %

No. with + reactions:

0

Total no. in group:

19

Remarks on result:

no indication of skin sensitisation

Remarks:

GPMT

Reading:

1st reading

Group:

test chemical

Dose level:

intradermal: 0.01 %; epicutane: 25 %

No. with + reactions:

0

Total no. in group:

19

Remarks on result:

no indication of skin sensitisation

Remarks:

GPMT

Reading:

1st reading

Group:

test chemical

Dose level:

2 %

No. with + reactions:

13

Remarks on result:

no indication of skin sensitisation

Remarks:

no isolated reactions to copper sulphate / human patch test

Routine patch testing

During the 3-year period, 1190 eczema patients were tested and 13 (1.1 %) showed some kind of reaction, Several doctors had carried out the readings and the highest scores as given in the protocols are presented in Table 1. 8 patients had a + reaction and 4 a ++ reaction. No isolated reactions to copper sulphate were observed. Patient no. 3 and 4 had several (7 and 10 respectively) + reactions and their reactions to copper were interpreted as expressions of the angry-back syndrome, rather than of true sensitivity. 4 of the patients were simultaneously positive to chromate. 6 to cobalt and 5 to nickel. Serial dilution tests were carried out with nickel and cobalt in 4 patients (nos. 5, 7, 11, 12); they were found to be extremely sensitive. In 2 patients, serial dilution tests with copper sulphate showed that one of them (no. 7) reacted down to 0.5% of the salt, while the other (no. 12) was negative to all concentrations.

Table 1. 13 patients reacting to 2.0% CuSO4 at routine patch testing

Patient	Sex	Age	Cu	Concomitant reactions
1	F	75	++	Cr. Co, turpentine, wood tars
2	F	23	+ +	Ni
3	F	48	+	Cr, seven + reactions
4	M	61	+	Ten + reactions
5	F	40	+	Ni (< 0.015 %), Co (0.0078 %), formaldehyde, fragrance mix
6	F	81	+	Cr. Co, colophony
7	F	32	+ (0.5%)	Ni (< 0.015 %), Co (0.0078 %)
8	F	24	+	wood tars
9	M	70	+ +	carba-mix, TMTD
10	M	56	+	Cr (0.0625 %)
11	F	41	++	Ni (0.039 %), Co (0.0139%), wood tars
12	F	54	+ + SDT:neg	Ni (0.0098%), Co (0.0625 %)
13	M	71	+	benzalkonium

Guinea pig maximization test

No difference between copper-exposed and control animals was observed in any of the 3 test series (Tables 2-4). In series 1 (Table 2) the tests with nickel sulphate were negative.

Table 2. Sensitization and testing of guinea pigs according to GPMT; the number of animals with positive test reactions at the different challenge concentrations are given.

Induction: CuSO4 x 5H2O Intradermal: 0.1 % Epicutaneous: 25 %
Challenge concentration (% w/w)		1	0.5	0.1	Control (pet.)
Controls (n = 18)	24 h	0	1	1	1
	48 h	1	1	0	1
Exposed (n = 19)	24 & 48 h	0	0	0	0
Evaluation	24 h	-	N.S.	N.S.	N.S.
	48 h	N.S.	N.S.	-	N.S.

Table 3. Sensitization and testing of guinea pigs according to GPMT

Induction: CuSO4 x 5H2O Intradermal: 0.05 % Epicutaneous: 25 %
Challenge concentration (% w/w)		1	0.5	0.1	Control (pet.)
Controls (n = 20)	24 h	0	0	0	0
	48 h	1	1	2	1
Exposed (n = 19)	24 h	0	0	0	0
	48 h	1	0	0	0
Evaluation	24 h	-	-	-	-
	48 h	-	N.S.	N.S.	N.S.

Table 4. Sensitization and testing of guinea pigs according to GPMT

Induction: CuSO4 x 5H2O Intradermal: 0.01 % Epicutaneous: 25 %
Challenge concentration (% w/w)		1	0.5	0.1	Control (pet.)
Controls (n = 18)	24 & 48 h	0	0	0	0
Exposed (n = 19)	24 & 48 h	0	0	0	0

Statistical method; X²-analysis. - not analyzed; N,S. not significant.

Atomic absorption spectrophotometry

Analysis of the copper sulphate used by atomic absorption spectrophotometry, showed that it contained 9 µg/g of nickel and < 6 µg/g of cobalt.

Interpretation of results:

not sensitising

Conclusions:

Copper sulphate pentahydrate was not conclusively sensitizing in patch test with 13 patients and was negative in guinea pig maximization test.

Executive summary:

Routine human patch testing with 2% copper sulphate did not reveal any conclusive case of contact sensitivity. Several concomitant reactions, especially to cobalt, nickel, and eliminate were seen in the 13 patients and the results of the serial dilution tests did not support the existence of a true sensitivity to copper. Serial dilution tests with nickel and cobalt demonstrated that impurities of the metals are possible explanations for some of the initial test reactions.

The guinea pig maximization tests explicitly demonstrated that copper sulphate is a grade 1 allergen according to the classification of Magnusson & Kligman. No difference between copper-exposed and control animals was observed in any of the 3 test series

Reference 8

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable well documented publication which meets basic scientific principles.

Qualifier:

no guideline followed

Principles of method if other than guideline:

126 enamellers and 64 decorators from 5 factories underwent dermatological 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

GLP compliance:

no

Type of study:

patch test

Justification for non-LLNA method:

human data serve as weight of evidence

Species:

human

Route:

epicutaneous, semiocclusive

Vehicle:

petrolatum

Concentration / amount:

5 %

Route:

epicutaneous, semiocclusive

Vehicle:

petrolatum

Concentration / amount:

5 %

Positive control substance(s):

no

Remarks:

allergens from different groups of chemical substances

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

5 %

No. with + reactions:

1

Total no. in group:

190

Clinical observations:

the sensitized person represents 0.5 %

No skin reactions to patch tests performed with vanadium pentoxide and sodium tripolyphosphate at different concentrations were observed in subjects undergoing standard patch testing, and no positive reactions to one or more allergens specific to the ceramics industry were discovered in healthy volunteers. Dermatitis was present in 22 workers (11.57 %). whereas 44 subjects (23.15 %) claimed to have had skin lesions in the past. In all subjects, the hands were or had been affected, and in 5 patients the forearms were also involved. 48 workers (corresponding to 25.26 % of the study population) were either mono- (42 subjects) or poly-sensitized (6 subjects), with a total of 55 positive patch tests. Table 2 shows the list of allergens, which brought about positive responses. 28 subjects (14.73 % of the total) were positive to nickel sulphate; of these, 17 were women. Furthermore, there were 17 positive reactions to substances specific to the ceramics industry: 7 to red iron oxide; 2 to antimony trioxide, manganese dioxide and maleic anhydride; 1 to red copper oxide, cadmium chloride, vanadium pentoxide and sodium tripolyphosphate.

Table 2. No. sensitizations to subslanees used in the ceramics Industry in enamellers and decorators

Hapten	Total 190 (100%)	Enamellers 126 (100%)	Decorators 64 (100%)
nickel sulphate	28 (14.7 %)	8 (6.3%)	20 (31.2%)
red iron oxide	7	6	1
cobalt chloride	5	2	3
antimony trioxide	2	1	1
mercapto mix	2	1	1
manganese dioxide	2	1	1
maleic anhydride	2	1	1
potassium dichromate	1	0	1
red copper oxide	1	1	0
cadmium chloride	1	1	0
carba mix	1	1	0
PPD mix	1	1	0
vanadium nentoxide	1	1	0
sodium tripolyphosphate	1	1	0

Interpretation of results:

ambiguous

Conclusions:

Copper is frequently employed in industry and has always been regarded as a weakly sensitizing metal. In this study, 1 out of 190 workers (0.5 %) was positive in patch test to copper oxide.

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 tripolyphosphate.

Copper is frequently employed in industry and has always been regarded as a weakly sensitizing metal. As previously mentioned, we only found 1 case (among enamellers only) of sensitization.

Reference 9

Endpoint:

skin sensitisation, other

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable peer-reviewed report on copper.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Summary of human and animal data on skin sensitization potential of copper compounds.

GLP compliance:

no

Remarks:

not applicable (it is a review)

Type of study:

other: summary of different test results

Justification for non-LLNA method:

reviewed data serve as weight of evidence

Parameter:

other: The observed dermal reactions were mostly either unspecific or cross reactions to a nickel allergy

Remarks on result:

no indication of skin sensitisation

SCOEL, 2013

Human data

Copper and copper sulphate may evoke allergic contact dermatitis. Testing of patients with contact eczema or of workers occupationally exposed to copper dust or fumes provoked dermal reactions following testing with copper sulphate in concentrations up to 5 % copper sulphate. However, the number of reported cases with a clear copper induced sensitisation is very low and was observed only at high concentrations of 5 % of copper salts (Walton et al 1983a, b). The observed dermal reactions were mostly either unspecific or cross reactions to a nickel allergy. In some cases, they may have been provoked by nickel contaminations of the copper (Greim 2004). A single case of occupational respiratory sensitisation is reported. A worker in the galvanic industry showed a 30 % decline of the forced expiratory volume after provocation with 1 mg copper sulphate/m3 (Cirla 1985).

Animal data

Two maximisation tests in guinea pigs with the pentahydrate of copper sulphate in petrolatum yielded conflicting results (Boman et al 1979, Karlberg et al 1983). As these studies were done by the same working group at similar conditions, the reason for this discrepancy is unknown. One Local Lymph Node Assay (LLNA) in mice with 10 % copper sulphate pentahydrate in ethanol failed to show a positive reaction (Ikarashi et al 1992). Another LLNA with copper chloride (1–5 % in DMSO) exhibited a strong lymphocytic proliferation, but this was attributed to the local necrotic action of the compound (Basketter et al 1999).

Interpretation of results:

not sensitising

Conclusions:

No sensitization potential can be attributed to copper due to the low number of cases with a clear copper induced sensitisation.

Executive summary:

There are only few reports of sensitisation to copper with an immunological aetiology. Most of the documented cases were regarded as either unspecific or cross reactions to nickel allergy (ATSDR 2004, Greim 2004). With regard to the extensive use of copper and its compounds and the small number of case reports, there is little concern about the sensitising properties of copper.

Human data

Copper and copper sulphate may evoke allergic contact dermatitis. Testing of patients with contact eczema or of workers occupationally exposed to copper dust or fumes provoked dermal reactions following testing with copper sulphate in concentrations up to 5 % copper sulphate. However, the number of reported cases with a clear copper induced sensitisation is very low and was observed only at high concentrations of 5 % of copper salts (Walton et al 1983a, b). The observed dermal reactions were mostly either unspecific or cross reactions to a nickel allergy. In some cases, they may have been provoked by nickel contaminations of the copper (Greim 2004). A single case of occupational respiratory sensitisation is reported. A worker in the galvanic industry showed a 30 % decline of the forced expiratory volume after provocation with 1 mg copper sulphate/m3 (Cirla 1985).

Animal data

Two maximisation tests in guinea pigs with the pentahydrate of copper sulphate in petrolatum yielded conflicting results (Boman et al 1979, Karlberg et al 1983). As these studies were done by the same working group at similar conditions, the reason for this discrepancy is unknown. One Local Lymph Node Assay (LLNA) in mice with 10 % copper sulphate pentahydrate in ethanol failed to show a positive reaction (Ikarashi et al 1992). Another LLNA with copper chloride (1–5 % in DMSO) exhibited a strong lymphocytic proliferation, but this was attributed to the local necrotic action of the compound (Basketter et al 1999).

Reference 10

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: A short communication report. A lot of details missing.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The main purpose of this investigation was to estimate the incidence of copper sensitivity in patients with eczema attending 4 dermatology departments in ihe Northern Region of England over a 5-month period. Copper sulphate (as 5 % in petrolatum) was used in the patch test with AI test strip and a porous tape. When positive tests were encountered, patch tests were repeated after an interval, using 0.25%, 0.5% and 1 % (pet.) copper sulphate. Reproducibility was confirmed with readings both at 48 and 96 h.

GLP compliance:

no

Type of study:

patch test

Justification for non-LLNA method:

human data serve as weight of evidence

Species:

human

Route:

epicutaneous, semiocclusive

Vehicle:

petrolatum

Concentration / amount:

0.25, 0.5, 1.0 and 5.0 %

Route:

epicutaneous, semiocclusive

Vehicle:

petrolatum

Concentration / amount:

0.25, 0.5, 1.0 and 5.0 %

Positive control substance(s):

yes

Remarks:

nickel sulphate

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

5.0 %

No. with + reactions:

6

Total no. in group:

354

Clinical observations:

sensitized persons: 1.7 %

Reading:

2nd reading

Hours after challenge:

96

Group:

test chemical

Dose level:

5.0 %

No. with + reactions:

6

Total no. in group:

354

Clinical observations:

sensitized persons: 1.7 %

354 patients were studied: 6 patients gave a positive reaction to copper sulphate and 39 to nickel sulphate; all patients reacting to copper sulphate were also nickel sensitive (Table 1). All the patients reacting to copper were females with hand eczema, but none were employed in an occupation in which copper was encountered, and none wore an mira-uterine copper contraceptive device (Table 2). Atopy was excluded in ihe positive patients by a negative personal and family history and negative reactivity on prick testing with house dust mite, grass pollen and animal furs. All 6 patients developed a positive eczematous response to 0.25%, 0.5%, 1% and 5 % concern rations of copper sulphate. The control site using the vehicle alone was negative.

Copper is used mainly in the electrical industry and for pipes conveying water or gas. It is also an important constituent of coins and printing plates. In spite of its widespread uses, its sensitising potential is extremely low.

Table 1. Battery palch testing (5-month period)

	No.	%
Patients tested	354
Negative	309	87.28
Positive to copper sulphate (5 % pet.)	6	1.70
Positive to nickel sulphate (2.5 % aq.)	39	11.02
Positive to both	6	1.70

Table 2. Analysis of copper-positive patients

Case No.	Sex	Age (years)	Occupation	Diagnosis	Nickel sensitivity
1.	female	19	sales assistant	hand eczema	present
2.	female	19	nurse	hand eczema	present
3.	female	17	student	hand eczema	present
4.	female	29	screen printer	hand ec/cma	present
5.	female	19	nurse	hand ec/cma	present
6.	female	16	unemployed	hand eczema	present

The high incidence of hand eczema among this group and the lack of occupational exposure to copper suggest that nickel- and copper-containing coins may be a potential source of sensitivity (Table 3). This study supports the clinical experience of most dermatologists, that allergic sensitivity to copper is rare. We suggest that nickel-sensitive patients who do not respond to nickel withdrawal should be patch tested to copper. Finally, we carried out further patch tests using concentrations of 10 % copper sulphate and above. Such concentrations resulted in some primary irritant reactions in patients with active eczema and we feel that it is not useful to test with a concentration higher than 5%.

Table 3. Metal content of coins

			% content
Coin, UK	Copper	Nickel	Tin	Zinc-bronze
50 p	75	25
10 p	75	25	-
5 p	75	25	-	-
2p	97	trace	0.5	2.5
1 p	97	trace	0.5	2.5
0.5 p	97	trace	0.5	2.5

Interpretation of results:

other: No conclusion can be made based on this study result. The patients reacting to copper were all nickel sensitive.

Conclusions:

In this study, 6 out of 354 patients (1.7 %) reacted positive to copper sulphate. There were however also sensitive to nickel.

Executive summary:

The main purpose of this investigation was to estimate the incidence of copper sensitivity in patients with eczema attending 4 Dermatology Departments in ihe Northern Region of England over a 5-month period. Copper sulphate (as 5 % in petrolatum) was used in the patch test with AI test strip and a porous tape. When positive tests were encountered, patch tests were repeated after an interval, using 0.25%, 0.5% and 1 % (pet.) copper sulphate. Reproducibility was confirmed with readings both at 48 and 96 h.

354 patients were studied: 6 patients gave a positive reaction to copper sulphate and 39 to nickel sulphate; all patients reacting to copper sulphate were also nickel sensitive. All the patients reacting to copper were females with hand eczema, but none were employed in an occupation in which copper was encountered, and none wore an intra-uterine copper contraceptive device. Atopy was excluded in ihe positive patients by a negative personal and family history and negative reactivity on prick testing with house dust mite, grass pollen and animal furs. All 6 patients developed a positive eczematous response to 0.25%, 0.5%, 1% and 5 % concern rations of copper sulphate. The control site using the vehicle alone was negative.

Copper is used mainly in the electrical industry and for pipes conveying water or gas. It is also an important constituent of coins and printing plates. In spite of its widespread uses, its sensitising potential is extremely low.

The high incidence of hand eczema among this group and the lack of occupational exposure to copper suggest that nickel- and copper-containing coins may be a potential source of sensitivity. This study lends support to the clinical experience of most dermatologists, that allergic sensitivity to copper is rare. We suggest that nickel-sensitive patients who do not respond to nickel withdrawal should be patch tested to copper. Finally, we carried out further patch tests using concentrations of 10 % copper sulphate and above. Such concentrations resulted in some primary irritant reactions in patients with active eczema and we feel that it is not useful to test with a concentration higher than 5%.

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

Based on the available information no skin sensitisation potential can be expected for Copper glucoheptonate. The substance does not need to be classified and labelled as skin sensitizer taking into account the provisions laid down in Council Directive 67/548/EEC and CLP Regulation (EC) No 1272/2008.