Registration Dossier

Administrative data

Description of key information

Occupational studies of exposed workers, together with many case reports, provide good evidence that certain soluble halogenated platinum salts are skin sensitisers. Urticaria (Type I immediate hypersensitivity) is most commonly reported, while allergic contact dermatitis appears to be rare. Results from laboratory animal studies support the human evidence. Skin sensitisation potential is essentially limited to complexes where halogen ligands are coordinated to the platinum atoms; hexachloroplatinic acid and the tetra- and hexachloroplatinate salts are mainly responsible for platinum-salt skin sensitisation.

 

Allergic respiratory tract sensitisation following occupational exposure to complex halogenated platinum compounds, in particular the chloroplatinates, is a well-established health hazard. Available epidemiology data have not yet permitted delineation of an induction threshold for complex halogenated platinum salt sensitivity (PSS) in workplace exposure scenarios.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Not reported
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
not applicable
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Study conducted in 1977
Species:
guinea pig
Strain:
not specified
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Porcellus animal breeding Ltd, Heathfield, Sussex, UK
- Weight at study initiation: 300-350 g
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17
- Humidity (%): 50-70
Route:
intradermal and epicutaneous
Vehicle:
other: saline for the induction injection, and petroleum jelly for the topical applications (induction and challenge phase)
Concentration / amount:
Induction: intradermal injection of saturated solution in saline, followed by topical application at 50% w/w in petroleum jelly. Challenge phase: 1, 5 and 10% w/w test material in petroleum jelly.
Route:
epicutaneous, occlusive
Vehicle:
other: saline for the induction injection, and petroleum jelly for the topical applications (induction and challenge phase)
Concentration / amount:
Induction: intradermal injection of saturated solution in saline, followed by topical application at 50% w/w in petroleum jelly. Challenge phase: 1, 5 and 10% w/w test material in petroleum jelly.
No. of animals per dose:
10 females
Details on study design:
RANGE FINDING TESTS:
Four guinea-pigs were given topical applications of 10, 20, 50 and 100% of the test material in petroleum jelly, sites examined at 24 and 48 hrs.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: Three pairs of simultaneous injections were made to the clipped skin with either 0.1 mL Freunds Complete Adjuvant (FCA), 0.1 mL test substance alone, or 0.05 ml of test substance with 0.05 mL FCA.
- Exposure period: One week after the injections (described above), the same area was clipped and shaved and a 4 x 2 cm patch of filter paper saturated with the test substance was applied to the previously injected area. This patch was secured by elastic adhesive bandage and left in position for 48 hrs.
- Test groups: 10 animals
- Control group: 4 animals (OECD guidelines recommend at least 5 animals)
- Site: shoulder
- Frequency of applications:
- Duration:
- Concentrations: Injection: 0.1 mL test material alone, or 0.05 ml test material with FCA. For the topical induction, 50% w/w in petroleum jelly.

B. CHALLENGE EXPOSURE
- No. of exposures: Animals were challenged two weeks after the topical induction with a 2 x 2 cm piece of filter paper saturated with the test substance.
- Exposure period: Patch held in place for 24 hours
- Test groups: 10 animals
- Control group: 4 animals
- Site: Flank
- Concentrations: 10% w/w in petroleum jelly. A second challenge (a further week later) was made with 1 and 5% dilutions in petroleum jelly
- Evaluation (hr after challenge): 24 and 48 hrs
Challenge controls:
Four guinea-pigs were treated with saline in place of the test substance at induction, but otherwise induction and challenge were the same as for the test animals (as described above)
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
10%
No. with + reactions:
8
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10%. No with. + reactions: 8.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
10%
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10%. No with. + reactions: 2.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10%
No. with + reactions:
1
Total no. in group:
4
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 4.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10%
No. with + reactions:
1
Total no. in group:
4
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10%. No with. + reactions: 1.0. Total no. in groups: 4.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
5%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 5%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
5%
No. with + reactions:
0
Total no. in group:
4
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 5%. No with. + reactions: 0.0. Total no. in groups: 4.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test group
Dose level:
1%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
1%
No. with + reactions:
0
Total no. in group:
4
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: 1%. No with. + reactions: 0.0. Total no. in groups: 4.0.
Interpretation of results:
GHS criteria not met
Conclusions:
No skin sensitization reactions were seen in a guinea pig maximisation test, involving topical challenge with ammonium hexachloroplatinate at 5% in petroleum.
Executive summary:

Ten guinea pigs were administered ammonium hexachloroplatinate by intradermal injection (with and without FCA) in the shoulder, followed a week later by a topical application of the test material at 50% in petroleum jelly with an occluded patch test placed over the clipped and shaved injection site for 48 hours. Two weeks later the animals were challenged with the test material at 10% in petroleum jelly on the clipped flank (24-hour occluded patch test). The challenge site was evaluated 24 and 48 hrs after removal of the patch. Eight of the ten animals challenged with ammonium hexachloroplatinate at 10% in petroleum exhibited a positive reaction, but so too did one of the four controls (and two others had doubtful reactions). The study investigators concluded that the reaction was caused by irritation rather than sensitization. A week later, no positive reactions were seen when the animals were re-challenged with the test substance at 1 and 5% in petroleum, or in the corresponding controls at these lower concentrations.

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reasonable-quality study (on read-across surrogate), not performed to OECD guideline, but it appears to have been well-conducted, matches the guideline in some important respects, and has been adequately reported.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
No mention of guideline in publication, but a similar methodology was employed
Deviations:
yes
Remarks:
Numerous - see "Any other information on materials and methods incl. tables", below
Principles of method if other than guideline:
Local lymph node (auricular lymph node; ALN) assay to detect primary immune response.
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: University of Dusseldorf
- Age at study initiation: 6-8 weeks
- Weight at study initiation: No data
- Housing: No data
- Diet (e.g. ad libitum): standard diet (not further specified) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
Vehicle:
other: acetone
Concentration:
5%.
[Results for "lower concentrations" of the test compound were briefly cited in the publication, but no further details were given.]
No. of animals per dose:
5
Details on study design:
Topical treatment (25 ul) to the dorsum of both ears on 4 consecutive days. Lymph node cells analysed around 48-hours after the last exposure.

End-point: ALN index (cell count from treated group divided by cell count from vehicle control); global ALN cell count (the former is a more sensitive parameter, presumably for measuring immume/sensitisation response.

Controls were treated with vehicle alone [no further details given].

Experiment repeated in triplicate.
Positive control substance(s):
other: oxazolone, 1% in acetone, single application around 48 hours before ALN cell analysis
Statistics:
Results were analyzed for significance emplpying the U-test of Mann-Whitney.
Positive control results:
The positive control caused a 16.5-fold increase in number of proliferating cells compared to the control.
Remarks on result:
other: caused a 23-fold increase in number of ALN (auricular lymph node) proliferating cells, and a 4 -fold increase in global ALN cell yield per animal compared to vehicle controls. This response was comparable to that seen in the positive control

Compared to controls, the test substance caused a 23-fold increase in number of auricular lymph node (ALN) proliferating cells (ALN index = 22.8), and there was a 4-fold increase in global ALN cell yield per animal (mean global ALN cell yield +/- SD, 16.9 +/- 3.7 vs 4.3 +/- 1.5 (x 1,000,000 cells), p<0.01). The response was said to be comparable to that obtained following a single dose of the potent skin sensitiser oxazolone.

At lower concentrations of test compound [not specified and no further details given], no such increase observed (ALN index <2); the vehicle elicited an ALN index of <1.5 (i.e. reported as no reactivity).

The proliferative response detected in the ALN following skin exposure to sodium hexachloroplatinate was said to provide suggestive evidence for the predominant activation of CD4+ T lymphocytes.

Interpretation of results:
other: Sensitising
Remarks:
Based on expert judgement
Conclusions:
In a study broadly comparable to the local lymph node assay in mice, disodium hexachloroplatinate induced a proliferation of auricular lymph node (ALN) cells consistent with a potential to cause skin sensitisation.
Executive summary:

In a study broadly comparable to the local lymph node assay (LLNA), groups of 5 mice were subjected to local applications, on both ears, of 5% disodium hexachloroplatinate on each of 4 consecutive days. Around 48 hours after the last exposure, the auricular lymph nodes cells were analysed.

The test substance caused a 23-fold increase in number of ALN (auricular lymph node) proliferating cells, and a 4 -fold increase in global ALN cell yield per animal compared to vehicle controls. This response was comparable to that seen in the positive control, indicating that disodium hexachlorplatinate has skin sensitisation potential.

Endpoint:
skin sensitisation
Remarks:
in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Apparently well-conducted and well-documented study; no relevant OECD guideline, but considered scientifically acceptable.
Qualifier:
no guideline available
Principles of method if other than guideline:
Repeated application of test compound to one ear of mice followed by challenge on other ear. Extent of swelling on the challenged ear was used to assess skin sensitising potential.
GLP compliance:
not specified
Type of study:
other: Modified mouse ear swelling test (MEST) to detect contact hypersensitivity
Species:
mouse
Strain:
Balb/c
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: University of Dusseldorf
- Age at study initiation: 6-8 weeks
- Weight at study initiation: No data
- Housing: No data
- Diet (e.g. ad libitum): standard diet (not further specified) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data
Route:
epicutaneous, open
Vehicle:
other: Acetone
Concentration / amount:
5%.
Route:
epicutaneous, open
Vehicle:
other: Acetone
Concentration / amount:
5%.
No. of animals per dose:
4-6 per induction schedule according to text; 4-5 per induction schedule according to tabulated data.
Details on study design:
Topical treatment (25 ul) to the dorsum of right ear on 4 or 8 consecutive days. Challenge on left ear 6 days after treatment with 0.5% or 2% disodium hexachloroplatinate in acetone. Ear thickness was determined before and 0.5, 24, 48 and 72 hours after challenge using an engineer's micrometer. Ears from an unspecified number of animals were histologically evaluated before challenge, and 48-hours afterwards.

Repeat challenges were performed on same group of animals at 4, 8 and 20 weeks after sensitisation.


Challenge controls:
Controls were induced with vehicle alone [no further details given].
Positive control substance(s):
yes
Remarks:
oxazolone, 1% in acetone, single induction application; challenge concentration 0.2% in acetone
Positive control results:
Response in excess of that inducible by repeated application of the test compound (approximately 65% mean increase in left ear swelling, according to a graphical illustration).
Reading:
1st reading
Hours after challenge:
24
Group:
other: Test group induced on 4 consecutive days
Dose level:
2% (challenge)
Clinical observations:
% increase in left ear thickness of 22.0 +/- 14.1
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group:
Reading:
2nd reading
Hours after challenge:
48
Group:
other: Test group induced on 4 consecutive days
Dose level:
2% (challenge)
Clinical observations:
% increase in left ear thickness of 22.0 +/- 8.8
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group:
Reading:
1st reading
Hours after challenge:
24
Group:
other: Test group induced on 8 consecutive days
Dose level:
2% (challenge)
Clinical observations:
% increase in left ear thickness of 18.2 +/- 7.3
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group:
Reading:
2nd reading
Hours after challenge:
48
Group:
other: Test group induced on 8 consecutive days
Dose level:
2% (challenge)
Clinical observations:
% increase in left ear thickness of 24.1 +/- 8.6
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group:

Statistically significant increases in left ear thickness were seen 24- and 48 -hours post-challenge with 2% test compound, in animals from both induction schedules (results from earlier post-challenge measurements were not presented). Similarly statistically-significant responses were seen upon rechallenge at 4 and 8 weeks (4 -day induction schedule group) and at 4 and 20 weeks (8 -day induction group). Vehicle and positive control results apparently validated the relevance of the test compound results.

Challenges with 0.5% test compound did not elicit a significant swelling-response in the left ears.

The induction concentration caused an irritant response in the right ears, as demonstrated by swelling; no further increase in right ear thickness was seen upon challenge on the left ear (data not shown).

Interpretation of results:
other: Sensitising
Remarks:
Based on expert judgement
Conclusions:
In a mouse ear-swelling test, disodium hexachloroplatinate induced a reaction consistent with a potential to cause skin sensitisation.
Executive summary:

In a mouse ear-swelling test, groups of 4 -6 mice were subjected to local applications of 5% disodium hexachloroplatinate in acetone (or acetone alone) on one ear on each of 4 or 8 consecutive days. They were challenged 1, 4 and 8 (or 20) weeks later on the other ear with a concentration of 2% disodium hexachloroplatinate, and the extent of swelling was recorded over 72 hours.

A significant increase in swelling of the challenge ears compared to controls (which were induced with vehicle alone) was recorded, indicating that disodium hexachlorplatinate has skin sensitisation potential.

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study not in accordance with any specific OECD guideline, but it appears to have been well-conducted and reported; results are scientifically acceptable.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Similar in methodology to local lymph node assay (LLNA), but measuring cytokine production (not lymph node cell proliferation). Aim was to explore the selective activation of different cytokine profiles in comparison to those provoked by a known respiratory allergen (TMA) and a known contact allergen (DNCB).
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: Harlan Seralab, Oxfordshire, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: No data
- Housing: In groups of 5 or 10 in metal cages on a flushing mouse rack
- Diet (e.g. ad libitum): SDS PCD pelleted diet from Special Diets Services Ltd, UK, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 2 degrees C
- Humidity (%): 55 +/- 10
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
dimethyl sulphoxide
Concentration:
0.25, 0.5 or 1%
No. of animals per dose:
5/test group; 10/control group
Details on study design:
RANGE FINDING TESTS:
None reported

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Modified LLNA (measuring cytokine production, not lymph node cell proliferation).
- Criteria used to consider a positive response: Comparison to other skin/respiratory sensitisers

TREATMENT PREPARATION AND ADMINISTRATION:
- Dosing schedule: 50 ul dose applied bilaterally on each shaved flank; 5 days later, treatment repeated. After a further 5 days, 25 ul test solution was applied to the dorsum of both ears daily for 3 consecutive days.
- 13 days after exposure initiation [i.e around 1 day after final application], the auricular lymph nodes were drained and analysed for cytokines IL-4, IFN-gamma, IL-10 (interleukin-4, interferon gamma, interleukin-10, respectively).

Positive controls were a respiratory (TMA) and a contact (DNCB) allergen, respectively - see below.
Negative control animals were treated with acetone: olive oil (4:1) (the positive control vehicle), DMSO (the negative control vehicle), or were untreated (naive).
Positive control substance(s):
other: Trimellitic anhydride (TMA) in acetone:olive oil (4:1) [10%]... (see attached file)
Statistics:
No data
Positive control results:
Mitogen (con A)-inducible interleukin-4 production: vigorously expressed for trimellitic anhydride positive control
Spontaneous (mitogen-independent) interleukin-10 secretion (Th-2 response): response with TMA (0.9-1.6 ng/ml; max levels after 120 hr culture) but not DNCB (as expected)
Interferon-g expression (Th-1 response): response with DNCB but not TMA (as expected)
Remarks on result:
other: Cytokine analyses were comparable to those seen with the respiratory allergen trimellitic anhydride (TMA) and the contact allergen 2,4 -dinitrochlorobenzene (DNCB)

Mitogen-inducible interleukin-4 production: vigorously expressed at 1% ammonium hexachloroplatinate (maximum levels and kinetics of production similar to those observed with trimellitic anhydride positive control), less so at 0.5%, minimal at 0.25%.

Spontaneous (mitogen-independent) interleukin-10 secretion (Th-2 response): strong response with all concentrations of ammonium hexachloroplatinate; comparable response to that with TMA positive control.

Interferon-g expression (Th-1 response): substantial production with all concentrations of ammonium hexachloroplatinate; comparable response to that with DNCB positive control.

Interpretation of results:
other: Sensitising
Remarks:
Cytokine profile indicative of Th2-type immediate-type hypersensitivity
Conclusions:
Topical exposure of mice to the platinum salt ammonium hexachloroplatinate induces immune responses comparable to those seen with the respiratory allergen trimellitic anhydride and the contact allergen 2,4-dinitrochlorobenzene. The data are compatible with an IgE-mediated or Th2-type mechanism for the immediate-type hypersensitivity reactions elicited by the platinum salts.
Executive summary:

In a published study similar in protocol to the mouse local lymph node assay (LLNA), groups of mice were exposed dermally to ammonium hexachloroplatinate (IV). Repeated applications were then made to the ears before the auricular lymph nodes were drained and analysed for three types of cytokine (interleukin-4, interleukin-10 and interferon-gamma). Cytokine analyses were comparable to those seen with the respiratory allergen trimellitic anhydride (TMA) and the contact allergen 2,4 -dinitrochlorobenzene (DNCB).

The data are compatible with an IgE-mediated or Th2 -type mechanism for the immediate-type hypersensitivity reaction elicited by certain platinum salts and are consistent with the observation that exposed symptomatic workers display both elevated total serum IgE concentration and specific IgE response. The expression of Th2 -type cytokines is consistent also with their ability to induce immune-type contact urticaria.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

No in vitro skin sensitisation studies were identified, or are required, as reliable in vivo studies are already available.

The development of skin sensitisation following occupational exposure to halogenated platinum compounds, in particular chloroplatinates, is a well-established health hazard, and has been addressed in comprehensive expert reviews (HCN, 2008; IPCS, 1991; SCOEL, 2011; US EPA, 2009; WHO, 2000, 2012). The following brief summary is based largely on information cited in these reviews and focuses on the key information to indicate an appropriate classification category according to the skin sensitisation criteria of Regulation (EC) No. 1272/2008, as amended.

 

WHO (2012) noted that urticaria (Type I immediate hypersensitivity) and allergic contact dermatitis are symptoms of platinum-specific allergic skin sensitisation in numerous case reports and occupational health studies on workers exposed to halogenated platinum salts (Baker et al., 1990; Bolm-Audorff et al., 1992; Calverley et al., 1995, 1999; Cristaudo et al., 2005; Hunter et al., 1945; IPCS, 1991; Marshall, 1952; Merget, 2000, Merget et al., 1988, 1999, 2000; Pepys, 1984; Pepys et al., 1972; WHO, 2000). Reactions are generally urticarial and eczematous in nature, while true allergic contact dermatitis from exposure to platinum compounds is rare (HCN, 2008). SCOEL and HCN noted that skin sensitisation potential is limited to complexes where halogen ligands are coordinated to the platinum atoms; hexachloroplatinic acid and the tetra- and hexachloroplatinate salts are mainly responsible for platinum-salt skin sensitisation. Uncharged complexes and complexes with ligands other than halogens appear to lack such potential (HCN, 2008; SCOEL, 2011).

 

Merget et al. (2000) reported the results of a 5-year prospective cohort study that found a dose-response relationship between airborne soluble platinum concentrations and newly occurring sensitisation cases. The study was performed during 1989-1995 (more than 20 years ago), and included 275 employees of a catalyst-production plant in Germany, of whom 115 worked in the production lines (‘high exposure’), 112 worked (regularly or irregularly) within the catalyst department but not in the production lines (‘low exposure’), and 48 never entered the catalyst building (‘no exposure’). 53% of the study population were already present when the study started. The subjects had undergone at least two examinations and had a negative response in a skin prick test against platinum at the initial survey. The results demonstrated that in a population of 160 workers, no new cases of sensitisation occurred during 5-year employment in the ‘no exposure’ and ‘low exposure’ areas but, in the ‘high exposure’ area, 14 new cases of sensitisation occurred in 115 exposed workers (11%). Smoking cigarettes was positively associated with the occurrence of new symptoms. It was concluded that exposures below the OEL value (generally 2000 ng Pt/m3) may still result in sensitisation (Merget et al., 2000) and WHO stated that “Qualitative evaluation of these data would suggest that halogenated platinum salts are potent or strong skin sensitizers” (WHO, 2012). However, the investigators themselves acknowledged that the study was not designed to establish a threshold for sensitisation induction and could not be used to establish an OEL (Merget et al., 2000). The major issues over characterisation of exposure were addressed in an industry report (EPMF, 2009) and SCOEL (2011) noted that the study was not conducted with the aim to find a no-observed-adverse-effect level (NOAEL), peak exposures were not quantified, high past exposures may have contributed to the sensitisation cases, exposure estimates were not based on the sampling, and exposures were highly variable, all of which may lead to unreliable exposure estimates. SCOEL concluded that “the database does not allow the recommendation of an OEL for soluble platinum compounds” (SCOEL, 2011).

 

More recently, a new epidemiological study (Heederik et al., 2016) has provided better insights into respiratory sensitisation risk at low exposures (see the section on Respiratory Sensitisation, below), but did not focus on skin sensitisation aspects.

 

Although a guinea pig maximization test found no evidence of skin sensitisation potential for ammonium hexachloroplatinate (Middleton, 1977), three published laboratory animal studies (Dearman et al., 1998; Schuppe et al., 1997) provide support for the view that halogenated platinum salts are dermal sensitisers. Schuppe et al. (1997) reported a significant positive reaction in BALB/c mice exposed to 5% sodium hexachloroplatinate in a LLNA (adapted to avoid the use of radioactive label) and in a modified ear swelling test (MEST). At that 5% concentration, the ALN Index (which presumably reflects the Stimulation Index (SI)) in the LLNA test exceeded 3 [the level used to differentiate sensitisers from non-sensitisers]. If that concentration is used as the EC3 [the effective concentration required to induce a 3-fold increase in the proliferation of lymph node cells compared with vehicle-treated controls], then the potency category for this halogenated platinum salt would be in the moderate range [CLP Sub-category 1B]. Lower (unspecified) concentrations evidently did not increase the ALN Index (Schuppe et al., 1997). Dearman et al. (1998) reported increases in production of interferon-g expression [typical of a skin sensitiser; Th1 response] and interleukin (IL-10) [characteristic of respiratory sensitizers; Th2 response] for diammonium hexachloroplatinate when applied to the ears of BALB/c mice at exposure concentrations down to 0.25%. In isolation, these results might indicate a potency category of strong [Sub-category 1A]. However, Dearman et al. (1998) only evaluated cytokine release, and the experiment did not include a LLNA or development of EC3 values. In addition, it should be noted that both the LLNA and MEST in isolation are unable to differentiate between immediate (Th2 type) and delayed (Th1 type) hypersensitivity responses. Diammonium and disodium hexachloroplatinate are considered to fall within the scope of the read-across category "hexachloroplatinate(IV) compounds". See section 13 in IUCLID for full read-across justification report.

 

Most reports do not include (dermal or inhalation) exposure data, making thresholds for induction impossible to determine. In respect of elicitation, in one study a positive skin reaction was elicited by skin patch application of 15 µl of a 0.01M solution of hexachloroplatinic acid, in 2 of 153 workers at a catalyst manufacturing and recycling factory; 22 had a positive skin prick test (SPT) indicative of IgE antibody involvement to the same substance (Cristaudo et al., 2005). Although data on suitable patch test concentrations are limited, WHO (2012) noted that published occupational data are available on challenge doses associated with a positive SPT response to halogenated platinum salts. Two cited papers reported that the lowest exposure concentration of halogenated platinum salts required to elicit a positive SPT ranged from 10−9 to 10−3 g/ml (six orders of magnitude) among individuals previously sensitized to halogenated platinum salts (Biagini et al., 1985; Brooks et al., 1990).

 

WHO felt that the low elicitation dose for halogenated platinum salts, based on SPT and occupational exposure data suggests that these salts sit at the higher end of sensitiser potency. WHO also concluded that the published laboratory animal data suggest that the potency category for some halogenated platinum salts would be moderate or strong (WHO, 2012). Overall, the significant data gaps and inadequate dermal exposure data preclude determination of an elicitation dose threshold for halogenated platinum salts, and there is little information to inform a qualitative evaluation. Published data on low exposures are inadequate to evaluate whether some halogenated platinum salts might be classified as strong sensitizers.

 

As indicated above, assays such as LLNA and MEST cannot differentiate between Th2 and Th1 immune responses and therefore in the case of the chloroplatinates positive responses do not necessarily indicate that delayed contact hypersensitivity has been induced. There is significant published evidence (e.g. Dearman et al., 1998), and unpublished data within the industry sector, which strongly suggests that the Th2 arm is preferentially induced on skin exposure to chloroplatinate salts and related Pt compounds. Extensive accumulated industrial experience from health surveillance systems in the platinum group metal sector indicates that exposure to complex halogenated salts of platinum, typified by soluble hexa- and tetra-chloroplatinates, results in the preferential induction of Th2 (IgE-mediated) responses in sensitisation reactions. These data encompass a sector historical record of more than 50 years, involving over 10 companies.

 

These chloroplatinate induced Th2-type responses involve activation of specific subsets of T lymphocytes and the cytokine products of these cells can be tracked with cytokine fingerprinting in both experimental toxicology studies and human clinical investigations. The end result of such activation is allergen-specific IgE antibody production, and the predominant reaction in symptomatic workers is respiratory sensitisation and/or allergic rhinoconjunctivitis, with contact urticaria being less commonly observed. In contrast, allergic contact dermatitis (ACD) as a result of non-IgE mediated mechanisms (i.e. Th1-based responses) has been rarely observed, particularly in terms of its occurrence in isolation from immediate hypersensitivity responses. It is estimated that ACD incidence accounts for <1% of symptomatic cases in sensitised worker populations.

 

Taking into account extensive human industrial experience of exposure to this substance where skin contact does not routinely result in allergic contract dermatitis (but can cause Th2 immediate hypersensitivity), the weight of evidence indicates that classification as Sub category 1B is appropriate for this substance (personal communication Johnson Matthey).

 

Several chloroplatinate compounds are being registered under REACH by the PMC: dipotassium tetrachloroplatinate (CAS RN 10025-99-7); dipotassium hexachloroplatinate (CAS RN 16921 30-5); diammonium hexachloroplatinate (CAS RN 16919-58-7); and hexachloroplatinic acid (CAS RN 16941-12-1). Occupational health studies, supported by case reports, provide sufficient evidence that halogenated platinum salts can induce skin sensitisation responses in exposed workers. Laboratory animal studies provide additional support for this potential. From the limited available data, dermal exposure thresholds for induction and elicitation cannot be robustly determined. The limited nature of the existing exposure data also precludes quantifying any relationship between dermal and inhalation exposure in inducing skin sensitisation. There is extensive evidence that these skin reactions can be mediated by Th2-type responses in humans, and this is supported by cytokine release profiles, SPT responses, and industry data indicative of IgE involvement. Therefore, it can be concluded that the available evidence is not supportive of the chloroplatinates having potent delayed contact hypersensitivity potential, and that the weight of evidence indicates the chloroplatinates should be classified as Sub-category 1B (low to moderate frequency of occurrence). In a recent non-guideline study, it was demonstrated that a single respiratory challenge to mice topically sensitised to ammonium hexachloroplatinate can induce dose dependent changes in pulmonary function indicative of an allergic lung response (Williams et al., 2015). This suggests that both dermal and inhalation exposure to chloroplatinates may play a role in occupational skin sensitisation and respiratory sensitisation/asthma, further supporting the decision to formulate a qualitative assessment approach (and consequent ‘high hazard’ banding) as most appropriate for the respiratory and dermal sensitisation endpoints.

 

 

References

Baker D et al. (1990). Cross-sectional study of platinum salts sensitization among precious metals refinery workers. American Journal of Industrial Medicine 18, 653-664 (cited in WHO, 2012).

 

Biagini RE et al. (1985). The diversity of reaginic immune responses to platinum and palladium metallic salts. Journal of Allergy and Clinical Immunology 76, 794-802 (cited in WHO, 2012).

 

Bolm-Audorff U et al. (1992). Prevalence of respiratory allergy in a platinum refinery. International Archives of Occupational and Environmental Health 64, 257-260 (cited in WHO, 2012).

 

Brooks SM et al. (1990). Cold air challenge and platinum skin reactivity in platinum refinery workers: bronchial reactivity precedes skin prick response. Chest 97, 1401-1407 (cited in WHO, 2012).

 

Calverley AE et al. (1995). Platinum salt sensitivity in refinery workers: incidence and effects of smoking and exposure. Occupational and Environmental Medicine 52, 661-666 (cited in WHO, 2012).

 

Calverley AE et al. (1999). Allergy to complex salts of platinum in refinery workers: prospective evaluations of IgE and Phadiatop® status. Clinical and Experimental Allergy 29, 703-711 (cited in WHO, 2012).

 

Cristaudo A et al. (2005). Occupational hypersensitivity to metal salts, including platinum, in the secondary industry. Allergy 60, 159-164 (cited in WHO, 2012).

 

Dearman R et al. (1998). Selective induction of type 2 cytokines following topical exposure of mice to platinum salts. Food and Chemical Toxicology 36,199-207 (cited in WHO, 2012).

 

EPMF (2009). European Precious Metals Federation. Comments on a US EPA draft toxicological review of halogenated platinum salts and platinum compounds (Docket ID No. EPA-HQ-ORD-2009-0040). Letter submitted to the US EPA.https://www.regulations.gov/#!documentDetail;D=EPA-HQ-ORD-2009-0040-0007

 

HCN (2008). Health Council of the Netherlands (DECOS). Platinum and platinum compounds. Health based recommended occupational exposure limit.https://www.gezondheidsraad.nl/sites/default/files/200812OSH_1.pdf

 

Heederik D, Jacobs J, Samadi S, van Rooy F, Portengen L and Houba R (2016). Exposure response analyses for platinum salt-exposed workers and sensitization: A retrospective cohort study among newly exposed workers using routinely collected surveillance data. Journal of Clinical Immunology 137, 922-929.

 

Hunter D et al. (1945). Asthma caused by the complex salts of platinum. British Journal of Industrial Medicine 2, 92-98 (cited in Ravindra et al., 2004; US EPA, 2009; WHO, 2012).

 

IPCS (1991). Platinum. Environmental Health Criteria 125. International Programme on Chemical Safety. World Health Organisation. Geneva.http://www.inchem.org/documents/ehc/ehc/ehc125.htm

 

Marshall J (1952). Asthma and dermatitis caused by chloroplatinic acid. South African Medical Journal 26, 8-9 (cited in WHO, 2012).

 

Merget R (2000). Occupational platinum salt allergy. Diagnosis, prognosis, prevention and therapy. In: Zereini F, Alt F, eds. Anthropogenic platinum-group element emissions: their impact on man and environment. New York, NY, Springer Verlag, pp. 257–265 (cited in US EPA, 2009; WHO, 2012).

 

Merget R et al. (1988). Asthma due to the complex salts of platinum—a cross-sectional survey of workers in a platinum refinery. Clinical Allergy 18, 569-580 (cited in WHO, 2012).

 

Merget R et al. (1999). Outcome of occupational asthma due to platinum salts after transferral to low-exposure areas. International Archives of Occupational and Environmental Health 72, 33-39 (cited in US EPA, 2009; WHO, 2012).

 

Merget R et al. (2000). Exposure–effect relationship of platinum salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study. Journal of Allergy and Clinical Immunology 105, 364-370 (cited in WHO, 2012).

 

Middleton JD (1977). Delayed dermal sensitization study in the guinea pig. CB14 – ammonium hexachloroplatinate(IV). Johnson Matthey report.

 

Pepys J et al. (1972). Asthma due to inhaled chemical agents—complex salts of platinum. Clinical Allergy 2, 391-396 (cited in WHO, 2012).

 

Pepys J (1984). Occupational allergy due to platinum complex salts. In: Clinics in immunology and allergy. Vol. 4. London, W.B. Saunders, pp. 131–158 (cited in WHO, 2012).

 

Ravindra K et al. (2004). Platinum group elements in the environment and their health risk. The Science of the Total Environment 318, 1-43.

 

Schuppe H et al. (1997). Contact hypersensitivity to disodium hexachloroplatinate in mice. Toxicological Letters 93, 125-133 (cited in US EPA, 2009; WHO, 2012).

 

SCOEL (2011). EU Scientific Committee on Occupational Exposure Limits. Recommendation from the Scientific Committee on Occupational Exposure Limits for Platinum and Platinum compounds. SCOEL/SUM/150. September 2011.http://ec.europa.eu/social/BlobServlet?docId=7303&langId=en

 

US EPA (2009). Draft: Toxicological review of halogenated platinum salts and platinum compounds. In support of summary information on the Integrated Risk Information System. EPA/635/R-08/018. January 2009.http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=203203#Download

 

WHO (2000). Air quality guidelines for Europe, 2nded. WHO Regional Publications, European Series, No. 91. World Health Organisation Regional Office for Europe, Copenhagen. Platinum, pp. 166-169.http://www.euro.who.int/__data/assets/pdf_file/0005/74732/E71922.pdf

 

WHO (2012). Guidance for immunotoxicity risk assessment for chemicals. Harmonization Project Document. Case-study 3: assessment of sensitization and allergic response to halogenated platinum salts. World Health Organisation. Geneva.http://www.who.int/ipcs/methods/harmonization/areas/guidance_immunotoxicity.pdf

 

Williams WC, Lehmann JR, Boykin E, Selgrade MK and Lehmann DM (2015). Lung function changes in mice sensitized to ammonium hexachloroplatinate. Inhalation Toxicology 27, 468-480.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

The development of allergic respiratory tract sensitisation following occupational exposure to halogenated platinum compounds, in particular chloroplatinates, is a well-established health hazard, and has been addressed in comprehensive expert reviews (HCN, 2008; IPCS, 1991; SCOEL, 2011; US EPA, 2009; WHO, 2000, 2012). The following brief summary is based largely on information cited in these reviews and focuses on the key information to indicate an appropriate classification category under the revised respiratory sensitisation criteria of Regulation (EC) No. 1272/2008, as amended.

 

Adverse occupational health effects following exposure to complex platinum salts have been reported as far back as a century ago (Karasek and Karasek, 1911). It was reported that 52 out of 91 (57%) precious metal workers in four British platinum refineries had symptoms of sneezing, wheezing and shortness of breath when exposed at airborne levels of between 0.9 and 1700 µg/m3 (Hunter et al., 1945).

 

A WHO (2012) evaluation cited a large number of case reports and occupational studies that identify the health effects in workers exposed to halogenated platinum salts – in particular certain chloroplatinates – as asthma, rhinitis and conjunctivitis (Baker et al., 1990; Bolm Audorff et al., 1992; Calverley et al., 1995; Cristaudo et al., 2005; Hunter et al., 1945; IPCS, 1991; Marshall, 1952; Merget, 2000; Merget et al., 1988, 1999, 2000; Pepys, 1984; Pepys et al., 1972; WHO, 2000). The WHO (2012) review noted that additional reports provide support for one or more of the above effects, consistent with respiratory sensitisers: viz asthma (Brooks et al., 1990; Merget et al., 1991, 1994, 1995, 1996), respiratory difficulties (Karasek and Karasek, 1911), inflammatory changes in the respiratory tract (Merget et al., 1996; Roberts, 1951), bronchospasm (Calverley et al., 1999) and bronchial hyperactivity (Biagini et al., 1985; Brooks et al., 1990; Merget et al., 1991). A similar extensive list of relevant reports is provided in US EPA (2009). Asymptotic respiratory sensitisation (detected by skin prick testing; SPT) can proceed to occupational asthma and rhinitis if exposure is continued, and such symptoms may be severe (Friedman-Jimenez et al., 2000; Merget et al., 1999). Severe cases of allergic sensitisation to halogenated platinum salts have included workers with bluish skin due to insufficient oxygen in the blood, feeble pulse, and extreme breathing difficulty, requiring the subject to maintain an upright position to breath (Roberts, 1951). Review of published epidemiology indicates that for chloroplatinate salts, latency from first exposure to the evidence of respiratory sensitisation varies from a few months to about ten years, with the majority occurring within approximately 3 years (Cochrane et al., 2015; HCN, 2008; IPCS, 1991; SCOEL, 2011; US EPA, 2009; WHO, 2000, 2012).

 

The respiratory sensitisation effects detected in the workplace have been attributed to complex halogenated salts, where the platinum atom is directly coordinated to halide atoms, and not where the halide, such as chloride, is present in ionic form (Cochrane et al., 2015; HCN, 2008; SCOEL, 2011; US EPA, 2009). The work environment of a platinum refinery or platinum catalyst production plant where individuals become sensitised to platinum compounds evidently primarily involves exposure to halogenated platinum salts, mainly chloroplatinates, ammonium tetrachloroplatinate, ammonium hexachloroplatinate, sodium hexachloroplatinate, potassium tetrachloroplatinate, potassium hexachloroplatinate or hexachloroplatinic acid (Cochrane et al., 2015; Heederik et al., 2016; Hunter et al., 1945; Merget et al., 1999, 2000; Parrot et al., 1969).

 

The allergenic potential may be related to the degree of chlorination (Cleare et al., 1976; Cristaudo et al., 2005; Linnett and Hughes, 1999). Results from laboratory animal studies provide data supporting a relationship between allergenic potential and the degree of chlorination (Murdoch and Pepys, 1984a,b, 1985, 1986; Schuppe et al., 1992, 1997; WHO, 2012), and some data suggest that there is a correlation between activity and the degree of chlorination between the series of hexachloroplatinate and tetrachloroplatinate salts.

 

From the various studies carried out to date (early 2016), it has not been possible to define a robust induction threshold for respiratory sensitisation in occupationally-exposed humans. WHO (2000) noted that the incidence of PSS fell following the adoption of an occupational exposure limit (OEL) with a threshold limit value (TLV) for soluble platinum salts of 2 µg/m3 (as Pt) as an 8-hour time-weighted average (TWA). However, several epidemiological studies have reported respiratory tract sensitisation in chloroplatinate workers even where the estimated workplace air concentrations were below this 2 μg/m3 OEL (Baker et al., 1990; Bolm-Audorff et al., 1992; Heederik et al., 2016; Linnett and Hughes, 1999; Merget et al., 2000).

 

In recent Expert Group attempts to evaluate respiratory sensitisation risk at low exposures to complex halogenated platinum salts (SCOEL, 2011; US EPA, 2009), an epidemiological study by Merget et al. (2000) played a central role. However, the investigators themselves acknowledged that the study was not designed to establish a threshold for PSS induction and could not be used to establish an OEL (Merget et al., 2000). The major issues over characterisation of exposure were addressed in an industry report (EPMF, 2009) and SCOEL (2011) was unable to recommend an OEL based on this study. More recently, a new epidemiological study (Heederik et al., 2016) has provided better insights into respiratory sensitisation risk at low exposures.

 

The older Merget et al. (2000) publication reported the results of a 5-year prospective cohort study that found a dose-response relationship between airborne soluble platinum concentrations and newly occurring sensitisation cases. The study was performed during 1989-1995 (more than 20 years ago), and included 275 employees of a catalyst-production plant in Germany, of whom 115 worked in the production lines (‘high exposure’), 112 worked (regularly or irregularly) within the catalyst department but not in the production lines (‘low exposure’), and 48 never entered the catalyst building (‘no exposure’). 53% of the study population were already present when the study started. The subjects had undergone at least two examinations and had a negative response in a skin prick test against platinum at the initial survey. The results demonstrated that in a population of 160 workers, no new cases of sensitisation occurred during 5-year employment in the ‘no exposure’ and ‘low exposure’ areas [The SCOEL (2011) summary of Merget et al. (2000) stated that the maximum concentrations of soluble platinum measured in the ‘low-exposure’ area were 8.6 and 1.5 ng/m3 in 1992 and 1993, respectively. In the ‘high exposure’ area, the maximum measured concentrations of soluble platinum were roughly 700 and 155 ng/m3 in 1992 and 1993, respectively. Personal sampling (of inhalable dust) in this area revealed a median value of 177 ng/m3 with a highest value of 3700 ng/m3; 3 samples out of 22 exceeded 2000 ng/m3 (8-hour sampling time). It was concluded that exposures below the occupational threshold limit value (generally 2000 ng Pt/m3) may still result in sensitisation; even exposure to soluble platinum salts at levels between 10 and 100 ng Pt/m3 may lead to sensitisation (Merget et al., 2000). However, important issues in regard to the exposure characterisation presented in this paper were subsequently noted (EPMF, 2009)] but, in the ‘high exposure’ area, 14 new cases of sensitisation occurred in 115 exposed workers (11%). Smoking cigarettes was positively associated with the occurrence of new symptoms. It was concluded that exposures below the OEL value (generally 2000 ng Pt/m3) may still result in sensitisation (Merget et al., 2000). Based on these results, SCOEL suggested that at exposure to levels below 10 ng/m3 sensitisation is not to be expected. Critically, SCOEL noted that the study was not conducted with the aim to find a no-observed-adverse-effect level (NOAEL), peak exposures had not been quantified, high exposures may have occurred in the past which could have contributed to the sensitisation cases, exposure estimates were not based on the sampling, and exposures were highly variable, all of which may lead to unreliable exposure estimates. SCOEL concluded that “the database does not allow the recommendation of an OEL for soluble platinum compounds” (SCOEL, 2011).

 

A recently-published retrospective cohort study designed to investigate PSS found a clear exposure-response relationship between chloroplatinate salts and respiratory sensitisation in workers. The study involved about 1040 refinery workers who newly joined one of five refineries during an 11-year period (1 January 2000 to 31 December 2010), and for whom a total of around 1760 personal time-weighted average exposure measurements (to soluble platinum; used as a surrogate for the various chloroplatinate intermediates in particulate and liquid aerosol forms) were available. Only personal time-weighted average measurements based on the inhalable or total dust fraction, and approximating to 8-hour workshift values were included in the exposure database. Sensitisation cases were detected by SPT, using a hexachloroplatinate salt, which is a method with high sensitivity and predictivity. The relationship was strongest for current (recent) and average exposure, and weaker for cumulative exposure. For current exposure categories of ≤49, >49 ≤100, >100-≤252 and >252 ng/m3, Risk Ratios (RRs) were 1 (reference), 1.4, 2.2 and 3.2, respectively, the latter two values being statistically significant (p<0.005 or better). For average exposure, RRs were 1, 1.8, 4.2 and 3.0, respectively, for the ≤51.1, >51.1-≤105, >105 ≤250 and >250 ng/m3 categories (all statistically significant at p<0.05 or better). The investigators concluded that “the exposure-relation for current exposure is characterized by an initial steep increase in risk starting at low exposure levels and levelling off at levels of greater than 200 ng/m3” (Heederik et al., 2016).

 

This recent, high-quality study (Heederik et al., 2016) is consistent with other epidemiology studies in demonstrating that PSS can be induced at estimated airborne soluble platinum concentrations (as a chloroplatinate surrogate measure) of less than 2 µg/m3 (2000 ng/m3) as an 8-hour TWA value. Although the study possessed higher statistical power than any previous epidemiology investigation of PSS, due to some limitations in the low-end exposure dataset it was not possible to define a robust induction threshold (airborne critical concentration) for respiratory sensitisation to chloroplatinates. 

 

In summary, there is extensive epidemiological evidence (from cohort studies and case reports) that halogenated platinum salts, in particular chloroplatinates, can act as respiratory sensitisers, with a large proportion of the exposed workers developing symptoms if the occupational levels are sufficiently high. On continued exposure, asymptomatic respiratory sensitisation (detected by SPT) can proceed to occupational asthma and rhinitis, and such symptoms may be severe. There is a lack of information with regards the particular compounds involved, but the human data, together with supporting laboratory animal studies, indicate the more highly chlorinated forms such as hexachloroplatinate and tetrachloroplatinate are more active as respiratory sensitisers than the less chlorinated forms.

 

Several chloroplatinate compounds are being registered under REACH by the PMC: dipotassium tetrachloroplatinate (CAS RN 10025-99-7); dipotassium hexachloroplatinate (CAS RN 16921 30-5); diammonium hexachloroplatinate (CAS RN 16919-58-7); and hexachloroplatinic acid (CAS RN 16941-12-1). Given the frequency of occurrence of respiratory sensitisation in workers exposed to sufficiently high occupational levels, and the severity of the symptoms that may develop, particularly if exposure is continued, the available data indicate that it is appropriate to classify these substances as respiratory sensitisers, in sub-category 1A, according to EU CLP criteria. The available epidemiology data have not yet permitted delineation of an induction threshold for PSS in workplace exposure scenarios. In a recent non-guideline study, it was demonstrated that a single respiratory challenge to mice topically sensitised to ammonium hexachloroplatinate can induce dose dependent changes in pulmonary function indicative of an allergic lung response (Williams et al., 2015). This suggests that both dermal and inhalation exposure to chloroplatinates may play a role in occupational respiratory sensitisation/asthma, further supporting the decision to formulate a qualitative assessment approach (and consequent ‘high hazard’ banding) as most appropriate for the respiratory and dermal sensitisation endpoints.

 

 

References

Baker DB, Gann PH, Brooks SM, Gallagher J and Bernstein IL (1990). Cross-sectional study of platinum salts sensitization among precious metals refinery workers. American Journal of Industrial Medicine 18, 653-664 (cited in WHO, 2012).

 

Biagini RE, Bernstein IL, Gallagher JS, Moorman WJ, Brooks S and Gann PH (1985). The diversity of reaginic immune responses to platinum and palladium metallic salts. Journal of Allergy and Clinical Immunology 76(6), 794-802 (cited in WHO, 2012).

 

Bolm-Audorff U, Bienfait HG, Burkhard J, Bury AH, Merget R, Pressel G and Schultze Werninghaus G (1992). Prevalence of respiratory allergy in a platinum refinery. International Archives of Occupational and Environmental Health 64, 257-260 (cited in WHO, 2012).

 

Brooks SM, Baker DB, Gann PH, Jarabek AM, Hertzberg V, Gallagher J, Biagini RE and Bernstein IL (1990). Cold air challenge and platinum skin reactivity in platinum refinery workers: bronchial reactivity precedes skin prick response. Chest 97, 1401-1407 (cited in WHO, 2012).

 

Calverley AE, Rees D, Dowdeswell RJ, Linnett PJ, Kielkowski D (1995). Platinum salt sensitivity in refinery workers: incidence and effects of smoking and exposure. Occupational and Environmental Medicine 52, 661-666 (cited in WHO, 2012).

 

Calverley AE, Rees D and Dowdeswell RJ (1999). Allergy to complex salts of platinum in refinery workers: prospective evaluations of IgE and Phadiatop® status. Clinical and Experimental Allergy 29, 703-711 (cited in WHO, 2012).

 

Cleare MJ, Hughes EG, Jacoby B and Pepys J (1976). Immediate (type I) allergic responses to platinum compounds. Clinical Allergy 6, 183-195 (cited in US EPA, 2009).

 

Cochrane SA, Arts JHE, Ehnes C, Hindle S, Hollnage HM, Poole A, Suto H and Kimber I (2015). Thresholds in chemical respiratory sensitisation. Toxicology 333, 179-194.

 

Cristaudo A, Sera F, Severino V, De Rocco M, Di Lella E and Picardo M (2005). Occupational hypersensitivity to metal salts, including platinum, in the secondary industry. Allergy 60, 159 164 (cited in WHO, 2012).

 

EPMF (2009). European Precious Metals Federation. Comments on a US EPA draft toxicological review of halogenated platinum salts and platinum compounds (Docket ID No. EPA-HQ-ORD-2009-0040). Letter submitted to the US EPA.https://www.regulations.gov/#!documentDetail;D=EPA-HQ-ORD-2009-0040-0007

 

Friedman-Jimenez G, Beckett WS, Szeinuk J and Petsonk EL (2000). Clinical evaluation, management, and prevention of work-related asthma. American Journal of Industrial Medicine 37(1), 121-141 (cited in US EPA, 2009).

 

HCN (2008). Health Council of the Netherlands (DECOS). Platinum and platinum compounds. Health based recommended occupational exposure limit.https://www.gezondheidsraad.nl/sites/default/files/200812OSH_1.pdf

 

Heederik D, Jacobs J, Samadi S, van Rooy F, Portengen L and Houba R (2016). Exposure response analyses for platinum salt-exposed workers and sensitization: A retrospective cohort study among newly exposed workers using routinely collected surveillance data. Journal of Clinical Immunology 137, 922-929.

 

Hunter D, Milton R and Perry KMA (1945). Asthma caused by the complex salts of platinum. British Journal of Industrial Medicine 2, 92-98 (cited in Ravindra et al., 2004; US EPA, 2009; WHO, 2012).

 

IPCS (1991). Platinum. Environmental Health Criteria 125. International Programme on Chemical Safety. World Health Organization, Geneva.http://www.inchem.org/documents/ehc/ehc/ehc125.htm

 

Karasek SR and Karasek M (1911). The use of platinum paper. Report of (Illinois) commission on occupational diseases to his Excellency Governor Charles S. Deneen, Chicago, Warner Printing Company, January 1911, p. 97 (cited in Ravindra et al., 2004; WHO 2012).

 

Linnett P and Hughes E (1999). 20 years of medical surveillance on exposure to allergenic and non-allergenic platinum compounds: the importance of chemical speciation. Occupational and Environmental Medicine 56, 191-196 (cited in US EPA, 2009).

 

Marshall J (1952). Asthma and dermatitis caused by chloroplatinic acid. South African Medical Journal 26(1), 8-9 (cited in WHO, 2012).

 

Merget R (2000). Occupational platinum salt allergy. Diagnosis, prognosis, prevention and therapy. In: Zereini F, Alt F, eds. Anthropogenic platinum-group element emissions: their impact on man and environment. New York, NY, Springer Verlag, pp. 257-265 (cited in US EPA, 2009; WHO, 2012).

 

Merget R, Schultze-Werninghaus G, Muthorst T, Friedrich W and Meier-Sydow J (1988). Asthma due to the complex salts of platinum—a cross-sectional survey of workers in a platinum refinery. Clinical Allergy 18(6), 569-580 (cited in WHO, 2012).

 

Merget R, Schultze-Werninghaus G, Bode F, Bergmann EM, Zachgo W and Meier-Sydow J (1991). Quantitative skin prick and bronchial provocation tests with platinum salt. British Journal of Industrial Medicine 48, 830-837 (cited in WHO, 2012).

 

Merget R, Reineke M, Rueckmann A, Bergmann EM and Schultze-Werninghaus G (1994). Nonspecific and specific bronchial responsiveness in occupational asthma caused by platinum salts after allergen avoidance. American Journal of Respiratory and Critical Care Medicine 150, 1146-1149 (cited in WHO, 2012).

 

Merget R, Caspari C, Kulzer R, Breitstadt R, Rueckmann A and Schultz-Werninghaus G (1995). The sequence of symptoms, sensitization and bronchial hyperresponsiveness in early occupational asthma due to platinum salts. International Archives of Allergy and Immunology 107(1-3), 406-407 (cited in WHO, 2012).

Merget R, Dierkes A, Rueckmann A, Bergmann EM and Schultze-Werninghaus G (1996). Absence of relationship between degree of nonspecific and specific bronchial responsiveness in occupational asthma due to platinum salts. European Respiratory Journal 9(2), 211-216 (cited in WHO, 2012).

 

Merget R, Schulte A, Gebler A, Breitstadt R, Kulzer R, Berndt ED, Baur X and Schultze-Werninghaus G (1999). Outcome of occupational asthma due to platinum salts after transferral to low-exposure areas. International Archives of Occupational and Environmental Health 72, 33-39 (cited in US EPA, 2009; WHO, 2012).

 

Merget R, Kulzer R, Dierkes-Globisch A, Breitstadt R, Gebler A, Kniffka A, Artelt S, Koenig HP, Alt F, Vormberg R, Baur X and Schultze-Werninghaus G (2000). Exposure-effect relationship of platinum salt allergy in a catalyst production plant: conclusions from a 5-year prospective cohort study. Journal of Allergy and Clinical Immunology 105, 364-370 (cited in WHO, 2012).

 

Murdoch R and Pepys J (1984a). Immunological responses to complex salts of platinum. I. Specific IgE antibody production in the rat. Clinical and Experimental Immunology 57,107 114 (cited in US EPA, 2009).

 

Murdoch R and Pepys J (1984b). Immunological responses to complex salts of platinum. II. Enhanced IgE antibody responses to ovalbumin with concurrent administration of platinum salts in the rat. Clinical and Experimental Immunology 58, 478-485 (cited in US EPA, 2009).

 

Murdoch R and Pepys J (1985). Cross reactivity studies with platinum group metal salts in platinum-sensitised rats. International Archives of Allergy and Applied Immunology 77, 456 458 (cited in US EPA, 2009).

 

Murdoch R and Pepys J (1986). Enhancement of antibody production by mercury and platinum group metal halide salts. Kinetics of total and ovalbumin-specific IgE synthesis. International Archives of Allergy and Applied Immunology 80, 405-411 (cited in US EPA, 2009).

 

Parrot JL, Hébert R, Saindelle A and Ruff F (1969). Platinum and platinosis. Allergy and histamine release due to some platinum salts. Archives of Environmental Health 19(5), 685 691 (cited in US EPA, 2009).

 

Pepys J, Pickering CA and Hughes EG (1972). Asthma due to inhaled chemical agents - complex salts of platinum. Clinical Allergy, 2(4), 391-396 (cited in WHO, 2012).

 

Pepys J (1984). Occupational allergy due to platinum complex salts. In: Clinics in immunology and allergy. Vol. 4. London, W.B. Saunders, pp. 131-158 (cited in WHO, 2012).

 

Ravindra K, Bencs L and Van Grieken R (2004). Platinum group elements in the environment and their health risk. The Science of the Total Environment 318, 1-43.

 

Roberts AE (1951). Platinosis: a five year study of the effects of soluble platinum salts on employees in a platinum laboratory and refinery. Archives of Industrial Hygiene 4, 549-559 (cited in Ravindra et al., 2004; US EPA, 2009; WHO, 2009).

 

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SCOEL (2011). EU Scientific Committee on Occupational Exposure Limits. Recommendation from the Scientific Committee on Occupational Exposure Limits for Platinum and Platinum compounds. SCOEL/SUM/150. September 2011.http://ec.europa.eu/social/BlobServlet?docId=7303&langId=en

 

US EPA (2009). US Environmental Protection Agency. Draft: Toxicological review of halogenated platinum salts and platinum compounds. In support of summary information on the Integrated Risk Information System. EPA/635/R-08/018. January 2009.https://cfpub.epa.gov/ncea/risk/recordisplay.cfm;jsessionid=6B186200AC05490D49C3BA317C3F7511.cfpub?deid=203203&CFID=70761249&CFTOKEN=32498238%20-%20Download

 

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WHO (2012). Guidance for immunotoxicity risk assessment for chemicals. Harmonization Project Document. Case-study 3: assessment of sensitization and allergic response to halogenated platinum salts. World Health Organization. Geneva.http://www.who.int/ipcs/methods/harmonization/areas/guidance_immunotoxicity.pdf

 

Williams WC, Lehmann JR, Boykin E, Selgrade MK and Lehmann DM (2015). Lung function changes in mice sensitized to ammonium hexachloroplatinate. Inhalation Toxicology 27, 468 480.

Justification for classification or non-classification

The well-known and extensive data set for halogenated platinum compounds indicates that classification for both skin and respiratory sensitisation are required for dipotassium hexachloroplatinate.

 

As discussed above, available evidence is not supportive of dipotassium hexachloroplatinate having potent delayed contact hypersensitivity potential. The weight of evidence indicates that this compound should be classified for skin sensitisation in sub-category 1B (low to moderate frequency of occurrence), according to EU CLP criteria (EC 1272/2008).

 

Given the high frequency of occurrence of respiratory sensitisation in workers exposed to sufficiently high occupational levels of chloroplatinates, and the severity of the symptoms that may develop, particularly if exposure is continued, the available data would indicate that it is appropriate to classify dipotassium hexachloroplatinate as a respiratory sensitiser, in sub-category 1A, according to EU CLP criteria (EC 1272/2008).