Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

There is no information available on the toxicity to reproduction or development of aluminium hydroxide.

In terms of hazard assessment of toxic effects, available data on the toxicity to reproduction/development of other aluminium compounds was taken into account by read-across following a structural analogue approach, since the pathways leading to toxic outcomes are likely to be dominated by the chemistry and biochemistry of the aluminium ion (Al3+) (Krewski et al., 2007;).

A few (five) developmental toxicity studies are available on aluminium hydroxide in mice and rats. In addition, a recent combined one-year developmental and chronic neurotoxicity study with Al-citrate is available (Poirier et al, 2011).

 

Domingo et al. (1989) investigated the embryotoxic and teratogenic potential of Al (OH)3 administered orally to pregnant Swiss mice. Mated female mice (20 animals per group) were administered (oral, gavage) 0, 66.5, 133 or 266 mg Al(OH)3/kg bw/day (equivalent to 23, 46, and 92 mg Al/kg bw/day) from gestation day 6 through 15. Dams were sacrificed on gestation day 18. No sign of maternal toxicity was observed in any group based on changes in maternal weight gain, food consumption and gross signs of abnormalities at post-mortem examination. The number of total implantations, the foetal sex ratio, body weights and lengths of foetuses were not significantly affected at any of the administered doses of aluminium hydroxide. The number of early resorptions/litter was increased in all Al(OH)3 treated groups (3.0 - in the 23 mg Al/kg group, 2.4 - in the 46 mg Al/kg group, and 1.3 – in the 133 mg Al/kg group versus 0.4 in the control group) and the number of live foetuses decreased in all groups (11.1 in the control group, 9.4 in the 23 mg Al/kg group, 9.2 in the 46 mg Al/kg group and 9.8 in the 92 mg Al/kg group) (n = 18-20 litters per group). Observed effects were not considered as treatment related effects as there was no dose-response relationship observed. The Al-treated foetuses did not exhibit any marked differences in external malformations, internal soft-tissue anomalities or skeletal abnormalities compared to the controls. Suggested NOAEL is 266 mg Al/kg (lack of embryo/fetal toxicity or teratogenicity). The authors suggested that the lack of developmental toxicity of Al(OH)3 was likely due to lower gastrointestinal absorption of this compound compared with other forms of aluminium. A Klimisch Score of 2 was assigned to this study.

A similar study was conducted by Gomez et al. (1990) in rats. Aluminium hydroxide was administered by gavage (2 times, daily) to pregnant Sprague-Dawley rats at dose levels of 192 (n = 18 animals per group), 384 (n = 18 animals per group) and 768 (n = 10 animals per group) mg/kg (equivalent to 66.5, 133 and 266 mg Al/kg bw/day, respectively) from day 6 through 15 of gestation. The animals were killed on day 20 of gestation. No adverse effects were reported on animal appearance, behaviour, maternal body weight, or absolute and relative organ weight (uterine, kidney and liver). No differences were observed for haematological and biochemical parameters but detailed results for these outcomes were not provided in the publication. Although not statistically significant, the incidence of early resorptions was higher in all Al(OH)3-treated groups than in the control group (0.4 - in the 46 mg Al/kg group, 1.3 - in the 92 mg Al/kg group, and 0.6 – in the 266 mg Al/kg group versus 0.0 in the control group). Increased post-implantation loss (%) was observed compared to the control group (3.6 - in the 46 mg Al/kg group, 12.5 - in the 92 mg Al/kg group, and 5.0 – in the 266 mg Al/kg group versus 0.6 in the control group).Observed changes were not considered as treatment related effects because no relationship to dose was observed. Increased post-implantation loss (2.2 times compared to the control group) was observed only in the dose 92 mg Al/kg group. Statistically significant decrease in maternal food consumption was not associated with decreased maternal body weight and no dose-response relationship was found. No Al-treatment related effects were observed on critical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight at any dose administered. During foetal examination, no external and visceral anomalities or skeletal malformation was detected. No significant differences in placental concentrations of aluminium were observed between the different groups. A Klimisch Score of 2 was assigned to this study. Suggested NOAEL is 266 mg Al/kg bw/day (lack ofembryo/fetal toxicity or teratogenicity).

The influence of citric acid on the embryonic and/or teratogenic effects of high doses of Al(OH)3 in rats was investigated by Gómez et al. (1991).Three groups of pregnant rats were administered daily doses (gavage) of Al(OH)3 (384 mg/kg bw/day, equal to 133 mg Al/kg bw/day , n = 18), aluminium citrate (1064 mg/kg bw/day, n = 15), or Al(OH)3 (384 mg/kg bw/day, equal to 133 mg Al/kg bw/day) concurrently with citric acid (62 mg/kg bw, n = 18) on gestational days 6 to 15. A control group received distilled water during the same period (n = 17). There were no treatment-related differences oncritical gestational parameters such as numbers of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weightin the group treated with Al(OH)3. No external and visceral abnormalities or skeletal malformation were detected on foetal examination. Maternal and foetal body weights were significantly reduced, the number of foetuses with delayed sternabrae and occipital ossification was significantly increased (p < 0.05), the number of foetuses with absence of xiphoides was increased in the group treated with Al(OH)3 and citric acid as compared to the control group. No significant differences in the number of malformations were detected between any of the groups (authors did not provide the quantitative data). A Klimisch Score of 2 was assigned to this study.

Colomina et al. (1992) evaluated the influence of lactate on developmental toxicity attributed to high doses of Al(OH)3 in mice. Oral (gavage) daily doses of Al(OH)3 (166 mg/kg bw, n = 11), aluminium lactate (627 mg/kg b, n = 10), or Al(OH)3 (166 mg/kg bw) with lactic acid (570 mg/ kg bw, n = 13) were administered to pregnant mice from gestational day 6 to 15.An additional group of mice received lactic acid alone (570 mg/kg bw).A control group (n = 13) received distilled water during the same period.No signs of maternal toxicity (no statistically significant changes in food consumption, maternal body and organ weight) were observed in the dams treated with Al(OH)3. No statistically significant treatment-related differences on critical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight were observedin the Al(OH)3-treated group and no external abnormalities or skeletal malformation were detected on foetal examination. However, aluminium concentrations were significantly higher in the bones of dams, and aluminium was detected in the whole foetus of the Al(OH)3-treated animals. Concurrent administration of Al(OH)3 and lactic acid resulted in significant reductions in maternal weight compared to the control group. In the group given lactate only, aluminium was detected in whole foetuses; however, this was not statistically different from the mean level found in the control group. Aluminium lactate administration resulted in significant decreases in maternal body weight and food consumption, foetal body weight accompanied by increases in the incidence of cleft palate. Delayed ossification was also observed in the aluminium lactate-treated animals. Although not statistically significant, the incidence of skeletal variations was higher in the group concurrently administered Al(OH)3 and lactic acid than in the control group. No other signs of developmental toxicity were detected in the Al(OH)3 and lactic acid group. In the lactiv acid group no changes in maternal body weight were observed during the gestation period although food consumption was significantly decreased in early treatment (GD 6-9, P < 0.05; GD 6-15, P < 0.01) and post- treatment periods (GD15-18, P < 0.05).Additionally increased numbers of dead foetuses and litters with dead foetuses were seen but not significant.An increased number of foetuses with delayed ossification (10/4 vs 0/0 compared to control, P < 0.05) were also observed.A Klimisch Score of 2 was assigned to this study.

In a similar experiment, Colomina et al. (1994) assessed the effect of concurrent ingestion of high doses of Al(OH)3and ascorbic acid on maternal and developmental toxicity in mice.Three groups of pregnant mice were given daily doses (gavage, 2 times daily) of Al(OH)3 (300 mg/kg bw or 103.8 mg Al/kg), ascorbic acid (85 mg/kg bw), or Al(OH)3 concurrent with ascorbic acid (85 mg/kg bw) from gestational day 6 to day 15. A fourth group of animals received distilled water and served as the control group. The animals were killed on gestation day 18. Thenumber of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, and foetal body weightdid not differ between the control and Al(OH)3-treated groups.No external and visceral abnormalities or skeletal malformations were detected on foetal examination. Placenta and kidney concentrations of aluminium were significantly higher in mice receiving Al(OH)3 and Al(OH)3 plus ascorbic acid than in controls.No information was provided on the number of dams and litters in the Al-treated and control groups. A Klimisch Score of 2 was assigned to this study.

In summary, available studies indicate that aluminium hydroxide did not produce neither maternal nor developmental toxicity when it was administered by gavage during the critical period of embryogenesis (GD 6-15) to mice at doses up to 92 mg Al/kg bw/day (Domingo et al., 1989) or to rats at doses up to 266 mg Al/kg bw/day (Gomez et al., 1990). The developmental toxicity of aluminium compounds following the oral route of exposure is highly dependent on the form of aluminium and the presence of organic chelators that influence bioavailability.

For all the studies with aluminium hydroxide, dose administration was by gavage, which would be expected to result in higher blood levels than dietary administration or administration via the drinking water, and very high dosages were used (ca. 200 – 2000x normal human exposure). Part of the reason for using such high dosages was the low solubility and bioavailability of aluminium hydroxide and the limited sensitivity of available analytical methods to determine small changes from endogenous levels of aluminium. However, the achieved dose of aluminium in maternal plasma was not measured in any of the studies reviewed. In the studies with aluminium administered in the diet or drinking water, dosages were generally identified in terms of the target dose, e.g. 1000 µg Al/g diet, without calculation of the actual dose administered based on the food or water consumption. Further, for the majority of the studies, there was no assessment of the background levels of aluminium in the food and water provided for the animals.

These factors generally lead to the conclusion that the dosages used in reproductive toxicity studies to date have been much greater than those that would be encountered in the human consumer or worker situation. In addition, the actual dose administered has usually been under-estimated because background aluminium levels in the diet and drinking water provided for the animals have not been taken into account. 

None of the studies on aluminium hydroxide showed any clear evidence of dose related developmental toxicity despite using daily dose levels up to 2000 fold higher than the normal aluminium levels of intake. Since bioavailability studies have shown that the absorption of aluminium oxide is less than that of aluminium hydroxide, it is unlikely that these would show any evidence of developmental toxicity at similar dose levels (Sullivan, 2010).

A recent combined one-year developmental and chronic neurotoxicity study with Al-citrate (Alberta Research Council Inc, 2010) may be of interest for the evaluation of the neurotoxicity of Aluminium hydroxide, taking into consideration the tenfold lower bioavailability of Al-hydroxide compared to Al-citrate and excluding effects that can likely be related to the salt rather than the cation. The study was conducted according to OECD TG 426 and GLP, and the exposure covered the period from gestation day 6, lactation and up to 1 year of age of the offspring. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions  via drinking water of  3225 mg/Al citrate/ kg bw/day (300 mg Al/kg bw/day); 1075 mg/Al citrate/kg bw/day (100 mg Al/kg bw/day); 322.5 mg/Al citrate/kg bw/day (30 mg Al/kg bw/day). The highest dose was a saturated solution of Al-citrate. Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L, equimolar in citrate to the high dose Al-citrate group) or plain water (control group). The Al citrate and Na-citrate were administered to dams ad libitum via drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at the same levels as their dams. Dams were sacrificed at PND 23. At PND 4  1 male and 1 female pup of each litter  were allocated to 4 testing groups: D23-sacrifice group for pre-weaning observations and D23 neuropathology, D64, D120 and D365 postweaning groups for post weaning observations and neuropathology at the respective days of sacrifice. Endpoints and observations in the dams included water consumption, body weight, morbidity and mortality and a Functional Observational Battery (FOB) (GD 3 and 10, PND 3 and 10). Pups were examined daily for morbidity and mortality. Additional neurobehavioral tests were performed at specified intervals and included, T-maze, Morris water maze, auditory startle, and motor activity. Female pups were monitored from PND26 for vaginal opening, male pups from day 35 for preputial separation. Clinical chemical and haematological analysis was performed for each group on the day of scheduled sacrifice. Al-concentrations were determined in blood, brain, liver, kidney, bone and spinal cord tissues by inductively coupled plasma mass spectrometric analysis. Further metals such as iron, manganese, copper and zinc were also determined. The pathological investigation includes rain weight and neuropathology. Statistical analyses were performed using the SAS software release 9.1. Data collected on dams and pups were analysed separately. All analysis on pups was performed separately for each sex. Statistical significance was declared from P ≤ 0.05.

Results: Dams: Eight high dose dams developed diarrhoea. In the Na-citrate group one dam stopped nursing and the pups were euthanized. No significant differences between mean body weights of dosed animals compared to controls were observed during gestation and lactation. During gestation and lactation low and mid dose group animals consumed considerably more fluid than controls and high dose group animals. This is not considered treatment related as there was no dose response. In all animals the target dose was exceeded during lactation due to the physiologically increased fluid consumption.

Pups: During the pre-weaning phase weights of mean body weights of male and females in the sodium citrate and high dose group were significantly lower than the untreated controls. This suggests a citrate rather than Al-related effect. No differences between treated and control animals were observed in the FOB. No other clearly treatment related effects were observed pre-weaning.

F1-postweaning: General toxicity

No significant differences in body weights throughout the study were observed between low and mid-dose animals sodium-citrate and untreated controls. High dose males had significant lower body weights than controls by PND 84. These animals also had clinical signs. At necropsy urinary tract lesions were observed in the animals of the high dose group, most pronounced in the males, hydronephrosis, uretal dilatation, obstruction and/or presence of calculi. All high dose males were sacrificed on study day 98. The effect is probably due to Al-citrate calculi precipitating in the urinary tract at this high dose level. This effect is related to the citrate salt and cannot be attributed to the Al-ion. Female high dose animals showed similar urinary tract lesions, but with a lower incidence and severity. Urinary tract lesions were also observed in single mid dose males, but also in a few sodium citrate and control animals. Fluid consumption during the study was increased in the sodium citrate and Al-citrate groups (in particular high and mid dose) compared to controls. This is probably due to the high osmolarity of the dosing solutions. However, the consumed dose levels decreased in all dose groups during the study. In the beginning the target dose was considerably exceeded, while versus the end of the study it was considerably below the target dose.  According to the authors the assigned dose levels still remain valid.

Developmental landmarks:

In sodium citrate controls and high dose males and females the number of days to reach preputial separation or vaginal opening was longer than in untreated control animals. This may be related to the lower body weights in these animals at the respective time-point. As the sodium citrate group showed similar retardation this effect cannot be allocated to the aluminium cation.

Neurobehavioral testing

No consistent treatment related effects that could be related to Al-ion exposure were observed in the FOB. No treatment related effects on autonomic or sensimotoric function were observed in the study. A weak association between Al exposure and reduced home cage activity, a very weak association with excitability, some association with neuromuscular performance were reported but according to the authors this may also be related to group differences in body weight, and an association with physiological function and is thus not considered clearly treatment related. No treatment related effect on general motor behavior was observed. No clearly treatment related effect on auditory startle response was observed. There was no evidence of any treatment related effect on learning and memory in the Morris Water Maze test and no clearly treatment related effects in the T-maze test. Hind limb grip strength and to a lesser extend foot splay were reported to be reduced compared to controls in high and mid dose male and female animals, more pronounced in younger than in older  rats. However, the observed effects can be related to the lower body weights of the individual animals undergoing this test. No details on the individual findings and historical control data are available. It can therefore not be concluded with certainty that the observed neuromuscular effects are primary effects of the treatment and attributable to Al3+. The NOAEL was reported based on this effect as 30 mgAl/kg bw in a conservative approach.

Haematology: No clinically significant differences in hematology were observed at the investigation on day 23. In day 64 and 120 females and day 64 males the high dose group showed slight reduction in hematocrit (males only), mean hemoglobin and mean corpuscular cell volume.No such changes were observed in the 364 day group.

Clinical chemistry: while a number of borderline statistically significant changes were observed, such as globuline levels, alkaline phosphatase and glucose in the high dose group little or no biological significance is associated with them. Elevated creatinine and urea levels in Day 64 males are consistent with the renal toxicity observed in these animals.

Organ weights: Brain weights did not differ among the groups, with two exceptions in the day 64 group males brain weights were significantly lower than controls. In the 120 day female high dose group brain weights were also significantly lower than controls. These findings were not reproduced at the other sacrifice times. Brains to body weight ratios were not significantly different and the lower brain weights can be attributed to the body weight.

Pathology: The main pathology findings were the renal lesions with precipitates in the urinary tract and secondary lesions such as hydronephrosis and uretal dilatation   in particular in the high dose group males and to a lesser extend females. Fluid colonic content was also observed in some high dose animals, in particular males. According to the authors the test item clearly precipitated in the urinary tract causing stone formation and blockage and resulted in fluid colonic content. No other macroscopic effects were observed in other organs.

Histopathology: No treatment related histopahological effects were observed in the nervous system at any time point.

Aluminium concentrations in different organs were dose related. Tissue concentrations were highest in blood, and then in decreasing order brainstem, femur, spinal cord, cerebellum, liver cerebral cortex.

A conservative NOAEL of  322 mg Al-citrate/kg bw  corresponding to 30 mg Al/kg bw was derived from this study (with a bioavailability correction this would correspond to ca. 300 mg Al from Al(OH)3).

The most important effects were however related to a precipitation of the citrate in the kidneys and urinary tract and this effect is not related to the Al3+ ion.  The effects on grip strength and foor splay observed can also not be attributed unequivocally to Al-exposure as they may have been secondary to the general toxicity and body weight differences between treated and control animals undergoing this test. Neurobehavioral effects as reported by e.g. Thorne et al., 1986 could not be confirmed in this study.

 

Inhalation Exposure

Overview of Epidemiological and Toxicological Studies

Aluminium metal, aluminium oxide and aluminium hydroxide

Human Studies

The effects of inhaled aluminium metal, aluminium oxide and aluminium hydroxide on reproductive/developmental outcomes have not been investigated directly in epidemiological studies.

Mur et al. (1998) reported a higher birth-rate among 692 French aluminium potroom workers who had always worked as potroom workers than among a control group of 588 male blue-collar workers who were employed in maintenance operations in the same 11 facilities. The control group had never worked in potrooms. Eligibility criteria to enroll in the study included: French nationality (to avoid cultural differences in sexual habits), marriage after entering the company (to ascertain the number of children born after the start of occupational exposure), and a length of employment of at least 1 year in the company, without any major change in the type of activity. The fertility data of the workers were obtained exclusively from the administrative files of the company. Based on the date of birth of the last child (dates of birth for all the children of each couple were not available), the annual birthrates of each couple after the marriage were calculated by dividing the total number of children of the couple by the number of years between the marriage date and the date of birth of the last child. No significant differences were observed between the ‘exposed’ and ‘control’ groups for the average year of marriage, the average age of the workers and of their spouses at the time of marriage, and the length of employment. Potroom workers were heavier smokers compared to the control group. The average number of live births in the potroom group was greater than that in the ‘control’ group; in addition, the average number of live births in both groups of aluminium industry workers was greater than the national average. After 30 years of marriage, the average numbers of live births were 2.63 (61.34) for the ‘control’ group, and 3.11 (61.74) for the ‘exposed’ group (P<0.05), the reference value for the entire French population being 2.28. The standardized birth ratio (SBR) in the control group was 1.04 (95% CI: 0.98 – 1.09) and 1.17 (95% CI: 1.12 – 1.23) in the potroom workers. The birthrate was higher in the exposed than in the unexposed group (birthrate ratio = 1.13; p < 0.001). The aim of this study was to evaluate the potential effects of occupational exposure to heat and static magnetic fields on male fertility. Exposure to aluminium compounds was not assessed. In addition, it was not possible to take into account a range of non-occupational and socio-economic factors that could influence fertility and birth-rate, for example income level, health status of male workers and their wives, and contraceptive practices. A Klimisch Score of 3 was assigned to this study.

 

Prasad et al. (2002) studied reproductive performance in 160 non-smoking aluminium foundry workers. These workers were engaged in melting aluminium ingots and alloying with magnesium and silicon followed by casting, rolling and coiling of aluminium wire, rods and conductors used for power transmission. The age range of the workers was 20 - 50 years and the duration of their employment in the factory ranged from 1 to 14 years. The exposed workers were compared with 150 male workers (control group) matched for age, smoking, drinking and socio-economic status with no occupational exposure to any known physical or chemical agents. Information on age, sex, duration of employment, health, medication, type of marriage (whether affinal or consanguineous), and reproductive history was collected by using a standard questionnaire. The reproductive parameters studied included the number of pregnancies in the workers’ wives, live births, stillbirths, abortions and the number of congenital defects, premature births, and neonatal deaths in their offspring. Air sampling was not undertaken in this study. There was no significant difference in fertility between the exposed and unexposed workers (99.33 versus 99.13, respectively, p < 0.05).There was a significant increase in the percentage of abortions (6.60% vs. 3.79%, compared to the control group, P < 0.05) and a decrease in the percentage of live births (89.28% vs. 93.94%, compared to the control group, P < 0.05) among the workers’ wives and more congenital defects in the offspring of the exposed workers than in the controls (1.03% vs. 0.03%, P < 0.05). Although there was an increase in the percentage of stillbirths and neonatal deaths in the offspring of the exposed, this increase was not statistically significant when compared with controls. No premature births were recorded in either the exposed or the control group. The authors mentioned that workers were exposed to polycyclic aromatic hydrocarbons, fluoride, fume of other metals, burnt gases, heat and static magnetic fields and high temperature. However, possible effects of these other hazardous compounds on male fertility were not assessed. Very limited details were provided on the study design and results. In addition, because of possible exposure to a range of confounding factors, the contribution of aluminium (from the foundry) to the reported adverse reproductive outcomes is unclear. A Klimisch Score of 3 was assigned to this study.

Hovatta et al. (1998) studied semen parameters (concentration, motility and morphology) and concentrations of aluminium, cadmium and lead in spermatozoa and seminal plasma from a group of workers in a refinery and a polyolefin factory (n =27, mean age 34 years, range 27 to 46 years)and a group of sperm bank donor candidates (n = 45, mean age 28 years, range 20 to 45 years).  The authors stated that the factories were located in a rural area of Finland with most of employees residing in the countryside while sperm bank donor candidates came from urban Helsinki. The concentration of aluminium in spermatozoa was lower in the group of employees than in the sperm donor candidates (0.93±0.69 (mean ± s.d. mg/kg) compared with 2.52 ± 4.14 mg/kg; p < 0.05). There was no significant difference between the groups with respect to aluminium content of seminal plasma. A weak but statistically significant inverse relation (Pearson r =-0.28; p<0.01) was observed between aluminium concentrations in the spermatozoa and sperm motility. A marginally significant inverse relationship was observed between sperm morphology and aluminium levels in the spermatozoa of men in the highest quartile of aluminium concentrations. Cadmium and lead levels did not show any statistically significant correlations with sperm parameters. The authors did not provide details of occupational exposures. Although the study provides some evidence for an association between aluminium levels in spermatozoa and sperm parameters, the small study size, the selected nature of the participants, and the lack of adequate characterization of possibly confounding occupational and environmental exposures limit its usefulness for hazard assessment. A Klimisch Score of 3 was assigned to this study.

 

Dawson et al. (1998) compared the levels of lead, cadmium and aluminium in relation to live sperm in semen samples from 64 healthy 21 to 35 year-old men. Spearman’s rank correlation between sperm viability and the semen plasma metal levels showed an inverse relation to aluminium (p < 0.01). The seminal plasma aluminium concentration was significantly higher in those with low sperm viability. Average concentrations were 1.01, 0.59 and 0.18 mg/L in the 18, 26 and 20 subjects with low, medium and high sperm viability, respectively. A Klimisch Score of 3 was assigned to this study.

Sakr et al. (2010) conducted a cross-sectional survey to examine reproductive outcomes in 710 active workers, both men and women, at a North America aluminium smelter. An anonymous questionnaire was developed to obtain information on the workers including age, level of education, occupational history and reproductive history (e.g., the pregnancies the workers had produced).  Participants were asked about the occupation of their partner during all pregnancies, the outcome of each pregnancy (pregnancy term, single live birth, multiple live birth, ectopic, abortion, spontaneous abortion, stillbirth, and molar), medical conditions experienced by mothers during the pregnancy (hypertension, diabetes, pre-eclampsia or eclampsia, thyroid disorder, systemic lupus, or other), age, smoking, and drinking habits. Normal live birth, miscarriage, live birth with congenital abnormally, and premature birth were selected for the analysis. Congenital anomalies were classified as major (an anomaly of surgical or cosmetic consequence) and minor (an anomaly with a little impact on individual well-being) by a nosologist (level of experience of a nosologist not provided) who was blinded to the employment status at the time of each pregnancy. All jobs at the aluminium smelter based on job titles were grouped into 3 categories: production, administration and laboratory. Random personal industrial hygiene samples for total dust, respirable dust, aluminium oxide, aluminium, asbestos, ammonia ,carbon monoxide, metallic and trivalent chromium, coal tar pitch volatiles as BSM, copper, cyanide (as CN), cyclohexane, fluorides (total), fluoride (particulate), fluoride gas (as HF), magnesium, manganese, metal and compounds, methanol, naphthalene, nickel, nickel compounds, RCF, crystalline silica, sulphur dioxide, and EMF were obtained through personal monitoring in the breathing zone of workers outside of any personal protective equipment.

To assess the occurrence of reported pregnancy outcomes among particular job categories, the authors identified reference groups in which all pregnancies had occurred during the pre-employment period (no details available on the selection and exclusion criteria of the reference groups). For each outcome, the proportion of pregnancies occurring during employment among the reference group was compared. The difference in proportions across employment groups was examined using the Chi square test. Logistical regression was used to account for the potential covariates. Data were stratified by gender. For the analysis of miscarriage, the data were stratified into pre-1999 and post-1999 due to increased awareness among workers in 1999 of the adverse pregnancy outcomes. The significance of the results was reported at P value less than 0.05.

The overall participation rate for the survey was 85% (621 of 730 workers); a higher proportion of women participated, 94% (106 of 113 workers) compared with 83% (515 of 617 workers) for men. All men and women who reported one or two pregnancies were included in the analysis (343 men and 76 women). The mean age at the time of the survey was 43.7 ± 6.3 years (mean ± SD) for men and 42.6 ± 7.3 for women. Most of men were involved in production-related jobs (80.5%) and 50% of the women held administrative positions. Most men had high school education (53.9%) whereas the majority of women had a college education (61.8%). Cigarette smoking and drinking were more prevalent before employment for both men and women.

The proportion of miscarriages reported by women and men was significantly lower in the pre-1999 than in the post-1999 period (76/759 or 10.01% vs. 37/160 or 23.13%; P<0.0001, respectively). Female workers had higher proportions of miscarriages than the spouses of male workers (34/184 or 18.48% vs. 79/735 or 10.75%, P=0.004, respectively). Working in the laboratory was significantly associated with the occurrence of congenital anomalies (OR, 7.89, CI 95% = 1.16 - 53.77). In women workers, the relationship between premature birth and most of the potential co-factors was not evaluated due to small number of reported cases (Table 3). For spouses of male workers, year of conception was also significantly associated with increased miscarriage (OR, 2.00, CI 95% = 1.05 to 3.80 for year of conception after 1999 compared to pre-1999 period). Working in a laboratory was associated with increased miscarriage for male workers but the difference in rate was not statistically significant (OR, 2.48, CI 95% = 0.74 to 8.31). For males, work in the production area was significantly associated with premature birth outcomes for their wives (OR, 2.85, CI 95% = 1.25 - 6.49). No statistically significant differences between rates of congenital anomaly in pregnancies fathered by male workers were reported. Overall, the results provide some evidence that both male and female workers of reproductive age and actively employed in the aluminium smelter experienced adverse reproductive outcomes during the period of employment (miscarriages, premature birth outcomes, and congenial abnormality). Prasad et al. (2002) reported increased congenial defects in offspring born to mothers/wives of the Al -exposed male workers employed at the aluminium foundry compared to the control group (P < 0.05); however, reported percentages were small (1.03% versus 0.03%, respectively). Since both female and male workers were exposed to other hazardous substances (burnt gases, SO2, coal-tar pitch volatiles, fluorides, etc.), in the workplace, the possibility that co-exposures to other toxicants resulted in the adverse effects cannot not be excluded. Study limitations include lack of data on the socio-economic status of the participants, previous exposure to hazardous substances, habits with regard to, and/or frequency of, use of contraceptive devices, and occurrence of genetic diseases in the families; also, the limited number of participants decreases the significance of reported findings. A Klimisch score 2 was assigned to this study.

Animal Studies

No adequate animal studies regarding the effect of the target aluminium compounds (aluminium metal, aluminium oxide and aluminium hydroxide) on developmental outcomes from exposure via inhalation were located. 

Other aluminium compounds

No histological changes were observed in reproductive organs and tissues (testes/ovaries, prostate/uterus, seminal vesicle) of Fischer 344 rats (male, female/10 animals per group) Hartley guinea pigs (male, females/10 animals per group) exposed by inhalation to 6.1 mg Al/m³ as aluminium chlorhydrate for 6 months, 6 hours per day, 5 days per week (Steinhagen et al., 1978). However, the authors did not examine reproduction function of the Al exposed animals.

Examination of reproductive function in male and female rats exposed by inhalation to 15.6±0.84 mg/m3of aluminium sulphate for 4 months did not reveal gonadotoxic or embryotoxic effects at the end of study (Grekhova et al., 1994).The authors provided only a very brief description of the study design and results which limits its reliability and usefulness for hazard assessment.

 

Oral exposure

It is likely that, once Al3+ has reached systemic circulation, its distribution is independent of the exposure route; therefore data obtained from studies of reproductive effects following oral exposure can be considered for assessment of this hazard following inhalation exposure. A few (five) developmental toxicity studies are available on aluminium hydroxide in mice and rats. For the exposure situations specified for the inhalation route, the most relevant studies are those in which either the target compounds have been administered (Domingo et al., 1989; Gomez et al., 1990; 1991; Colomina et al., 1992; 1994). A brief description of these studies and results is provided in the oral exposure section.

 

Weight of Evidence for Reproductive/Developmental Effects in Humans

Epidemiological studies of the effects of oral exposure to aluminium or its compounds on reproductive (developmenta) outcomes have not been conducted. The evidence from human studies is insufficient.

It is assumed that the aluminium ion, Al3+, is “the biologically active moiety” once the target substances are absorbed (following inhalation, ingestion or dermal contact)and “…likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion)” (Guidance on Grouping of Chemicals, OECD, 2007)[1].The cumulative weight of evidence based on the extensive database from animal studies examining various effects of soluble aluminium compounds on reproduction is modest. 

No reproductive toxicity studies are available for on the developmental toxicity of aluminium oxide or aluminium metal. Five studies on the developmental toxicity of aluminium hydroxide are available (Domingo et al., 1989; Gomez et al., 1990, 1991; Colomina et al., 1992, 1994). No clear evidence of dose-related developmental toxicity available based on these studies.

The weight of evidence for the association between exposure to aluminium metal, aluminium oxide and aluminium hydroxide and developmental toxicity in humans is limited.

Weight of Evidence for Reproductive Effects in Humans

Epidemiological studies of developmental toxicity associated with inhalation exposure to aluminium oxide, aluminium hydroxide and aluminium metal were not identified. The evidence from human studies is insufficient.

No animal studies were identified that investigated the effects of exposure to the the target aluminium compounds via inhalation on reproductive toxicity (developmental effects). As reproductive toxicity is a systemic effect, results from studies of effects from exposure via the oral route are relevant. Based on the reviewed animal studies, it is concluded that there is at presence no evidence of an association between inhalation exposure to the target aluminium compounds and developmental effects in both males and females.

Short description of key information:

-Beekhuijzen, 2007

[Al chloride (basic), rats, Klimisch Score 2]

NOAEL is > 90 mg Al/kg  (rat, male, female,  lack of  pre-natal and neonatal developmental toxicity)

Effects on developmental toxicity

Description of key information

-Gomez et al.(1990) [Al hydroxide, rat, Klimisch Score 2]

NOAEL is > 266  mg Al/kg ( rat, relevant embryotoxic and teratogenic effects)

Additional information

A few (five) developmental toxicity studies are available on aluminium hydroxide in mice and rats. In addition, a recent combined one-year developmental and chronic neurotoxicity study with Al-citrate is available (Poirier et al, 2011).

Domingo et al. (1989) investigated the embryotoxic and teratogenic potential of Al (OH)3 administered orally to pregnant Swiss mice. Mated female mice (20 animals per group) were administered (oral, gavage) 0, 66.5, 133 or 266 mg Al(OH)3/kg bw/day (equivalent to 23, 46, and 92 mg Al/kg bw/day) from gestation day 6 through 15. Dams were sacrificed on gestation day 18. No sign of maternal toxicity was observed in any group based on changes in maternal weight gain, food consumption and gross signs of abnormalities at post-mortem examination. The number of total implantations, the foetal sex ratio, body weights and lengths of foetuses were not significantly affected at any of the administered doses of aluminium hydroxide. The number of early resorptions/litter was increased in all Al(OH)3 treated groups (3.0 - in the 23 mg Al/kg group, 2.4 - in the 46 mg Al/kg group, and 1.3 – in the 133 mg Al/kg group versus 0.4 in the control group) and the number of live foetuses decreased in all groups (11.1 in the control group, 9.4 in the 23 mg Al/kg group, 9.2 in the 46 mg Al/kg group and 9.8 in the 92 mg Al/kg group) (n = 18-20 litters per group). Observed effects were not considered as treatment related effects as there was no dose-response relationship observed. The Al-treated foetuses did not exhibit any marked differences in external malformations, internal soft-tissue anomalities or skeletal abnormalities compared to the controls. Suggested NOAEL is 266 mg Al/kg (lack of embryo/fetal toxicity or teratogenicity). The authors suggested that the lack of developmental toxicity of Al(OH)3 was likely due to lower gastrointestinal absorption of this compound compared with other forms of aluminium. A Klimisch Score of 2 was assigned to this study.

A similar study was conducted by Gomez et al. (1990) in rats. Aluminium hydroxide was administered by gavage (2 times, daily) to pregnant Sprague-Dawley rats at dose levels of 192 (n = 18 animals per group), 384 (n = 18 animals per group) and 768 (n = 10 animals per group) mg/kg (equivalent to 66.5, 133 and 266 mg Al/kg bw/day, respectively) from day 6 through 15 of gestation. The animals were killed on day 20 of gestation. No adverse effects were reported on animal appearance, behaviour, maternal body weight, or absolute and relative organ weight (uterine, kidney and liver). No differences were observed for haematological and biochemical parameters but detailed results for these outcomes were not provided in the publication. Although not statistically significant, the incidence of early resorptions was higher in all Al(OH)3-treated groups than in the control group (0.4 - in the 46 mg Al/kg group, 1.3 - in the 92 mg Al/kg group, and 0.6 – in the 266 mg Al/kg group versus 0.0 in the control group). Increased post-implantation loss (%) was observed compared to the control group (3.6 - in the 46 mg Al/kg group, 12.5 - in the 92 mg Al/kg group, and 5.0 – in the 266 mg Al/kg group versus 0.6 in the control group).Observed changes were not considered as treatment related effects because no relationship to dose was observed. Increased post-implantation loss (2.2 times compared to the control group) was observed only in the dose 92 mg Al/kg group. Statistically significant decrease in maternal food consumption was not associated with decreased maternal body weight and no dose-response relationship was found. No Al-treatment related effects were observed on critical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight at any dose administered. During foetal examination, no external and visceral anomalities or skeletal malformation was detected. No significant differences in placental concentrations of aluminium were observed between the different groups. A Klimisch Score of 2 was assigned to this study. Suggested NOAEL is 266 mg Al/kg bw/day (lack ofembryo/fetal toxicity or teratogenicity).

The influence of citric acid on the embryonic and/or teratogenic effects of high doses of Al(OH)3 in rats was investigated by Gómez et al. (1991).Three groups of pregnant rats were administered daily doses (gavage) of Al(OH)3 (384 mg/kg bw/day, equal to 133 mg Al/kg bw/day , n = 18), aluminium citrate (1064 mg/kg bw/day, n = 15), or Al(OH)3 (384 mg/kg bw/day, equal to 133 mg Al/kg bw/day) concurrently with citric acid (62 mg/kg bw, n = 18) on gestational days 6 to 15. A control group received distilled water during the same period (n = 17). There were no treatment-related differences oncritical gestational parameters such as numbers of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weightin the group treated with Al(OH)3. No external and visceral abnormalities or skeletal malformation were detected on foetal examination. Maternal and foetal body weights were significantly reduced, the number of foetuses with delayed sternabrae and occipital ossification was significantly increased (p < 0.05), the number of foetuses with absence of xiphoides was increased in the group treated with Al(OH)3 and citric acid as compared to the control group. No significant differences in the number of malformations were detected between any of the groups (authors did not provide the quantitative data). A Klimisch Score of 2 was assigned to this study.

Colomina et al. (1992) evaluated the influence of lactate on developmental toxicity attributed to high doses of Al(OH)3 in mice. Oral (gavage) daily doses of Al(OH)3 (166 mg/kg bw, n = 11), aluminium lactate (627 mg/kg b, n = 10), or Al(OH)3 (166 mg/kg bw) with lactic acid (570 mg/ kg bw, n = 13) were administered to pregnant mice from gestational day 6 to 15.An additional group of mice received lactic acid alone (570 mg/kg bw).A control group (n = 13) received distilled water during the same period.No signs of maternal toxicity (no statistically significant changes in food consumption, maternal body and organ weight) were observed in the dams treated with Al(OH)3. No statistically significant treatment-related differences on critical gestational parameters such as number of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, or foetal body weight were observedin the Al(OH)3-treated group and no external abnormalities or skeletal malformation were detected on foetal examination. However, aluminium concentrations were significantly higher in the bones of dams, and aluminium was detected in the whole foetus of the Al(OH)3-treated animals. Concurrent administration of Al(OH)3 and lactic acid resulted in significant reductions in maternal weight compared to the control group. In the group given lactate only, aluminium was detected in whole foetuses; however, this was not statistically different from the mean level found in the control group. Aluminium lactate administration resulted in significant decreases in maternal body weight and food consumption, foetal body weight accompanied by increases in the incidence of cleft palate. Delayed ossification was also observed in the aluminium lactate-treated animals. Although not statistically significant, the incidence of skeletal variations was higher in the group concurrently administered Al(OH)3 and lactic acid than in the control group. No other signs of developmental toxicity were detected in the Al(OH)3 and lactic acid group. In the lactiv acid group no changes in maternal body weight were observed during the gestation period although food consumption was significantly decreased in early treatment (GD 6-9, P < 0.05; GD 6-15, P < 0.01) and post- treatment periods (GD15-18, P < 0.05).Additionally increased numbers of dead foetuses and litters with dead foetuses were seen but not significant.An increased number of foetuses with delayed ossification (10/4 vs 0/0 compared to control, P < 0.05) were also observed.A Klimisch Score of 2 was assigned to this study.

In a similar experiment, Colomina et al. (1994) assessed the effect of concurrent ingestion of high doses of Al(OH)3and ascorbic acid on maternal and developmental toxicity in mice.Three groups of pregnant mice were given daily doses (gavage, 2 times daily) of Al(OH)3 (300 mg/kg bw or 103.8 mg Al/kg), ascorbic acid (85 mg/kg bw), or Al(OH)3 concurrent with ascorbic acid (85 mg/kg bw) from gestational day 6 to day 15. A fourth group of animals received distilled water and served as the control group. The animals were killed on gestation day 18. Thenumber of litters, corpora lutea, number of total implantations, number of live foetuses, sex ratio, and foetal body weightdid not differ between the control and Al(OH)3-treated groups.No external and visceral abnormalities or skeletal malformations were detected on foetal examination. Placenta and kidney concentrations of aluminium were significantly higher in mice receiving Al(OH)3 and Al(OH)3 plus ascorbic acid than in controls.No information was provided on the number of dams and litters in the Al-treated and control groups. A Klimisch Score of 2 was assigned to this study.

In summary, available studies indicate that aluminium hydroxide did not produce neither maternal nor developmental toxicity when it was administered by gavage during the critical period of embryogenesis (GD 6-15) to mice at doses up to 92 mg Al/kg bw/day (Domingo et al., 1989) or to rats at doses up to 266 mg Al/kg bw/day (Gomez et al., 1990). The developmental toxicity of aluminium compounds following the oral route of exposure is highly dependent on the form of aluminium and the presence of organic chelators that influence bioavailability.

For all the studies with aluminium hydroxide, dose administration was by gavage, which would be expected to result in higher blood levels than dietary administration or administration via the drinking water, and very high dosages were used (ca. 200 – 2000x normal human exposure). Part of the reason for using such high dosages was the low solubility and bioavailability of aluminium hydroxide and the limited sensitivity of available analytical methods to determine small changes from endogenous levels of aluminium. However, the achieved dose of aluminium in maternal plasma was not measured in any of the studies reviewed. In the studies with aluminium administered in the diet or drinking water, dosages were generally identified in terms of the target dose, e.g. 1000 µg Al/g diet, without calculation of the actual dose administered based on the food or water consumption. Further, for the majority of the studies, there was no assessment of the background levels of aluminium in the food and water provided for the animals.

These factors generally lead to the conclusion that the dosages used in reproductive toxicity studies to date have been much greater than those that would be encountered in the human consumer or worker situation. In addition, the actual dose administered has usually been under-estimated because background aluminium levels in the diet and drinking water provided for the animals have not been taken into account. 

None of the studies on aluminium hydroxide showed any clear evidence of dose related developmental toxicity despite using daily dose levels up to 2000 fold higher than the normal aluminium levels of intake. Since bioavailability studies have shown that the absorption of aluminium oxide is less than that of aluminium hydroxide, it is unlikely that these would show any evidence of developmental toxicity at similar dose levels (Sullivan, 2010).

A recent combined one-year developmental and chronic neurotoxicity study with Al-citrate (Alberta Research Council Inc, 2010) may be of interest for the evaluation of the neurotoxicity of Aluminium hydroxide, Aluminium metal, and Aluminium oxide taking into consideration the tenfold lower bioavailability of Aluminium hydroxide, Aluminium metal and Aluminium oxide compared to Al-citrate and excluding effects that can likely be related to the salt rather than the cation. The study was conducted according to OECD TG 426 and GLP, and the exposure covered the period from gestation day 6, lactation and up to 1 year of age of the offspring. Pregnant Sprague-Dawley dams (n=20 per group) were administered aqueous solutions  via drinking water of  3225 mg/Al citrate/ kg bw/day (300 mg Al/kg bw/day); 1075 mg/Al citrate/kg bw/day (100 mg Al/kg bw/day); 322.5 mg/Al citrate/kg bw/day (30 mg Al/kg bw/day). The highest dose was a saturated solution of Al-citrate. Two control groups received either a sodium citrate solution (citrate control with 27.2 g/L, equimolar in citrate to the high dose Al-citrate group) or plain water (control group). The Al citrate and Na-citrate were administered to dams ad libitum via drinking water from gestation day 6 until weaning of offspring. Litter sizes were normalized (4 males and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at the same levels as their dams. Dams were sacrificed at PND 23. At PND 4  1 male and 1 female pup of each litter  were allocated to 4 testing groups: D23-sacrifice group for pre-weaning observations and D23 neuropathology, D64, D120 and D365 postweaning groups for post weaning observations and neuropathology at the respective days of sacrifice. Endpoints and observations in the dams included water consumption, body weight, morbidity and mortality and a Functional Observational Battery (FOB) (GD 3 and 10, PND 3 and 10). Pups were examined daily for morbidity and mortality. Additional neurobehavioral tests were performed at specified intervals and included, T-maze, Morris water maze, auditory startle, and motor activity. Female pups were monitored from PND26 for vaginal opening, male pups from day 35 for preputial separation. Clinical chemical and haematological analysis was performed for each group on the day of scheduled sacrifice. Al-concentrations were determined in blood, brain, liver, kidney, bone and spinal cord tissues by inductively coupled plasma mass spectrometric analysis. Further metals such as iron, manganese, copper and zinc were also determined. The pathological investigation includes rain weight and neuropathology. Statistical analyses were performed using the SAS software release 9.1. Data collected on dams and pups were analysed separately. All analysis on pups was performed separately for each sex. Statistical significance was declared from P ≤ 0.05.

Results: Dams: Eight high dose dams developed diarrhoea. In the Na-citrate group one dam stopped nursing and the pups were euthanized. No significant differences between mean body weights of dosed animals compared to controls were observed during gestation and lactation. During gestation and lactation low and mid dose group animals consumed considerably more fluid than controls and high dose group animals. This is not considered treatment related as there was no dose response. In all animals the target dose was exceeded during lactation due to the physiologically increased fluid consumption.

Pups: During the pre-weaning phase weights of mean body weights of male and females in the sodium citrate and high dose group were significantly lower than the untreated controls. This suggests a citrate rather than Al-related effect. No differences between treated and control animals were observed in the FOB. No other clearly treatment related effects were observed pre-weaning.

F1-postweaning: General toxicity

No significant differences in body weights throughout the study were observed between low and mid-dose animals sodium-citrate and untreated controls. High dose males had significant lower body weights than controls by PND 84. These animals also had clinical signs. At necropsy urinary tract lesions were observed in the animals of the high dose group, most pronounced in the males, hydronephrosis, uretal dilatation, obstruction and/or presence of calculi. All high dose males were sacrificed on study day 98. The effect is probably due to Al-citrate calculi precipitating in the urinary tract at this high dose level. This effect is related to the citrate salt and cannot be attributed to the Al-ion. Female high dose animals showed similar urinary tract lesions, but with a lower incidence and severity. Urinary tract lesions were also observed in single mid dose males, but also in a few sodium citrate and control animals. Fluid consumption during the study was increased in the sodium citrate and Al-citrate groups (in particular high and mid dose) compared to controls. This is probably due to the high osmolarity of the dosing solutions. However, the consumed dose levels decreased in all dose groups during the study. In the beginning the target dose was considerably exceeded, while versus the end of the study it was considerably below the target dose.  According to the authors the assigned dose levels still remain valid.

Developmental landmarks:

In sodium citrate controls and high dose males and females the number of days to reach preputial separation or vaginal opening was longer than in untreated control animals. This may be related to the lower body weights in these animals at the respective time-point. As the sodium citrate group showed similar retardation this effect cannot be allocated to the aluminium cation.

Neurobehavioral testing

No consistent treatment related effects that could be related to Al-ion exposure were observed in the FOB. No treatment related effects on autonomic or sensimotoric function were observed in the study. A weak association between Al exposure and reduced home cage activity, a very weak association with excitability, some association with neuromuscular performance were reported but according to the authors this may also be related to group differences in body weight, and an association with physiological function and is thus not considered clearly treatment related. No treatment related effect on general motor behavior was observed. No clearly treatment related effect on auditory startle response was observed. There was no evidence of any treatment related effect on learning and memory in the Morris Water Maze test and no clearly treatment related effects in the T-maze test. Hind limb grip strength and to a lesser extend foot splay were reported to be reduced compared to controls in high and mid dose male and female animals, more pronounced in younger than in older  rats. However, the observed effects can be related to the lower body weights of the individual animals undergoing this test. No details on the individual findings and historical control data are available. It can therefore not be concluded with certainty that the observed neuromuscular effects are primary effects of the treatment and attributable to Al3+. The NOAEL was reported based on this effect as 30 mgAl/kg bw in a conservative approach.

Haematology: No clinically significant differences in hematology were observed at the investigation on day 23. In day 64 and 120 females and day 64 males the high dose group showed slight reduction in hematocrit (males only), mean hemoglobin and mean corpuscular cell volume.No such changes were observed in the 364 day group.

Clinical chemistry: while a number of borderline statistically significant changes were observed, such as globuline levels, alkaline phosphatase and glucose in the high dose group little or no biological significance is associated with them. Elevated creatinine and urea levels in Day 64 males are consistent with the renal toxicity observed in these animals.

Organ weights: Brain weights did not differ among the groups, with two exceptions in the day 64 group males brain weights were significantly lower than controls. In the 120 day female high dose group brain weights were also significantly lower than controls. These findings were not reproduced at the other sacrifice times. Brains to body weight ratios were not significantly different and the lower brain weights can be attributed to the body weight.

Pathology: The main pathology findings were the renal lesions with precipitates in the urinary tract and secondary lesions such as hydronephrosis and uretal dilatation   in particular in the high dose group males and to a lesser extend females. Fluid colonic content was also observed in some high dose animals, in particular males. According to the authors the test item clearly precipitated in the urinary tract causing stone formation and blockage and resulted in fluid colonic content. No other macroscopic effects were observed in other organs.

Histopathology: No treatment related histopahological effects were observed in the nervous system at any time point.

Aluminium concentrations in different organs were dose related. Tissue concentrations were highest in blood, and then in decreasing order brainstem, femur, spinal cord, cerebellum, liver cerebral cortex.

A conservative NOAEL of  322 mg Al-citrate/kg bw  corresponding to 30 mg Al/kg bw was derived from this study (with a bioavailability correction this would correspond to ca. 300 mg Al from Al(OH)3).

The most important effects were however related to a precipitation of the citrate in the kidneys and urinary tract and this effect is not related to the Al3+ ion.  The effects on grip strength and foor splay observed can also not be attributed unequivocally to Al-exposure as they may have been secondary to the general toxicity and body weight differences between treated and control animals undergoing this test. Neurobehavioral effects as reported by e.g. Thorne et al., 1986 could not be confirmed in this study.

 

Inhalation Exposure

Overview of Epidemiological and Toxicological Studies

Aluminium metal, aluminium oxide and aluminium hydroxide

Human Studies

The effects of inhaled aluminium metal, aluminium oxide and aluminium hydroxide on reproductive/developmental outcomes have not been investigated directly in epidemiological studies.

Mur et al. (1998) reported a higher birth-rate among 692 French aluminium potroom workers who had always worked as potroom workers than among a control group of 588 male blue-collar workers who were employed in maintenance operations in the same 11 facilities. The control group had never worked in potrooms. Eligibility criteria to enroll in the study included: French nationality (to avoid cultural differences in sexual habits), marriage after entering the company (to ascertain the number of children born after the start of occupational exposure), and a length of employment of at least 1 year in the company, without any major change in the type of activity. The fertility data of the workers were obtained exclusively from the administrative files of the company. Based on the date of birth of the last child (dates of birth for all the children of each couple were not available), the annual birthrates of each couple after the marriage were calculated by dividing the total number of children of the couple by the number of years between the marriage date and the date of birth of the last child. No significant differences were observed between the ‘exposed’ and ‘control’ groups for the average year of marriage, the average age of the workers and of their spouses at the time of marriage, and the length of employment. Potroom workers were heavier smokers compared to the control group. The average number of live births in the potroom group was greater than that in the ‘control’ group; in addition, the average number of live births in both groups of aluminium industry workers was greater than the national average. After 30 years of marriage, the average numbers of live births were 2.63 (61.34) for the ‘control’ group, and 3.11 (61.74) for the ‘exposed’ group (P<0.05), the reference value for the entire French population being 2.28. The standardized birth ratio (SBR) in the control group was 1.04 (95% CI: 0.98 – 1.09) and 1.17 (95% CI: 1.12 – 1.23) in the potroom workers. The birthrate was higher in the exposed than in the unexposed group (birthrate ratio = 1.13; p < 0.001). The aim of this study was to evaluate the potential effects of occupational exposure to heat and static magnetic fields on male fertility. Exposure to aluminium compounds was not assessed. In addition, it was not possible to take into account a range of non-occupational and socio-economic factors that could influence fertility and birth-rate, for example income level, health status of male workers and their wives, and contraceptive practices. A Klimisch Score of 3 was assigned to this study.

 

Prasad et al. (2002) studied reproductive performance in 160 non-smoking aluminium foundry workers. These workers were engaged in melting aluminium ingots and alloying with magnesium and silicon followed by casting, rolling and coiling of aluminium wire, rods and conductors used for power transmission. The age range of the workers was 20 - 50 years and the duration of their employment in the factory ranged from 1 to 14 years. The exposed workers were compared with 150 male workers (control group) matched for age, smoking, drinking and socio-economic status with no occupational exposure to any known physical or chemical agents. Information on age, sex, duration of employment, health, medication, type of marriage (whether affinal or consanguineous), and reproductive history was collected by using a standard questionnaire. The reproductive parameters studied included the number of pregnancies in the workers’ wives, live births, stillbirths, abortions and the number of congenital defects, premature births, and neonatal deaths in their offspring. Air sampling was not undertaken in this study. There was no significant difference in fertility between the exposed and unexposed workers (99.33 versus 99.13, respectively, p < 0.05).There was a significant increase in the percentage of abortions (6.60% vs. 3.79%, compared to the control group, P < 0.05) and a decrease in the percentage of live births (89.28% vs. 93.94%, compared to the control group, P < 0.05) among the workers’ wives and more congenital defects in the offspring of the exposed workers than in the controls (1.03% vs. 0.03%, P < 0.05). Although there was an increase in the percentage of stillbirths and neonatal deaths in the offspring of the exposed, this increase was not statistically significant when compared with controls. No premature births were recorded in either the exposed or the control group. The authors mentioned that workers were exposed to polycyclic aromatic hydrocarbons, fluoride, fume of other metals, burnt gases, heat and static magnetic fields and high temperature. However, possible effects of these other hazardous compounds on male fertility were not assessed. Very limited details were provided on the study design and results. In addition, because of possible exposure to a range of confounding factors, the contribution of aluminium (from the foundry) to the reported adverse reproductive outcomes is unclear. A Klimisch Score of 3 was assigned to this study.

Hovatta et al. (1998) studied semen parameters (concentration, motility and morphology) and concentrations of aluminium, cadmium and lead in spermatozoa and seminal plasma from a group of workers in a refinery and a polyolefin factory (n =27, mean age 34 years, range 27 to 46 years)and a group of sperm bank donor candidates (n = 45, mean age 28 years, range 20 to 45 years).  The authors stated that the factories were located in a rural area of Finland with most of employees residing in the countryside while sperm bank donor candidates came from urban Helsinki. The concentration of aluminium in spermatozoa was lower in the group of employees than in the sperm donor candidates (0.93±0.69 (mean ± s.d. mg/kg) compared with 2.52 ± 4.14 mg/kg; p < 0.05). There was no significant difference between the groups with respect to aluminium content of seminal plasma. A weak but statistically significant inverse relation (Pearson r =-0.28; p<0.01) was observed between aluminium concentrations in the spermatozoa and sperm motility. A marginally significant inverse relationship was observed between sperm morphology and aluminium levels in the spermatozoa of men in the highest quartile of aluminium concentrations. Cadmium and lead levels did not show any statistically significant correlations with sperm parameters. The authors did not provide details of occupational exposures. Although the study provides some evidence for an association between aluminium levels in spermatozoa and sperm parameters, the small study size, the selected nature of the participants, and the lack of adequate characterization of possibly confounding occupational and environmental exposures limit its usefulness for hazard assessment. A Klimisch Score of 3 was assigned to this study.

 

Dawson et al. (1998) compared the levels of lead, cadmium and aluminium in relation to live sperm in semen samples from 64 healthy 21 to 35 year-old men. Spearman’s rank correlation between sperm viability and the semen plasma metal levels showed an inverse relation to aluminium (p < 0.01). The seminal plasma aluminium concentration was significantly higher in those with low sperm viability. Average concentrations were 1.01, 0.59 and 0.18 mg/L in the 18, 26 and 20 subjects with low, medium and high sperm viability, respectively. A Klimisch Score of 3 was assigned to this study.

Sakr et al. (2010) conducted a cross-sectional survey to examine reproductive outcomes in 710 active workers, both men and women, at a North America aluminium smelter. An anonymous questionnaire was developed to obtain information on the workers including age, level of education, occupational history and reproductive history (e.g., the pregnancies the workers had produced).  Participants were asked about the occupation of their partner during all pregnancies, the outcome of each pregnancy (pregnancy term, single live birth, multiple live birth, ectopic, abortion, spontaneous abortion, stillbirth, and molar), medical conditions experienced by mothers during the pregnancy (hypertension, diabetes, pre-eclampsia or eclampsia, thyroid disorder, systemic lupus, or other), age, smoking, and drinking habits. Normal live birth, miscarriage, live birth with congenital abnormally, and premature birth were selected for the analysis. Congenital anomalies were classified as major (an anomaly of surgical or cosmetic consequence) and minor (an anomaly with a little impact on individual well-being) by a nosologist (level of experience of a nosologist not provided) who was blinded to the employment status at the time of each pregnancy. All jobs at the aluminium smelter based on job titles were grouped into 3 categories: production, administration and laboratory. Random personal industrial hygiene samples for total dust, respirable dust, aluminium oxide, aluminium, asbestos, ammonia ,carbon monoxide, metallic and trivalent chromium, coal tar pitch volatiles as BSM, copper, cyanide (as CN), cyclohexane, fluorides (total), fluoride (particulate), fluoride gas (as HF), magnesium, manganese, metal and compounds, methanol, naphthalene, nickel, nickel compounds, RCF, crystalline silica, sulphur dioxide, and EMF were obtained through personal monitoring in the breathing zone of workers outside of any personal protective equipment.

To assess the occurrence of reported pregnancy outcomes among particular job categories, the authors identified reference groups in which all pregnancies had occurred during the pre-employment period (no details available on the selection and exclusion criteria of the reference groups). For each outcome, the proportion of pregnancies occurring during employment among the reference group was compared. The difference in proportions across employment groups was examined using the Chi square test. Logistical regression was used to account for the potential covariates. Data were stratified by gender. For the analysis of miscarriage, the data were stratified into pre-1999 and post-1999 due to increased awareness among workers in 1999 of the adverse pregnancy outcomes. The significance of the results was reported at P value less than 0.05.

The overall participation rate for the survey was 85% (621 of 730 workers); a higher proportion of women participated, 94% (106 of 113 workers) compared with 83% (515 of 617 workers) for men. All men and women who reported one or two pregnancies were included in the analysis (343 men and 76 women). The mean age at the time of the survey was 43.7 ± 6.3 years (mean ± SD) for men and 42.6 ± 7.3 for women. Most of men were involved in production-related jobs (80.5%) and 50% of the women held administrative positions. Most men had high school education (53.9%) whereas the majority of women had a college education (61.8%). Cigarette smoking and drinking were more prevalent before employment for both men and women.

The proportion of miscarriages reported by women and men was significantly lower in the pre-1999 than in the post-1999 period (76/759 or 10.01% vs. 37/160 or 23.13%; P<0.0001, respectively). Female workers had higher proportions of miscarriages than the spouses of male workers (34/184 or 18.48% vs. 79/735 or 10.75%, P=0.004, respectively). Working in the laboratory was significantly associated with the occurrence of congenital anomalies (OR, 7.89, CI 95% = 1.16 - 53.77). In women workers, the relationship between premature birth and most of the potential co-factors was not evaluated due to small number of reported cases (Table 3). For spouses of male workers, year of conception was also significantly associated with increased miscarriage (OR, 2.00, CI 95% = 1.05 to 3.80 for year of conception after 1999 compared to pre-1999 period). Working in a laboratory was associated with increased miscarriage for male workers but the difference in rate was not statistically significant (OR, 2.48, CI 95% = 0.74 to 8.31). For males, work in the production area was significantly associated with premature birth outcomes for their wives (OR, 2.85, CI 95% = 1.25 - 6.49). No statistically significant differences between rates of congenital anomaly in pregnancies fathered by male workers were reported. Overall, the results provide some evidence that both male and female workers of reproductive age and actively employed in the aluminium smelter experienced adverse reproductive outcomes during the period of employment (miscarriages, premature birth outcomes, and congenial abnormality). Prasad et al. (2002) reported increased congenial defects in offspring born to mothers/wives of the Al -exposed male workers employed at the aluminium foundry compared to the control group (P < 0.05); however, reported percentages were small (1.03% versus 0.03%, respectively). Since both female and male workers were exposed to other hazardous substances (burnt gases, SO2, coal-tar pitch volatiles, fluorides, etc.), in the workplace, the possibility that co-exposures to other toxicants resulted in the adverse effects cannot not be excluded. Study limitations include lack of data on the socio-economic status of the participants, previous exposure to hazardous substances, habits with regard to, and/or frequency of, use of contraceptive devices, and occurrence of genetic diseases in the families; also, the limited number of participants decreases the significance of reported findings. A Klimisch score 2 was assigned to this study.

Animal Studies

No adequate animal studies regarding the effect of the target aluminium compounds (aluminium metal, aluminium oxide and aluminium hydroxide) on developmental outcomes from exposure via inhalation were located. 

Other aluminium compounds

No histological changes were observed in reproductive organs and tissues (testes/ovaries, prostate/uterus, seminal vesicle) of Fischer 344 rats (male, female/10 animals per group) Hartley guinea pigs (male, females/10 animals per group) exposed by inhalation to 6.1 mg Al/m³ as aluminium chlorhydrate for 6 months, 6 hours per day, 5 days per week (Steinhagen et al., 1978). However, the authors did not examine reproduction function of the Al exposed animals.

Examination of reproductive function in male and female rats exposed by inhalation to 15.6±0.84 mg/m3of aluminium sulphate for 4 months did not reveal gonadotoxic or embryotoxic effects at the end of study (Grekhova et al., 1994).The authors provided only a very brief description of the study design and results which limits its reliability and usefulness for hazard assessment.

 

Oral exposure

It is likely that, once Al3+ has reached systemic circulation, its distribution is independent of the exposure route; therefore data obtained from studies of reproductive effects following oral exposure can be considered for assessment of this hazard following inhalation exposure. A few (five) developmental toxicity studies are available on aluminium hydroxide in mice and rats. For the exposure situations specified for the inhalation route, the most relevant studies are those in which either the target compounds have been administered (Domingo et al., 1989; Gomez et al., 1990; 1991; Colomina et al., 1992; 1994). A brief description of these studies and results is provided in the oral exposure section.

 

Weight of Evidence for Reproductive/Developmental Effects in Humans

Epidemiological studies of the effects of oral exposure to aluminium or its compounds on reproductive (developmenta) outcomes have not been conducted. The evidence from human studies is insufficient.

It is assumed that the aluminium ion, Al3+, is “the biologically active moiety” once the target substances are absorbed (following inhalation, ingestion or dermal contact)and “…likely to be similar or follow a similar pattern as a result of the presence of a common metal ion (or ion complex including a hydrated metal ion)” (Guidance on Grouping of Chemicals, OECD, 2007)[1].The cumulative weight of evidence based on the extensive database from animal studies examining various effects of soluble aluminium compounds on reproduction is modest. 

No reproductive toxicity studies are available for on the developmental toxicity of aluminium oxide or aluminium metal. Five studies on the developmental toxicity of aluminium hydroxide are available (Domingo et al., 1989; Gomez et al., 1990, 1991; Colomina et al., 1992, 1994). No clear evidence of dose-related developmental toxicity available based on these studies.

The weight of evidence for the association between exposure to aluminium metal, aluminium oxide and aluminium hydroxide and developmental toxicity in humans is limited.

Weight of Evidence for Reproductive Effects in Humans

Epidemiological studies of developmental toxicity associated with inhalation exposure to aluminium oxide, aluminium hydroxide and aluminium metal were not identified. The evidence from human studies is insufficient.

No animal studies were identified that investigated the effects of exposure to the target aluminium compounds via inhalation on reproductive toxicity (developmental effects). As reproductive toxicity is a systemic effect, results from studies of effects from exposure via the oral route are relevant. Based on the reviewed animal studies, it is concluded that there is at presence no evidence of an association between inhalation exposure to the target aluminium compounds and developmental effects in both males and females.

 


 

Justification for classification or non-classification

Classification and Labelling

 

According toRegulation (EC) No 1272/2008, classification as a reproductive toxicant is to be based on an assessment of the total weight of evidence.A weight of evidence approach is adopted in this document to identify of hazards to human health. Asubstantial number of studies using different animal models support the association between oral exposure to Al and developmental effects (Krewski et al., 2007; WHO, 2007; EFSA, 2008; ATSDR, 2008; Health Canada, 2010).

Given that a critical factor influencing developmental toxicity is the concentration of the substance at the actual target site (ECHA, 2008, Chapter 7.12, p.148), “the human health hazard assessment shall consider the toxicokinetic profile (i.e. absorption, metabolism, distribution and elimination, ADME) of the substance” (Annex I, Section 1.0.2.). The occurrence and severity of reproductive effects of ingested aluminium compounds are a function of the bioavailability of the Al ion (Domingo, 1995; Golub & Domingo, 1996; Domingo et al., 2000; Krewski et al., 2007; ATSDR, 2008) and bioavailability is therefore relevant assessing the hazards of the target substances.Gastrointestinal absorption of the water soluble forms of aluminium compounds - aluminium nitrate nonanydate, aluminium chloride, and aluminium citrate - has been shown to be considerably higher than that of the sparingly soluble aluminium oxide, aluminium metal and aluminium hydroxide (Priest 2010).

Five reproductive toxicity studies with aluminium hydroxide were conducted with administration of high doses of aluminium hydroxide via the oral route of exposure. Collectively, these studies provide no clear evidenceof treatment-related developmental toxicity following oral exposure to aluminium hydroxide.A weight of evidence assessment based on the available reproductive toxicity studies with aluminium hydroxide does not support Classification and Labelling (EC No.1272/2008) requirements for developmental toxicity following oral exposure to aluminium hydroxide.

No studies on the reproductive toxicity of aluminium metal or aluminium oxide were located. However, the relatively similar aluminium bioavailability of all three targeted compounds (aluminium hydroxide, aluminium oxide and aluminium metal) following oral administration to laboratory animals (Piest, 2010) suggest that the availability of the aluminium ion for systemic effects will be similar for all compounds and aluminium metal and aluminium oxide also have a low potential to cause adverse developmental effects. 

Classification and Labelling for Adverse Health Effects on or via Lactation

In the current REGULATION (EC) No 1272/2008 on Classification and Labelling (page 109), effects on, or via, lactation are allocated to a separate single category; therein it is stated: “…….substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies”.

Classification can be assigned on the basis of:

(a) human evidence indicating a hazard to babies during the lactation period; and/or

(b) results of one or two generation studies in animals which provide clear evidence of adverse effects in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c) absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk (EC, No 1272/2008).

Based on available data, there is evidence to suggest that aluminium absorbed bywomen can interfere with lactation (Yokel, 1984, 1985), and may be present in breast milk in amounts sufficient to cause concern for the healthof a breastfed child. However, currently, no data are available to confidently evaluate the toxicological significance and potential adverse health outcomes of aluminium levels found in breast milk (Krewski et al., 2007, p. 199).  

The magnitude of the contribution to the aluminium in breast milk from REACH-relevant exposures to aluminium metal, aluminium hydroxide or aluminium oxide is likely to be very small.

Overall, Based on the read-across from aluminium compounds for the toxicity to reproduction or development of aluminium hydroxide, no classification is required according to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria.