Registration Dossier

Classification & Labelling & PBT assessment

GHS

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General Information

Remarks:
The classification for acute oral toxicity with H301/R23 is not appropriate for beryllium metal as demonstrated in an acute oral toxicity study presented in this dossier (7.2.1). The same applies to the classification as irritating, as no irritating potential of beryllium metal towards skin and eye were identified in acute irritation/corrosion studies presented in this dossier (7.3). No sensitizing properties of beryllium metal were identified in a recent guinea pig maximization test (7.4), and thus classification with H317/R43 is not appropriate for the metal.
The well known risk of chronic beryllium disease upon inhalation is most accurately expressed by classification with H372/R48.
As discussed in this dossier, beryllium metal is not mutagenic (see 7.6.1) and should not be classified as carcinogenic.
The Acute Tox.2 and H330/R26 do not apply to beryllium metal. As discussed in this dossier, acute inhalation toxicity with corresponding potentially fatal consequences only apply to soluble beryllium compounds.
Assessment of animal studies indicated tumours were only observed in rats at doses of beryllium metal that overloaded the lung’s clearance capacity. Such high doses did not lead to tumour formation in mice. All reports on rats are abstracts and thus the data situation on the rat for beryllium metal is not considered reliable.
Up through 2013 all epidemiological cancer studies were conducted in the United States and only at facilities where workers were exposed to both soluble and insoluble forms of beryllium. In addition, these studies have been subject to significant scientific debate in the published literature where methodologies and analytical techniques have been questioned.
In 2014, Boffetta et al. published an epidemiological study entitled: “A mortality study of workers exposed to insoluble forms of beryllium”(European Journal of Cancer Prevention March 2014). This is the first and only study to investigate lung cancer and other disease risks at facilities that only used insoluble forms of beryllium. A cohort of 4950 workers from four US insoluble beryllium manufacturing facilities were followed through 2009. The standardized mortality ratio from lung cancer was 96.0 (95% confidence interval 80.0, 114.3). Their work concluded: “This study on beryllium workers employed at four facilities and exposed to insoluble beryllium does not provide evidence of an increased risk of lung cancer or any other neoplastic or non-neoplastic disease. The results support the conclusions of previous reviews that the increased mortality from lung cancer identified among workers employed in the early technological phase of the industry with high exposure to soluble beryllium is not relevant to the risk among workers employed in this industry under ‘modern’ circumstances entailing exposure to insoluble beryllium.
The findings of Boffetta align closely with studies in Europe where only insoluble beryllium materials are utilized in manufacturing. For example, an analysis of the UK Beryllium Registry (Williams, W. J. 1996) that includes all cases of chronic beryllium and expected beryllium disease found no cancer related deaths among the 69 deaths associated with exposure to beryllium. Additionally, in a publication by the German/Austrian Cancer Society (DK, 2009) no cases of lung cancer were listed in the beryllium disease registry. This report assessed occupational disease cases from 1978 to 2003. Furthermore, The Industrial Injuries Advisory Council Position Paper 27, December 2009 Beryllium and Lung Cancer“ states: “The main epidemiological evidence on occupational risks of lung cancer in beryllium‐exposed workers derives from large US studies of beryllium process workers and of a US national register of beryllium workers. Although there have been several research reports, the evidence base is restricted to only a few cohorts with relevant data. The Council found no UK‐relevant studies to inform its inquiries.” “The Council has concluded that at present there is insufficient evidence to recommend that lung cancer in relation to beryllium should be added to the list of prescribed diseases. ”
A critical analysis of the literature clearly demonstrates that there is not sufficient evidence to conclude that beryllium metal causes cancer in humans even at the high doses that existed decades ago in production facilities in the United States which are not even relevant to activities within the EU.
The above justification is based on a review of publications relating to beryllium-induced carcinogenicity from PubMed, MedPilot, ToxNET and Toxline Special. One thousand-five hundred-thirty-one (1531) publications were identified dealing directly with toxicity of beryllium and its compounds, of which thirty-eight addressed carcinogenicity and twenty-one genotoxicity. The results were screened for beryllium metal as the substance of interest. Five studies addressing carcinogenicity after lung exposure to beryllium metal (representing the most relevant route of exposure) were identified (some one of these being reported in several publications). None of the genotoxicity studies were conducted with beryllium metal, and no carcinogenicity study with oral or dermal exposure to beryllium metal was identified. However, one study with beryllium metal was identified (Hueper et al. 1954), but not considered to add relevant information for risk characterization under human exposure conditions due to the unphysiologic routes of exposure in this study (intramuscular or intrapleural injection). None of the identified studies were conducted under GLP and only three studies were designed and reported in a way that they could be evaluated as “reliable with restrictions (2)” according to the system proposed by Klimisch (Klimisch et al. 1997). The other publications were “not assignable (4)” under the Klimisch system, as methods and results were only reported in abstract form without description of any experimental details or tabulation of data. However, despite the overall low quality of reporting, application of a weight-of-evidence approach leads to the conclusion that the rat shows a carcinogenic response to inhaled beryllium metal even after single exposure. Experimental attempts were made to reproduce this effect in other species. No carcinogenic responses in mice and guinea pigs could be demonstrated (Nikula et al. 1995; Schepers et al. 1961; Finch et al. 1995 and 1998a/b) and only strongly challenging the situation by sensitive animal models (mice of the A/J-strain with a known high background incidence of approximately 20% lung tumors in controls, and p53 knockout mice) revealed a weak positive response to inhaled beryllium metal. Differences between rats and other rodent/non-rodent species in response to inhalation exposure to poorly soluble particulate substances have been observed and discussed (see point 7.7 of this dossier). The effects observed in the rat lung are highly likely secondary effects to lung overload.

Related composition

Related composition:
Composition 1

Classificationopen allclose all

Explosives
Reason for no classification:
conclusive but not sufficient for classification
Flammable gases and chemically unstable gases
Reason for no classification:
conclusive but not sufficient for classification
Aerosols
Reason for no classification:
conclusive but not sufficient for classification
Oxidising gases
Reason for no classification:
conclusive but not sufficient for classification
Gases under pressure
Reason for no classification:
conclusive but not sufficient for classification
Flammable liquids
Reason for no classification:
conclusive but not sufficient for classification
Flammable solids
Reason for no classification:
conclusive but not sufficient for classification
Self-reactive substances and mixtures
Reason for no classification:
conclusive but not sufficient for classification
Pyrophoric liquids
Reason for no classification:
conclusive but not sufficient for classification
Pyrophoric solids
Reason for no classification:
conclusive but not sufficient for classification
Self-heating substances and mixtures
Reason for no classification:
conclusive but not sufficient for classification
Substances and mixtures which in contact with water emit flammable gases
Reason for no classification:
conclusive but not sufficient for classification
Oxidising liquids
Reason for no classification:
conclusive but not sufficient for classification
Oxidising solids
Reason for no classification:
conclusive but not sufficient for classification
Organic peroxides
Reason for no classification:
conclusive but not sufficient for classification
Corrosive to metals
Reason for no classification:
conclusive but not sufficient for classification
Desensitized explosives
Reason for no classification:
data lacking
Acute toxicity - oral
Reason for no classification:
conclusive but not sufficient for classification
Acute toxicity - dermal
Reason for no classification:
data lacking
Acute toxicity - inhalation
Reason for no classification:
conclusive but not sufficient for classification
Skin corrosion / irritation
Reason for no classification:
conclusive but not sufficient for classification
Serious eye damage / eye irritation
Reason for no classification:
conclusive but not sufficient for classification
Respiratory sensitisation
Reason for no classification:
conclusive but not sufficient for classification
Skin sensitisation
Reason for no classification:
conclusive but not sufficient for classification
Aspiration hazard
Reason for no classification:
conclusive but not sufficient for classification
Reproductive toxicity
Reason for no classification:
data lacking
Effects on or via lactation
Reason for no classification:
data lacking
Germ cell mutagenicity
Reason for no classification:
conclusive but not sufficient for classification
Carcinogenicity
Reason for no classification:
conclusive but not sufficient for classification
1. Specific target organ toxicity - single
Reason for no classification:
inconclusive
1. Specific target organ toxicity - repeated
Hazard category:
STOT Rep. Exp. 1
Hazard statement:
H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.
Affected organs:
lung
Route of exposure:
Inhalation
Hazardous to the aquatic environment (acute / short-term)
Reason for no classification:
data lacking
Hazardous to the aquatic environment (long-term)
Reason for no classification:
data lacking
Hazardous to the ozone layer
Reason for no classification:
data lacking

Labelling

Signal word:
Danger

Hazard pictogram

GHS08: health hazard

Hazard statements

H372: Causes damage to organs <or state all organs affected, if known> through prolonged or repeated exposure <state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard>.
H372: H372: Causes damage to the lung through prolonged or repeated exposure by inhalation

Precautionary statements

P201: Obtain special instructions before use.
P260: Do not breathe dust/fume/gas/mist/vapours/spray.

Notes