Magnesium ethanolate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No data/information is available for the parent compound itself, magnesium ethanolate, concerning fertility. As this compound is unstable in the presence of water (hydrolysis), results obtained with the hydrolysis products, Mg(OH)2 and ethanol, have been taken into account:

 

Ethanol:

All available studies on ethanol use extremely high doses. Some establish NOAELs and are the most useful, whilst others do not establish NOAELs at such very high doses.  Clearly, the most useful studies are those that are closer to guideline (in terms of observations and number of dose levels used) and those that establish true NOAELs at the lowest doses.  Such studies are given greater weight in the overall interpretation of the data for this end point.

 

The most reliable study performed to the most appropriate protocol is a two-generation study that investigated the effects of 5%, 10% and 15% ethanol in drinking water in reproduction and fertility (George et al., 1985). Male and female CD-1 mice were continuously treated for 1 week prior to mating and for a 14 week breeding period followed by a 21 day holding period when they were separated and housed individually. The F1 offspring of the 15% ethanol pairs had fewer live pups per litter but ethanol treatment had no effect on the proportion of breeding pairs producing at least 1 litter during the continuous breeding phase or the number of litters per pair. The F1 offspring from the 15% group had decreased bodyweight at weaning and mating, and a decreased weight of testis, epididymites and seminal vesicles which was no longer evident when these were adjusted for body weight. There was also a significantly decreased percentage of motile sperm but no changes in sperm concentration, and percentage of abnormal sperm or tailless sperm. When reproductive performance of F1 control and 15% ethanol-treated breeding pairs was assessed at 74 days of age, there was no significant difference in mating and fertility between the groups. However, adjusted live pup weight for the ethanol group was significantly reduced compared to controls which was likely due to generalized maternal toxicity.

 

All other available studies are incomplete in comparison to guidelines (usually either single sex treatment or truncated exposures).  However, in total, they provide useful additional information.

 

In a fertility study, male Sprague-Dawley rats were exposed 7 hours per day for six weeks to 10,000 or 16,000ppm ethanol by inhalation and then mated with untreated female rats. Pregnant females received the same experimental treatment from day 1 -19 of gestation and were allowed to deliver their offspring. Treatment with ethanol did not affect the weight gain of parental animals. Incidence of fertility did not differ from controls and no group differences were found for litter size, number of dead pups, or length of pregnancy. Offspring survival and weight gain was also not affected by ethanol treatment.  Adult male rats were kept in a chamber providing 22, 23, 25, or 27 mg/l ethanol air concentrations continuously for a 4 to 5 weeks period. At the end of the exposure period the animals were sacrificed and plasma testosterone levels and sex organ weights for testis, seminal vesicles and prostate were determined. Blood ethanol levels of = 130mg/100ml were compatible with adequate body weight and not associated with diminished plasma testosterone levels or reduced sex organ weights, whereas blood ethanol levels >=180 mg/100ml were associated with inhibition of testosterone secretion only in those animals who failed to grow. No adverse fertility effects were seen at the maximum dose, although weight loss was seen from 25mg/l and above.

 

Male rats were exposed to 6% v/v ethanol containing liquid diet (providing 35% of calories) which was increased to 10% after 1 week (58% of dietary calories), estimated as 7.2 -14.4g/kg/day. After two weeks they were paired with untreated females during the hours of darkness when they had no access to food or drink. The treatment with ethanol for males continued during the hours of light for 5 weeks. All pregnancies were terminated on day 20 of gestation. Ethanol treated animals showed signs of intoxication and weight loss compared to controls from the start of the study, suggesting a LOAEL <6% for such effects. The treatment with ethanol reduced the number of successful matings, litter number, and increased the incidence of early resorptions compared to controls.  

Male rats were administered 2.5 or 5g/kg ethanol daily by gavage for 3 weeks or 9 weeks. Animals in the 2.5 g/kg and control groups were pair fed to those in the 5 g/kg group. Males were bred once after 3 weeks of treatment and twice after 9 weeks of treatment. Females in the first two breedings were sacrificed on day 20 of gestation and their offspring examined. Females in the third breeding were allowed to deliver their litters. There were no apparent treatment effects on resorptions or litter size. Fecundity was reduced in females bred to the high dose ethanol-treated males when all breedings were pooled. The number of male fetuses was increased in the high dose ethanol treated group. There was a significant dose related increase in fetal weights at the week 3 and 9 breedings and a significant increase in placental weights at the 9 week breedings. However, there were no treatment related effects on newborns sired by ethanol treated males. The main finding and only finding consistent and repeated across both breedings was an increase in fetal weights of offspring sired by alcohol treated males. It is not clear if this is an adverse toxicological finding.

Male adult rats were given a liquid diet with 36% of the daily calories derived from ethanol (approximately 13.6 g/kg bw/day), an isocaloric control diet, or standard laboratory chow, for 55 days. Reproductive function was assessed in two separate studies, following either natural mating, or with artificially inseminated females. Ethanol treatment impaired sexual behaviour, and only 22% of these rats reached ejaculation (compared with 50 and 70% in isocaloric and lab-chow controls, respectively). Fertility of ethanol-treated animals was significantly reduced, mainly following the natural matings. Ethanol treatment at this dose also significantly reduced serum testosterone levels, daily sperm production, and epididymal sperm count, associated with an acceleration of the sperm transit time in the cauda epididymis, decrease in sperm motility and increase in the percentage of abnormal shaped sperm cells.

 

Male mice were exposed to a nutritionally balanced diet providing 10% or 25% of ethanol-derived calories and mated with untreated females for 4 hours a day sequentially for 7 weeks. No toxic responses were noted in treated males other than decreased bodyweight gain at 25% ethanol-derived calories in diet. Paternal treatment did not affect fertility during the period studied nor litter size, or weight at birth or at weanling.  The 25% dose is equivalent to 21.5g/kg ethanol.  Male mice were treated with a diet containing 5% or 6% ethanol for 10 weeks and 5 weeks, respectively. After treatment with ethanol was completed, animals were hemicastrated (right testis and accessory organs) and were then left in an ethanol-free diet for 10 weeks to determine the recovery of reproductive effects. The treatment with ethanol diet induced a decrease in testicular weight and in seminal vesicle/prostate weight which was reversible at the end of 10 week treatment abstinence. Significant increases in frequencies of germ cell desquamation and of inactive seminiferous tubules were observed and these remained elevated except for the inactive seminiferous tubule levels in the 5% group which returned to control levels. Ethanol treatment affected the quality of spermatogenesis, caudal epididymal sperm content, sperm motility and in vitro fertilization of mouse oocytes but the changes disappeared after following 10 weeks abstinence. Forward progression of sperm was reduced in both treatments but persisted in the 6% group. No NOAEL was established (5% ethanol diet, 166mg% BAL). However, for persistent effects the NOAEL would appear to be close to 5% ethanol diet, which is estimated to be ~14g/kg/day.

 

Twenty-day old female rats were administered 2.5% or 5% ethanol in a liquid diet for period of 50 -55 days during which their oestrous cycle was determined. At the end of the treatment ovaries, uteri and vaginae were excised for histological examination. Ovarian function was suppressed only in the animals that received 5% ethanol as manifested by absence of oestrous cycles, a delay in vaginal opening, the absence of several generations of corpora lutea, inhibition of growth of the uteri and vaginae, and a reduction of ovarian and uterine weights. A NOAEL was established of approximately 8g/kg/day.  Twenty eight-day old female rats were fed a liquid diet providing 36% ethanol-derived calories (5% of a liquid feed) or a pair-fed isocaloric diet for 49 days. This dose is estimated to be in the range 5.4 -11.4g/kg/day. At the end of the exposure period the animals were sacrificed and the uterus, fallopian tubes, ovaries, cervix, vagina and liver were macro- and microscopically examined. Ethanol-treated animals experienced a reduced weight gain compared to controls whilst their livers were larger and of fatty appearance. Serum liver enzymes, alkaline phosphatase, glutamic oxalo-acetic-acid-transaminase, glutamic pyruvic transaminase and gamma glutamyl transpeptidase were significantly increased compared with controls. Ethanol treatment reduced the weight of the ovaries, uterus and fallopian tubes compared with pair-fed isocaloric control group. Histological examination revealed differences in the appearance of uterus, cervix and vagina between treated and untreated animals, and absence of developing follicles, corpus lutea and corpus hemorrhagica in the ovaries of the treated animals. Compared with isocaloric controls, plasma estradiol and progesterone were reduced in ethanol-treated animals, whereas significantly higher plasma estrone levels were observed.  Female rats were fed 5% ethanol in a liquid diet for 16 weeks, or for 8 weeks followed by laboratory chow and water for another 8 weeks. (Doses equivalent to 14 -21g/day and estimated to produce average serum ethanol levels of around 250mg%). Pair-fed controls and ad libitum fed controls were also included in the study. Vaginal patency was significantly delayed in the ethanol groups and irregular and longer oestrous cycles were noted in the 16-week ethanol treated group. After 16 week treatment females were mated with untreated males and their ethanol exposure was stopped till they delivered their litter. No adverse effect on fertility, litter size or neonatal bodyweight was detected.

 

Magnesium hydroxide

In a combined repeated dose reproductive toxicity screening tests according to OECD No. 422 and GLP no effects on male and female rat fertility were observed up to the highest dose tested of 1000 mg/kg bw/day for magnesium hydroxide. In addition the absence of effects of magnesium ions on the reproductive organs of males and females was also reported in 90-day dietary studies in rats and mice with magnesium chloride hexahydrate up to the highest dose levels tested (11400 mg/kg bw for males and 13830 mg/kg bw for females in mice; corresponding dose of magnesium hydroxide to 1856 mg/kg b day and 2251 mg/kg bw/day; 1600 mg/kg bw of test substance for male rats and 1531 mg/kg test substance for female rats corresponding to a Mg(OH)2dose of 261 mg/kg bw/d and 249 mg/kg bw/day for males and females respectively) and in a 92-week dietary carcinogenicity study with magnesium chloride hexahydrate up to the highest dose of2810 mg/kg bw per day in males and 3930 mg/kg bw in females corresponding to 457 and 640 mg magnesium hydroxide/kg bw/day. It can be concluded that the weight of evidence of existing studies indicates that magnesium hydroxide is unlikely to exert effects on male or female fertility at dose levels not causing other systemic effects. Further testing for toxicity to reproduction is therefore not proposed also taking into consideration animal protection aspects.

Effects on embryo-fetal development

In a combined repeated dose reproductive toxicity screening tests according to OECD No. 422 and GLP no effects on embryo or fetal development parameters were observed up to the highest dose tested of 1000 mg/kg bw/d of magnesium hydroxide. No toxicologically relevant changes were noted in any of the parental parameters investigated (i. e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). Additionally a developmental toxicity study was reported in the literature with the structural analogue magnesium chloride hexahydrate administered by oral gavage to pregnant Wistar rats. No maternal toxicity and no developmental toxicity was observed in this study. The NOAEL was greater than the highest dose tested of 800 mg/kg bw of test substance per day (corresponding to 130 mg/kg/day of magnesium hydroxide).

In an additional supporting study, the effects of Magnesium sulphate on fetal rats after repeated intravenous administrations was investigated. The findings from these study showed that Magnesium sulphate did not have an adverse effect on fetal body weight, size and brain development.

Experience with therapeutic use of magnesium sulphate infusions as tocolytic agent in pregnant women showed no negative effect on newborn infants and their development at dose levels that do not lead to maternal effects and do not lead to a clinically significant imbalance of the Ca2+/Mg2+ratio.

 

 

Short description of key information: 

Ethanol data Mouse (fertility unless stated): NOAEL 13.8g/kg (pups/litter, sperm effects in F1 generation) - NOAEL: 21.5g/kg (F1 male, other effects) - NOAEL (male)>6g/kg - LOAEL (male) ~14g/kg/day Rat (fertility unless stated) - NOAEC: >16000ppm (male and female), >16000ppm (male only), >14000ppm (male only) 12000ppm (males, weight gain) - LOAEL: 7.2-14.4g/kg (fertility, weight loss), 7.2g/kg (intoxication) - NOAEL: (female) 8g/kg - LOAEL female <5.4-11.4g/kg depending on method of estimation. - NOAEL: (male)>5g/kg: (female, fecundity): 2.5g/kg NOEL F1 (based on weight increase of fetus): <2.5g/kg - NOAEL: (male)<13.8g/kg Based on Blood ethanol concentrations for rat and fertility end point: - NOAEL (male)= 127, 248, 338 mg/100ml BAC - LOAEL (male) = 163 mg/100ml BAC; 166 (close to NOAEL) - Rat female parental NOAEL <14-21g/kg/day, NOAEL F1=14-21g/kg/day - LOAEL (female) = 110, 249, 250 mg/100ml BAC - NOAEL (female rat fertility) = 155+/-9 mg/100ml BAC - NOAEL (female rat fertility) < 110+/-9 mg/100ml BAC - NOAEL (female rat fertility) <249mg/100ml (oestrus cycle disturbance)

 

Ethanol data on teratogenicity:

NOAEC (inhalation, rat) maternal toxicity 16000ppm, teratogenicity >20000ppm NOAEL (oral diet or drinking water, mouse) maternal toxicity ~13.7, <12, 16 g/kg, <23.7g/kg; teratogenicity 13.7, <12, 16, >23.7g/kg respectively NOAEL (oral, gavage, mouse): maternal toxicity 2.2g/kg, embryotoxicity >3.6g/kg, teratogenicity >6400g/kg NOAEL (oral, drinking water, rat): maternal toxicity <6.7g/kg, fetotoxicity <5.7g/kg, teratogenicity >6.7g/kg NOAEL (oral, drinking water, rabbit): maternal toxicity <14.2g/kg, teratogenicity >14.2g/kg NOAEL (oral, liquid diet, rat): maternal toxicity 8.2g/kg, developmental toxicity =5.2g/kg

 

Magnesium hydroxide – NOAEL (male/female rats)= 1000mg/kg/bw

 

No developmental toxicity was observed in a repeated dose reproduction screening test up to the highest dose of 1000 mg/kg bw/day for magnesium hydroxide. A developmental toxicity study with Magnesium chloride at dose levels that just did not lead to maternal toxicity (as concluded from a dose range finding study) did not show any test substance developmental toxicity. A limited study with magnesium sulphate after i.v. administration to rats corroborates the absence of developmental effects. Taken together the available evidence suggests that magnesium hydroxide is unlikely to be a developmental toxicant and no further studies are warranted for this endpoint. 

 

Justification for selection of Effect on fertility via oral route: 

Because magnesium ethanolate reacts rapidly with water and gastric fluid under formation of magnesium hydroxide (together with gastric HCl to magnesium chloride) and ethanol it is not considered to be useful to derive a NAOEL for magnesium ethanolate. Based on this fact all physiological effect concentrations are a function of the bioavailable amounts and the relative toxic potential of the hydrolytic products (ethanol and magnesium hydroxide). Magnesium hydroxide and magnesium chloride show high tolerance following oral ingestion.

 

Justification for selection of Effect on fertility via inhalation route: 

As magnesium ethanolate is very likely to instantaneously react with the humidity of the nasal cavity and the thoracic tract under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEC for magnesium ethanolate. 

 

Justification for selection of Effect on fertility via dermal route: 

As magnesium ethanolate is a granular powder and reacts with perspiration or air moisture under formation of magnesium hydroxide and ethanol it is not considered to be useful to derive a NOAEL for magnesium ethanolate. Based on provided information about the hydrolysis products the amount of dermal resorption is negligible to achieve significant concentrations for effects on fertility. Therefore, no study was chosen to derive a NOAEL.

Effects on developmental toxicity

Description of key information

Ethanol data:
NOAEC (inhalation, rat) maternal toxicity 16000ppm, teratogenicity >20000ppm
NOAEL (oral diet or drinking water, mouse) maternal toxicity ~13.7, <12, 16 g/kg, <23.7g/kg; teratogenicity 13.7, <12, 16, >23.7g/kg respectively
NOAEL (oral, gavage, mouse): maternal toxicity 2.2g/kg, embryotoxicity >3.6g/kg, teratogenicity >6400g/kg
NOAEL (oral, drinking water, rat): maternal toxicity <6.7g/kg, fetotoxicity <5.7g/kg, teratogenicity >6.7g/kg
NOAEL (oral, drinking water, rabbit): maternal toxicity <14.2g/kg, teratogenicity >14.2g/kg
NOAEL (oral, liquid diet, rat): maternal toxicity 8.2g/kg, developmental toxicity =5.2g/kg

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No data/information is available for the parent compound itself, magnesium ethanolate, regarding intrauterine development.

As this compound is unstable in the presence of water (hydrolysis), results obtained with the hydrolysis products, Mg(OH)2 and ethanol, have been taken into account.

Ethanol:

Pregnant female rats were exposed to ethanol by inhalation at concentrations of 10000, 16000, or 20000ppm in a chamber for 7 hours per day on gestation days 1 -19. On day 20 the animals were euthanized and their fetuses examined. There was no definite increase in malformations at any level of ethanol exposure, although the incidence in the 20000ppm group was of borderline significance. There was clear maternal toxicity evident at the highest dose (narcosis, food intake reduction).  A NOAEL for maternal toxicity of 16,000ppm was established (30,400mg/m3 ethanol, 58,6000mg/m3 ethyl acetate equivalent theoretical concentration) and a NOAEL for teratogenicity of 20,000ppm (38,000mg/m3 ethanol) was established.

 

Pregnant female mice were exposed to ethanol at 2200, 3600, 5000, 6400 and 7800 mg/kg/day by gavage from day 8 to 14 of gestation. Dams were sacrificed on day 18 and the content of the uterus and litters examined. Maternal mice treated at concentrations of 3600mg/kg ethanol and higher were lethargic and showed staggered gait and/or laboured breathing. Lethality in maternal animals increased dose dependently from 3600 mg/kg up to the highest dose group resulting in the death of all animals. At 5000 mg/kg, resorption of litters was increased, and live fetuses/litters were decreased. This was not apparent in the one litter at 6400 mg/kg. No other fetal effects were seen.  This study determined a NOAEL of 3600mg/kg ethanol (equivalent to 6900mg/kg for ethyl acetate) for embryotoxicity and 2200mg/kg for maternal toxicity.  No teratogenic effects were seen even at the highest dose tested.

Pregnant mice were fed a liquid diet containing 17%, 25%, or 30% ethanol-derived calories from day 4 to day 9 of gestation. Dams were sacrificed on day 18 of gestation. Ethanol treatment in dams did not induce any increase in mortality or change in weight gain with respect to controls. The incidence of fetal resorptions and congenital malformations increased in a dose-related manner with significant effects in the groups treated with 25% and 30% ethanol-derived calorie diets, but no significant adverse effects were seen in the low dose group (estimated daily dose ~13-14g/day).

 

Female CBA and CH3 mice were exposed to liquid ethanol diet providing between 15%, and 25% ethanol derived calories for a period of at least 30 days before mating untreated males, and throughout gestation. Females were killed on day 18 of gestation and offspring examined for skeletal and soft tissue abnormalities. The CBA mice were more sensitive: at 15% and higher doses an increase in resorptions and significant number of abnormalities were noted.  However, the high doses used in this study and the fact that no NOAEL was established makes it of limited use in predicting the effects from non-oral consumption of ethanol.

Pregnant rats were exposed to 15% ethanol in drinking water from day 6 through 15 of gestation. Animals were sacrificed on day 21 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. Mean consumption of food and liquid by rats given ethanol was significantly less than that of control rats during the experimental period. As a result, mean gain in body weight of the exposed rats was also significantly less between days 6 and 16 of gestation. Ethanol ingestion did not affect fetal survival adversely but mean fetal body weight was significantly less than that of the control litters. No malformed fetuses were found in the experimental litters. Some skeletal variants consisting of unfused bones of the skull and cervical vertebra with missing centra occurred in the ethanol litters at an incidence significantly greater than in the control litters. It was suggested this was an expected manifestation of the decreased fetal body weight observed.

 

Pregnant female CD-1 mice were exposed to 15% ethanol in drinking water from day 6 through 15 of gestation. Animals were sacrificed on day 18 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. Maternal body weight gain reflected the decreased consumption of food and liquid in ethanol treated mice. The incidence of exencephaly, open eye, and cleft palate did not differ significantly from control values. Skeletal malformations were not detected but the incidence of several minor skeletal variants e.g. delayed ossification of the centra of cervical vertebra, non-fused sternebrae and delayed ossification of sternebrae was significantly increased among the litters of mice ingesting ethanol. It was suggested that this increase was an expected manifestation of the decreased fetal body weight observed.

 

Pregnant female New Zealand rabbits were exposed to 15% ethanol in drinking water from day 6 through 18 of gestation. Animals were sacrificed on day 29 of gestation and their litters examined for resorption, number, vitality, weight, size, sex, cleft palate and external alterations of fetuses. There was an increase in resorptions, primarily due to the complete resorption of two litters in the ethanol group which was attributed to the reduction of liquid intake and loss of weight observed in this group. Fetal body measurements and the number of malformed fetuses were comparable between the control and experimental litters.

 

Groups of female Sprague-Dawley rats were given liquid diets with 15, 25, or 36% ethanol-derived calories, or without ethanol (pair-fed isocaloric or ad libitum control) for 3 weeks prior to mating, and throughout 21 days of gestation. Prenatal ethanol exposure at 36% ethanol-derived calories (E36, about 10.4 g ethanol/kg bw/day) decreased fetal body weight and length, and skeletal ossification, compared with pair-fed (PF36) and ad libitum controls at GD21. Significant effects on ossification, but not body weight or length, were seen at E25 (corresponding to a dose of about 8.2 g ethanol/kg bw/day), compared to PF25 isocaloric controls. No significant effects on fetal growth or ossification were seen in the E15 group (a dose of about 5.2 g ethanol/kg bw/day from 3 weeks prior to mating to GD 21) compared to the PF15 isocaloric controls. A delay in the development of body weight and skeletal ossification was seen in the ethanol-treated (E25 and E36) fetuses on GD21, compared to the ab libitum controls.

 

Ethanol clearly can cause developmental toxicity.  However, the doses required to cause such effects in animals are exceeding high compared to doses normally used to assess the hazards of chemical substances.  Such doses are clearly also associated with maternal toxicity and are likely to cause significant disturbance of homeostasis, e.g. through nutritional effects.  In addition, the blood ethanol concentrations required to cause adverse developmental consequences, known as 'foetal alcohol syndrome' in humans, have been found to be in the range commonly found in alcoholics (150-200 mg/100 ml) and higher (350-800 mg/100 ml). Adverse effects similar to those reported for humans have been induced in rats by large doses of ethanol that result in similar blood ethanol concentrations. However, inhalation exposure of up to 20,000 ppm ethanol did not cause fertility, developmental or neurotoxic effects. Blood ethanol concentrations following the 0, 10,000, 16,000 and 20,000 ppm ethanol inhalation exposures were 0, 3, 50 and 180 mg/100 ml respectively.

 

Magnesium hydroxide

 

Effects on embryo-fetal development:

In a combined repeated dose reproductive toxicity screening tests according to OECD No. 422 and GLP no effects on embryo or fetal development parameters were observed up to the highest dose tested of 1000 mg/kg bw/d of magnesium hydroxide. No toxicologically relevant changes were noted in any of the parental parameters investigated (i. e. clinical appearance, functional observations, body weight, food consumption, clinical laboratory investigations, macroscopic examination, organ weights, and microscopic examination). Additionally, a developmental toxicity study was reported in the literature with the structural analogue magnesium chloride hexahydrate administered by oral gavage to pregnant Wistar rats. No maternal toxicity and no developmental toxicity were observed in this study. The NOAEL was greater than the highest dose tested of 800 mg/kg bw of test substance per day (corresponding to 130 mg/kg/day of magnesium hydroxide).

 

Justification for selection of Effect on developmental toxicity: via oral route: 

Because magnesium ethanolate reacts rapidly with water and gastric fluid under formation of magnesium hydroxide (together with gastric HCl to magnesium chloride) and ethanol it is not considered to be useful to derive a NAOEL for magnesium ethanolate. Based on this fact all physiological effect concentrations are a function of the bioavailable amounts of the hydrolytic products (ethanol and magnesium hydroxide). 

Justification for selection of Effect on developmental toxicity: via inhalation route: 

Because magnesium ethanolate reacts with water and lung fluid under formation of magnesium hydroxide and ethanol it is not considered to be useful to derive a NAOEC for magnesium ethanolate.

 

Justification for selection of Effect on developmental toxicity: via dermal route: 

Because magnesium ethanolate reacts with perspiration or air moisture under formation of magnesium hydroxide and ethanol it is not considered to be useful to derive a NAOEL for magnesium ethanolate. Based on this, the amount of dermal resorption is negligible to achieve significant concentrations for effects on developmental toxicity

Justification for classification or non-classification

Ethanol

Overall, it can be concluded that adverse effects from the effects of ethanol treatment are only seen at very high doses only relevant to deliberate and repeated oral consumption of ethanol.  The most important studies are the 2-generation study which shows a NOAEL of 13.8g/kg and the inhalation studies that show a NOAEC of 16000ppm (the maximum tested exposure, which is close to or exceeding 50% of the lower explosive limit.)  On this basis, it can be concluded that it is impossible to reach the doses of magnesium ethanolate required to produce any sort of adverse reproductive response other than by repeated oral consumption of large amounts of magnesium ethanolate, doses normally only associated with problem ethanol drinking, and therefore classification for reproductive or developmental toxicity in the context of a chemical substance is not appropriate or warranted. 

 

Magnesium hydroxide

The weight of evidence from a repeated dose reproduction screening study reproduction toxicity study carried out on magnesium hydroxide that yielded an NOAEL of 1000 mg/kg bw/day, the results of several repeated dose studies of 90-day and longer duration with magnesium chloride and developmental toxicity tests with magnesium chloride and sulphate, all indicating no effects on reproductive endpoints up to the highest dose tested and human experience from medical uses suggests that no classification for  any of the hazard categories for reproductive toxicants contained in Regulation (EC) No. 1272/2008 is warranted. Therefore, it can be concluded that Magnesium hydroxide is not classified as a reproductive toxicant.