Gallium arsenide

Carcinogenicity

Description of key information

GaAs-dust:
Carcinogenic effects of gallium arsenide on male and female rats and mice were examined in 2-year inhalation toxicity studies (NTP, 2000). Inhalative exposure to GaAs-dust causes a specific reaction of the lung of rats and mice: alveolar proteinosis leading to chronic active inflammation after exposure to a GaAs dust with a MMAD of 0.8 to 1.0 µm. The criteria of CLP, including the specific considerations of 3.6.2.2, for a classification and labelling of carcinogenicity are not fulfilled (see below).
GaAs in its massive form:
GaAs in its massive form and therefore also GaAs-wafers do not have to be classified and labelled according to CLP regulation and subsequent regulations.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion

Dose descriptor:

LOAEC

0.01 mg/m³

Justification for classification or non-classification

The criteria of CLP-regulation (EC) 1272/2008, including the specific considerations of section 3.6.2.2, for a classification and labelling of carcinogenicity are not fulfilled.

A detailed comparison with the criteria for classification into categories of carcinogenicity of the CLP-regulation is presented in the following table.

Categories/ sections in CLP-Regulation	Criteria in CLP-Regulation	Comments for GaAs – fine dust
Category 1	Known or presumed human carcinogens A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:
Category 1A	Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or	There is no human evidence from any of the reliable epidemiological data.
Category 1B	Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.	see below.
	The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:	see below.
	— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or	There is no human evidence from any of the reliable epidemiological data.
	— animal experiments for which there is sufficient (1) evidence to demonstrate animal carcinogenicity (presumed human carcinogen).	There is no sufficient evidence to demonstrate animal carcinogenicity (- There is no evidence of carcinogenic effects in male rats as well as in male and female mice - in female F344/N rats inhalation study (NTP, 2000): increased incidence of benign and malignant neoplasms in the lung can be interpreted as sequelae of non-neoplastic histopathologic effects (chronic active inflammation, atypical hyperplasia, alveolar epithelial hyperplasia, proteinosis, alveolar epithelial metaplasia in the lungs, which can be interpreted as sequelae of chronic local irritation of the epithelial lung tissue); The occurrence of mononuclear cell leukaemia in females of the highest concentration has little if any human relevance. This tumor is very strain-specific to the F344 rat with a high spontaneous variability and has several times been evaluated as not predictive for humans partly because of curious results (Caldwell, 1999; Elwell et al. 1996; Lington et al. 1997). The same holds true for the increased incidence of benign pheochromocytomas in females of the highest concentration (Greim et al. 2009). Interestingly, a correlation between non-neoplastic chronic pulmonary lesions and adrenal pheochromocytoma has been identified in 9 NTP 2-year particulate inhalation studies in male F344 rats. There were significant associations of pheochromocytomas with the severity of inflammation and fibrosis. Systemic hypoxemia, occurring in space-occupying lung pathologies such as inflammation reduces the gas exchange area and stimulates catecholamine secretion from the adrenal medulla where chronic endocrine hyperactivity may lead to hyperplasia and neoplasms (Osaki et al. 2002). It is nearest to assume that a chronic inflammation in the lung will have a resonance in the body. Anemia, for example, is a known consequence of a chronic inflammation and is also observed in the NTP studies. Further disturbations of physiological processes can be assumed) For specific considerations (See 3.6.2.2.4. below).
	In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.	There is no evidence at all for carcinogenicity in humans. And, there is no evidence of carcinogenicity in experimental animals (see above).
CATEGORY 2	Suspected human carcinogens The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited (1) evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.	The substance GaAs is not placed in Cat. 2 because the criteria are not fulfilled. For details see considerations below. Increased tumor rates in the lung of female rats are explained as a secondary effect of the toxicity of GaAs dust in the lung and by strain-specific properties.
(1) Note: See 3.6.2.2.4.
3.6.2.2	Specific considerations for classification of substances as carcinogens	see below.
3.6.2.2.1	Classification as a carcinogen is made on the basis of evidence from reliable and acceptable studies and is intended to be used for substances which have an intrinsic property to cause cancer. The evaluations shall be based on all existing data, peer-reviewed published studies and additional acceptable data.	There are 2 reliable carcinogenicity studies in mice and rats (NTP, 2000) for the evaluation.
3.6.2.2.2.	Classification of a substance as a carcinogen is a process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.	see below.
3.6.2.2.3	Strength of evidence involves the enumeration of tumours in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the substance and an increased incidence of tumours. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. The terms ‘sufficient’ and ‘limited’ have been used here as they have been defined by the International Agency for Research on Cancer (IARC) and read as follows:	Human studies: no positive association and no causal relationship between exposure and cancer. Animal studies: There is neither sufficient nor limited evidence of carcinogenicity.
3.6.2.2.3.(a)	Carcinogenicity in humans The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories: — sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;	Humans: no causal relationship between exposure and cancer from reliable epidemiological studies
	— limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.	Humans: There is no positive association between exposure and cancer from reliable epidemiological studies.
3.6.2.2.3.(b)	Carcinogenicity in experimental animals Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:	see below.
	— sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;	The criteria for „sufficient evidence“ are not fulfilled: - incidences of neoplasms only in one sex of one species. Tumors are interpreted as sequelae of toxicity at test concentrations at the site of administration (chronic active inflammation, atypical hyperplasia, alveolar epithelial hyperplasia, proteinosis, alveolar epithelial metaplasia in the lungs, which can be interpreted as sequelae of chronic local irritation of the epithelial lung tissue).
	— limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.	a) single experiment only in females positive, male rat and male and female mice negative. b) adequate study design c) the observed tumors in the lung are secondary effects of pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation and occurred at concentrations far above the lowest effective concentration and not a direct effect of GaAs. d) increased tumor rates were only observed in the lung at the site of exposure. Therefore it is concluded that there is no limited evidence of carcinogenicity of GaAs.
3.6.2.2.4.	Additional considerations (as part of the weight of evidence approach (see 1.1.1)). Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors need to be considered that influence the overall likelihood that a substance poses a carcinogenic hazard in humans. The full list of factors that influence this determination would be very lengthy, but some of the more important ones are considered here.	see below.
3.6.2.2.5.	The factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumour findings and the other factors in a case-by-case manner.	see below.
3.6.2.2.6.	Some important factors which may be taken into consideration, when assessing the overall level of concern are:	see below.
3.6.2.2.6.(a)	tumour type and background incidence;	Tumor type: alveolar / bronchiolar adenoma/ carcinoma  Increased tumor rates in the lung of female rats are explained as a secondary effect of the toxicity of GaAs dust in the lung and by strain-specific properties. → decreased level of concern
3.6.2.2.6.(b)	multi-site responses;	only local tumors at the site of exposure in the lung → decreased level of concern
3.6.2.2.6.(c)	progression of lesions to malignancy;	no progression observed → decreased level of concern
3.6.2.2.6.(d)	reduced tumour latency;	not observed → decreased level of concern
3.6.2.2.6.(e)	whether responses are in single or both sexes;	Responses in female rats only → decreased level of concern
3.6.2.2.6.(f)	whether responses are in a single species or several species;	single species → decreased level of concern
3.6.2.2.6.(g)	structural similarity to a substance(s) for which there is good evidence of carcinogenicity;	There is no substance with structural similarity to GaAs especially there is no structural similarity to As2O3. Oxidation to As2O3 is only expected when crystalline structure is damaged. As2O3: legally classified as category 2 (index No. 033-003-00-0). Nevertheless with GaAs fully reliable carcinogenicity studies are published. Evaluation of the carcinoginicity of GaAs on the basis of these studies. → decreased level of concern
3.6.2.2.6.(h)	routes of exposure;	inhalation only, no toxicity after oral or dermal administration observed → decreased level of concern
3.6.2.2.6.(i)	comparison of absorption, distribution, metabolism and excretion between test animals and humans;	no differences known.
3.6.2.2.6.(j)	the possibility of a confounding effect of excessive toxicity at test doses;	At the lowest and higher tested concentration: pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation , in histopathologoy seen as: chronic active inflammation, atypical hyperplasia, alveolar epithelial hyperplasia, proteinosis, alveolar epithelial metaplasia in the lungs (which can be interpreted as sequelae of chronic local irritation of the epithelial lung tissue) → decreased level of concern
3.6.2.2.6.(k)	mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity. Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.	cytotoxicity with growth stimulation: not observed Mitogenesis: not observed Immunosuppression: not observed. There is no mutagenicity seen in the available studies. → decreased level of concern
3.6.2.2.7.	A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g. for benzidine congener dyes.	As the substance GaAs (fine dust) itself was tested for carcinogenicity there is no need to use data for read across from other substances.
3.6.2.2.8.	The classification shall take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumours at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.	Only local tumors at the site of exposure (lung). No acute toxicity of GaAs after oral and dermal application. The lowest exposure with 0.1 mg/m3 caused pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation in a number of animals, although no increased blood levels of total Gallium and total Arsenic were found in comparison to control animals (NTP, 2000). Solubility tests in pure water under oxygen free conditions resulted in 13 µg/L As(III). Assumption: after dermal or oral administration GaAs is not absorbed. Arsenic blood levels of the control animals (male rats) in NTP-Studies (2000) after 2 years were 24 µg/g (mg/kg).
3.6.2.2.9.	It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e. structure activity relationship, is taken into consideration when undertaking classification.	Our knowledge on physico-chemical, toxicokinetic and toxicodynamic properties of the substance GaAs was taken into consideration as well as the available relevant information on chemical analogues. There is no chemical analogues to GaAs.

From the detailed evaluation of the available reliable data in comparison with the criteria set out in the CLP-regulation (see table above and section discussion) it is concluded that GaAs dust and of course GaAs in its solid massive form (and GaAs wafers) do not need to be classified with regard to carcinogenicity.

The classification and labelling according to COMMISSION REGULATION (EU) No 944/2013 of 2 October 2013 with regard to carcinogenicity (Carc. 1B, H350) is not supported by the authors of this document (The classification and labelling in COMMISSION REGULATION (EU) No 944/2013 is based on an invalid evaluation process (RAC opinion)). The reasons for non classification are stated in the justification above.

Additional information

With a dust of GaAs there are 2 carcinogenicity studies with full reliability available (NTP, 2000).

Exposure in these studies was whole-body 6h/d, 5d/week for 105 weeks to a dust of GaA with median mass aerodynamic particle diameters (MMAD) of 0.8 μm in the 0.01 mg/m³ group, 1.0 μm in the 0.10 mg/m³ group and 0.9 μm in the 1.0 mg/m³ group (geometric standard deviation (GSD) 1.9 each).

 

In the 2-year inhalation toxicity studies, there was no evidence of a carcinogenic activity of gallium arsenide in male F344/N rats (exposed to 0.01, 0.1 and 1 mg/m³) and male or female B6C3F1 mice (exposed to 0.1, 0.5 and 1.0 mg/m³).

 

However, an evidence of carcinogenic activity was observed in female F344/N rats based on increased incidences of benign and malignant neoplasms in the lungs (alveolar/bronchiolar adenoma/carcinoma) at exposure concentrations of 0.1 and 1.0 mg/m³, increased incidence of mononuclear cell leukemia at the exposure concentration of 1.0 mg GaAs/m³, and the increased incidence of benign pheochromocytomas at 1.0 mg/m³.

 

Predominant non-neoplastic histopathologic effects were chronic active inflammation, atypical hyperplasia, alveolar epithelial hyperplasia, proteinosis, and alveolar epithelial metaplasia in the lungs. This can be interpreted as sequelae of chronic local irritation of the epithelial lung tissue.

 

In summary the NTP studies (NTP, 2000) with rats and mice revealed that after inhalative exposure to a dust of GaAs a severe local reaction in the lung is triggered. This reaction can be described as pulmonary alveolar proteinosis leading to chronic active inflammation.

The irritating effects of GaAs in the lungs were somehow different in mice and rats, rats were more sensitive than mice to the irritating effects of GaAs in the lung.

The degree of the local changes in the lungs increased with higher exposure concentrations. In the 2 year studies inhalative exposure of 0.01 mg GaAs/m³ to rats caused the same effects as inhalative exposure of mice to 0.1 mg GaAs/m³.

 

In both studies, in the 2-year rat and in the 2-year mouse study, the animals of the lowest dose group showed weaker effects and a smaller number of animals was affected than in the higher dose groups, nevertheless both studies missed to demonstrate a no-effect level.

 

The occurrence of an increased incidence of alveolar/bronchiolar neoplasms in females (which in this respect were found to be more sensitive than males) can be interpreted as sequel of the lung effects and not as an indication of a primary carcinogenic effect of GaAs.

 

A wide array of chronic inflammatory conditions predisposes susceptible cells to neoplastic transformation and the longer the inflammation persists, the higher the risk of cancer (Federico et al. 2007).

 

The occurrence of mononuclear cell leukaemia in females of the highest concentration has little if any human relevance. This tumor is very strain-specific to the F344/N rat with a high spontaneous variability and has several times been evaluated as not predictive for humans partly because of curious results (Caldwell, 1999; Elwell et al. 1996; Lington et al. 1997).

 

The same holds true for the increased incidence of benign pheochromocytomas in females of the highest concentration (Greim et al. 2009). Interestingly, a correlation between non-neoplastic chronic pulmonary lesions and adrenal pheochromocytoma has been identified in 9 NTP 2-year particulate inhalation studies in male F344/N rats. There were significant associations of pheochromocytomas with the severity of inflammation and fibrosis. Systemic hypoxemia, occurring in space-occupying lung pathologies such as inflammation reduces the gas exchange area and stimulates catecholamine secretion from the adrenal medulla where chronic endocrine hyperactivity may lead to hyperplasia and neoplasms (Osaki et al. 2002).

 

Taking the available results from the NTP study in female F344/N rats with the aforementioned considerations and data together it is concluded that GaAs under the conditions described is not a primary carcinogenic compound. This assumption is supported by the lack of genotoxicity of GaAs in various test systems (Ames, HPRT, MNT in vitro; MNT in vivo) and the lack of carcinogenic effects in male rats as well as in male and female mice.

 

The criteria of CLP, including the specific considerations of 3.6.2.2, for a classification and labelling of carcinogenicity are not fulfilled.

 

According to CLP-guidance page 31: „Classification (and labelling) is based on intrinsic hazards, i.e. the basic properties of a substance as determined in standard tests or by other means to identify hazards.“

As a consequence GaAs in its massive form and therefore also GaAs-wafers do not have to be classified and labelled according to CLP regulation and subsequent regulations.

During production and processing of the blocs dusts can occur containing gallium arsenide particles, which may lead to exposure to aerosols. These particle dusts/aerosols, however, are not part of the registration. The primary target of inhalative exposure to gallium arsenide aerosols at particle sizes (MMAD) of 0.8 – 1.0 μm in the NTP studies was the lung. Due to the long half-life of gallium arsenide particles in the lungs an accumulation of particles occurred and severely affected the lung morphology.

The particle size distribution at the workplace (Weißhaupt, 2011) is fundamentally different from that in the NTP studies (larger particles at the workplace), which may explain that reports on lung effects/tumors in production and processing of the ingots and wafers are absent. The relevance of the results of the NTP studies for humans at the workplace is thus questionable (for a detailed evaluation see Bomhard, 2010a,b).

Inhalative exposure to very fine GaAs-dust causes a specific reaction of the lung of rats and mice: alveolar proteinosis leading to chronic active inflammation after repeated respiration of dust.

In a review article of Bomhard et al. (2013b) the authors came to the conclusion “that there is no evidence for a primary carcinogenic effect of GaAs” after evaluation of the IARC classification of GaAs as carcinogenic to humans (group 1) based on the assumption that As and Ga ions are bioavailable and the conclusion of the ECHA`s Risk Assessment Committee that GaAs should be classified into Carcinogenicity Category 1B (presumed to have carcinogenic potential for humans). The authors stated that alveolar proteinosis followed by chronic active inflammation was the predominant non-neoplastic pulmonary findings.The likely tumorigenic MOA is lung toxicity related to particulate-induced inflammation and increased proliferation (Bomhard et al. 2013b).