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Effects on fertility

Effect on fertility: via inhalation route
Dose descriptor:
NOAEC
1 mg/m³
Additional information
Potential effects on male and female rat and mice fertility were evaluated in the context of 14 -week inhalation toxicity studies (NTP, 2000) by examination of male sperm parameters, histopathology of reproductive organs and vaginal cytology.

Two further studies with intratracheal instillation of GaAs to male hamsters and male rats are not sufficiently reliable and therefore ignored.

In a study of Morrissey et al. 1987, developmental toxicity of intratracheally instilled GaAs was investigated in rats. No maternal effects and developmental effects up do a dose of 200 mg/kg GaAs have been observed. However, the study is available as meeting abstract only and reliability could not be evaluated. The study was considered as not assignable.

Exposure in the 2 reliable studies was whole-body 6h/d, 5d/week for 14 weeks to aerosols with median mass aerodynamic particle diameters (MMAD 0.8 - 1.0 µm). For the evaluation of potential effect on fertility male and female rats and mice were treated with concentrations of 0, 10, 37 and 75 mg/m³ gallium arsenide.

There was no effect of exposure on the estrous cycles of female rats or mice.

Rats:

Testicular atrophy and epididymal hypospermia were abserved in all males exposed to 37 or 75 mg/m³. Atrophy was generally of minimal severity in the 37 mg/m³ group and of moderate to marked severity in the 75 mg/m³ group. Atrophy consisted of decreased thickness of the germinal epithelium of seminiferous tubules due to variable loss of spermatogonia, spermatids, and spermatozoa. Sertoli cells lined severely affected tubules almost exclusively. Variable numbers of multinucleated syncytial cells were present in atrophic tubules. Epididymal hypospermia was generally of mild severity in the 37 mg/m³ group and of marked severity in the 75 mg/m³ group. Hypospermia consisted of decreased number of spermatozoa and the presence of cellular debris and large nucleated cells within the lumina of the epididymis.

Mice:

The right testis weight of males exposed to 37 or 75 mg/m³ were decreased, and the weights of the left testis, cauda epididymis, and epididymis were decreased in males exposed to 10 mg/m³ or higher. The total spermatid heads per testis and per gram testis, spermatid counts, and motility of epididymal spermatozoa were significantly decreased in males exposed to 37 and 75 mg/m³. The decreases in spermatozoa motilities of males exposed to 37 mg/m³ or greater were almost 100%. The concentrations of epididymal spermatozoa were decreased in all groups exposed to 10 mg/m³ or greater.

In summary:

Based on detailed sperm parameter analysis in rats and mice, the concentration of 10 mg/m³ represents a LOAEC for effects on male fertility in rats and mice. Although detailed examinations were not performed at lower concentration levels in these studies, the lack of effects on testicular weights and histopathology of male reproductive organs at concentrations of 10 mg/m³ and below gives sufficient evidence for a NOAEC to be established at 1 mg/m³.

Testicular effects were only seen at concentrations much higher than the lowest effect level. In the 14-week study testicular effects occurred at 10 mg/m³ or higher concentrations with mice as well as with rats. But these effects only occured in animals whose lungs showed marked inflammation and also had haematological changes like anemia. The time- and concentration-dependent progressive nature of the lung and blood effects together with the bioavailability data on gallium and arsenic lead to the conclusion that the testicular/sperm effects are secondary to hypoxemia resulting from lung damage and blood effects rather than due to a direct chemical effect of gallium or arsenide (Bomhard, E.M., et al. Evaluation of the male reproductive toxicity of gallium arsenide. Regul. Toxicol. Pharmacol. (2012) and Bomhard E. M. and Gelbke H-P. Hypoxaemia affects male reproduction: a case study of how to differentiate between primary and secondary hypoxic testicular toxicity due to chemical exposure. Archives of Toxicology (2013) 87: 1201-1218)).

Short description of key information:
Effects of gallium arsenide on male and female reproductive organs were examined in 14-week inhalation toxicity studies in rats and mice (NTP, 2000).
2 further studies with intratracheal instillation of GaAs to hamsters and rats are not sufficiently reliable and therefore ignored.
Exposure in the reliable studies was whole-body 6h/d, 5d/week for 14 weeks to a GaAs dust with a median mass aerodynamic particle diameter (MMAD) 0.8 - 1.0 µm. Testicular effects were only seen at concentrations much higher than the lowest effect level.

In the 14-week study testicular effects occurred at 10 mg/m³ or higher concentrations with mice as well as with rats. But these effects only occured in animals whose lungs showed marked inflammation and had also haematological changes like anemia and hemolysis. The time- and concentration-dependent progressive nature of the lung and blood effects together with the bioavailability data on gallium and arsenic lead to the conclusion that the testicular/sperm effects are secondary to hypoxemia resulting from lung damage and blood effects rather than due to a direct chemical effect of gallium or arsenide (Bomhard, E.M., et al. Evaluation of the male reproductive toxicity of gallium arsenide. Regul. Toxicol. Pharmacol. (2012) and Bomhard E. M. and Gelbke H-P. Hypoxaemia affects male reproduction: a case study of how to differentiate between primary and secondary hypoxic testicular toxicity due to chemical exposure. Archives of Toxicology (2013) 87: 1201-1218)).

GaAs powder/dust and GaAs in its massive form and therefore also GaAs-wafers do not have to be classified and labelled with regard to reproduction toxicity according to the criteria of the CLP regulation (and of course according to Directive 67/548/EEC) and subsequent regulations.

Effects on developmental toxicity

Description of key information
The potential for gallium arsenide to cause developmental toxicity was assessed in Sprague-Dawley rats and CD-l (Swiss1) mice exposed to 0, 10, 37 or 75 mg/m³, 6 hours/day, 7 days/week. Rats were exposed on days 4 to 19 of gestation (gd) and mice on days 4 to 17 of gestation.
MICE: The two highest exposure concentrations were maternally lethal, and body weights and body weight gains were reduced in survivors. In mice, signs of pulmonary toxicity (dyspnoe and grey, mottled lungs) were seen at and above 37 mg/m³, and minimal pulmonary toxicity was already observed in mice of the 10 mg/m³ group, thus no NOAEC for maternal toxicity was established in mice. Developmental toxicity was evident in all three exposure groups in mice, and became statistically significant at and above 37 mg/m³.
RATS: Developmental toxicity in rats became obvious by increased incidences of concentration-related growth retardation, evidenced as reduced fetal body weight and an increased incidence of skeletal variations at and above 37 mg/m³. There was no evidence of embryotoxicity or frank teratogenicity. The NOAEC for developmental toxicity was 10 mg/m³. No mortality and effects on body weights were seen in rats. In rats signs of pulmonary toxicity (dyspnoe and grey, mottled lungs) were seen at and above 10 mg/m³.
Effect on developmental toxicity: via inhalation route
Dose descriptor:
NOAEC
10 mg/m³
Additional information

In a set of 2 fully reliable developmental toxicity studies, one with rats and one with mice, GaAs was tested for possible teratogenic effects (Mast et al., 1990). Exposure in these studies was whole-body 6h/d, 7d/week weeks to aerosols of 0, 10, 37 or 75 mg/m³ gallium arsenide. The overall average median mass aerodynamic particle diameter (MMAD) of the aerosol was 1.1 µm with a geometric standard deviation ranging beween 2.0 and 2.1.

MICE: The potential for gallium arsenide to cause developmental toxicity was assessed in CD-l (Swiss1) mice exposed on days 4 -17 of gestation (dg).

The two highest exposure concentrations were maternally lethal in mice, and body weights and body weight gains were reduced in survivors. Signs of pulmonary toxicity (dyspnoe and grey, mottled lungs) were seen at and above 37 mg/m³, and minimal pulmonary toxicity was observed in the 10 mg/m³ group, thus no NOAEC for maternal toxicity was established in mice. Developmental toxicity was evident in all three exposure groups in mice, and became statistically significant at and above 37 mg/m³.

RATS:

The potential for gallium arsenide to cause developmental toxicity was assessed in Sprague-Dawley rats exposed on days 4 -19 of gestation (dg).

No mortality and effects on body weights were seen in rats. Signs of pulmonary toxicity (dyspnoe and grey, mottled lungs) were seen at and above 37 mg/m³. Developmental toxicity in rats became obvious by increased incidences of concentration-related growth retardation, evidenced as reduced fetal body weight and an increased incidence of skeletal variations at and above 37 mg/m³. There was no evidence of embryotoxicity or frank teratogenicity. The NOAEC for developmental toxicity was 10 mg/m³.

Pregnant and virgin rats exhibited signs of pulmonary toxicity (dyspnoe and grey, mottled lungs), however, there were no effects on maternal body weight. The maternal NOAEL for inhaled gallium arsenide in rats was at least 10 mg/m³.

For both tests, developmental toxicity in the form of concentration-related growth retardation, evidenced as reduced fetal body weight and an increased incidence of skeletal variations became statistically significant at and above 37 mg/m³. There was no evidence of embryotoxicity or frank teratogenicity. The NOAEL for developmental toxicity was 10 mg/m³ if determined solely on the basis of adverse effects achieving statistical significance.

Reproduction toxicity effects were only seen at concentrations much higher than the lowest effect level. The lowest effect level in the 2-year rat study (NTP, 2000), 0.01 mg GaAs/m³, caused pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation in a considerable number of rats. The lowest effect level in the 2-year mouse study, 0.1 mg GaAs/m³, caused an increased incidence of cellular infiltration in the lung.

In Mast et al. (1990), developmental effects only occurred at exposure concentrations where marked inflammation of the lungs with consecutive haematologic changes such as anemia were seen.

The time- and concentration-dependent progressive nature of the lung and blood effects together with the bioavailability data on gallium and arsenic lead to the conclusion that the developmental effects are secondary to hypoxemia resulting form lung damage rather than due to a direct chemical effect of gallium or arsenide (Bomhard, E.M., et al. Evaluation of the male reproductive toxicity of gallium arsenide. Regul. Toxicol. Pharmacol. (2012) and Bomhard E. M. and Gelbke H-P. Hypoxaemia affects male reproduction: a case study of how to differentiate between primary and secondary hypoxic testicular toxicity due to chemical exposure. Archives of Toxicology (2013) 87: 1201-1218)). As a consequence GaAs powder/dust and GaAs in its massive form and therefore also GaAs-wafers do not have to be classified and labelled with regard to reproduction toxicity according to CLP regulation (and of course according to Directive 67/548/EEC) and subsequent regulations.

Justification for classification or non-classification

From the detailed evaluation of the available reliable data in comparison with the criteria set out in the CLP-regulation (see table below 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 reprotoxicity.

Table: Criteria of CLP Regulation (EC) 1272/2008 and basis for classification for reproductive toxicants in comparison with GaAs data

Categories/ sections in CLP-Regulation Criteria in CLP-Regulation Comment for GaAs (fine dust)
Category 1 Known or presumed human reproductive toxicant Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).
Human data: criteria are not fulfilled.
Animal data: criteria are not fulfilled. See below.
Category 1A Known human reproductive toxicant
The classification of a substance in Category 1A is largely based on evidence from humans.
There is no evidence from humans available.
Category 1B Presumed human reproductive toxicant
The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.
Effects on male fertility were only seen when other toxic effects were present.
The observed adverse effects on fertility are considered to be a secondary non-specific consequence of other toxic effects (exudative chronic

pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation

, see details in section discussion).
CATEGORY 2 Suspected human reproductive toxicant Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring
together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.
Again the following criteria are not fulfilled: „Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.“
Effects are clearly considered as secondary non-specific consequence of other toxic effects (exudative chronic

pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation

, see details in section discussion).
3.7.2.2. Basis of classification
3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances shall not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.
The substance GaAs shall not be classified as a reproductive toxicant because the observed effects on fertility were produced solely as a non-specific secondary consequence of the exudative

pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation

.

Pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation

was observed at much lower concentrations as the concentrations which showed reproduction toxicity.
The intrinsic, specific property to produce an adverse effect on reproduction is not given.
The classification of a substance is derived from the hazard categories in the following order of precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lactation. If a substance meets the criteria for classification into both of the main categories (for example Category 1B for
effects on sexual function and fertility and also Category 2 for development) then both hazard differentiations shall be communicated by the respective hazard statements. Classification in the additional category for effects on or via lactation will be considered irrespective of a classification into Category 1A, Category 1B or Category 2.
not fulfilled.
3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is
important to consider the possible influence of maternal toxicity (see
section 3.7.2.4).
Two reliable studies on embryo toxicity are published. Embryotoxic effects were only seen at dosages showing clear maternal toxicity (

pulmonary alveolar proteinosis leading to pulmonary chronic active inflammation

).
3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A
classification there must be reliable evidence of an adverse effect on
reproduction in humans. Evidence used for classification shall
ideally be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and
due consideration of bias or confounding factors. Less rigorous data from studies in humans shall be supplemented with adequate data
from studies in experimental animals and classification in Category 1B shall be considered.

There is no evidence of an adverse effect on
reproduction in humans from reliable epidemiological data.