Sodium ethanolate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

No data/information is available for sodium ethanolate regarding toxicity to reproduction/developmental toxicity.

But data are available for reaction product ethanol.

The most reliable study performed is a two-generation study investigating the effects of 5 %, 10 % and 15 % ethanol in drinking water in reproduction and fertility (Georg et al., 1985). 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 or the number of litters per pair. The F1 offspring from the 15 % group had decreased bodyweight at weaning and mating, and decreased abs. weight of testis, epididymides and seminal vesicles. There was also a significantly decreased percentage motile sperm but no changes in sperm concentration, and percentage of abnormal sperm or tailless sperm. There were no effects on mating and fertility between the groups. Lower live pup weight for the ethanol group was possibly based on maternal toxicity. In summary, no demonstrable effects on fertility were seen and the NOAELs were 15 % for parental animals, 10 % for the F1-generation and < 15 % for the F2-generation.

All other available studies are incomplete in comparison to guidelines. However, in total, they provide useful additional information.

In a fertility study published by Nelson et al. (1988), male Sprague-Dawley rats were exposed 7 hours per day for six weeks to 10,000 or 16,000 ppm 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. No treatment-related effects regarding body weight gain (parents and offspring), fertility, offspring survival, litter size, number of dead pubs, or length of pregnancy could be detected. Blood ethanol levels >=180 mg/100 ml 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 25 mg/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 -14.4 g/kg/day (Klassen and Persaud, 1976). After two weeks, they were paired with untreated females and treatment with ethanol for males continued for 5 weeks. Ethanol treated animals showed signs of intoxication and weight loss compared to controls, leading to a LOAEL of 6 %. The treatment with ethanol reduced the number of successful matings, litter number, and increased the incidence of early resorptions compared to controls.

Abel published a study where male rats were administered 2.5 or 5 g/kg ethanol daily by gavage for 3 weeks or 9 weeks (Abel 1995). Males were bred once after 3 weeks of treatment and twice after 9 weeks of treatment with untreated females. There were no apparent treatment effects on resorptions or litter size. Fecundity was reduced and the number of male fetuses was increased in females bred to the high dose ethanol-treated males. Fetal weights at the week 3 and 9 breedings were increased as well as the placental weights at the 9 week breedings. It is not clear if these changes were an adverse toxicological finding. However, there were no treatment related effects on newborns.

Oliva et al., reported a study where male adult rats were given ethanol as a liquid diet with approximately 13.6 g/kg bw/day for 55 days (Oliva et al., 2006). Ethanol treatment impaired sexual behaviour, and only 22 % of these rats reached ejaculation. 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 21.5 g/kg ethanol (Abel, 1989). 

Male mice were treated with a diet containing 5 % or 6 % ethanol for 10 weeks and 5 weeks, respectively (Anderson et al., 1985). Animals were hemicastrated and then left in an ethanol-free diet for recovery of reproductive effects. Decreases in testicular weight and in seminal vesicle/prostate weight were reversible after 10 weeks of recovery. Increases in frequencies of germ cell desquamation and of inactive seminiferous tubules were observed remaining elevated except for the inactive seminiferous tubule levels in the 5% group which returned to control levels. Effects on the quality of spermatogenesis, caudal epididymal sperm content, sperm motility and in vitro fertilization of mouse oocytes disappeared after recovery period. Forward progression of sperm was reduced in both treatments but persisted in the 6 % group. For persistent effects the NOAEL would be close to 5 % ethanol diet, which is estimated to be ~14 g/kg/day.

Bo et al., (1982) published a study with female rats which received 2.5 % or 5 % ethanol for period of 50-55 days. 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 8 g/kg/day. 

Abel El (1993) reported a fertility study with ethanol. There was no effect on fertility in both, the 3000 and 2000 mg/kg ethanol group. Although fertility was unaffected, this study did reveal higher incidences of runted pups in the resulting offspring, especially at the highest exposure level. The NOAEL for parental animals was > 3000 mg/kg b.w./day and the NOAEL for the F1-generation was 2000 mg/kg b.w./day.

In a study described by Van Thiel in 1976, female rats received 36 % ethanol-derived calories (5 % of a liquid feed) or a pair-fed isocaloric diet for 49 days (equivalent to 5.4 -11.4 g/kg/day). Treatment resulted in a reduced body weight gain, enlarged livers and fatty appearance. Serum liver enzymes, alkaline phosphatase, glutamic oxalo-acetic-acid-transaminase, glutamic pyruvic transaminase and gamma glutamyl transpeptidase were significantly increased compared to controls. Weight of ovaries, uterus and fallopian tubes were reduced. 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 (equivalent to 14 -21 g/day) in a liquid diet for 16 weeks, or for 8 weeks followed by laboratory chow and water for another 8 weeks (Krueger et al., 1982). Vaginal patency was significantly delayed and irregular and longer oestrous cycles were noted. After 16 week treatment, females were mated with untreated males. No adverse effects on fertility, litter size or neonatal body weight were detected.

Abel (1993) published a study where male rats were treated with 2 or 3 g/kg ethanol twice a day by gavage for 9 weeks and paired with untreated females. Paternal alcohol exposure did not influence litter size, average birth weight per pup or postnatal bodyweights in offspring. However, it induced a significant increase in the number of runts in the highest dose group suggesting an influence on individual sperms. No statistically significant findings were detected. 

In a study published by Cebral et al. (2011) morphological sperm and oocyte alterations after sub-acute ethanol intake in mice was evaluated. Applied dose was 10 %, equivalent to 22 -23 g/kg/day. Abnormal sperms (head and tail defects) and elevated parthenogenetic activated oocyte frequency were seen. Effects at such high concentrations are difficult to extrapolate to hazards likely to be present at exposure during use of ethanol in the workplace or from the use of ethanol containing consumer products.

All available studies on ethanol use extremely high doses. In regard to the caustic properties of sodium ethanolate, secondary exposure to ethanol is considered to be low and reproductive and systemic toxicity from ethanol to be absent.

Effects on developmental toxicity

Additional information

No data/information is available for sodium ethanolate regarding developmental toxicity. But data are available for reaction product ethanol.

Simpson et al. (2005) reported a study where groups of female Sprague-Dawley rats received liquid diets with 15, 25, or 36 % ethanol-derived calories for 3 weeks prior to mating, and throughout 21 days of gestation. Prenatal ethanol exposure at 36 % ethanol-derived calories (10.4 g ethanol/kg) decreased fetal body weight. In addition, ethanol induced a statistically significant delay in the ossification of individual bones, particularly at the highest dose group. The radius and scapula showed the greatest delay at the middle and high dose group, followed by the ulna and tibia. Taken together, the data suggest that prenatal ethanol exposure (at 8.2 g/kg bw/day and above), caused a delay in the early development (ossification) of the fetal skeleton (by 0 - 0.5 days). No skeletal malformations or variations were reported.Nelson et al. (1985) reported a teratological assessment of methanol and ethanol at high inhalation levels in rats. The animals received daily concentrations (7 h/d) of 10000, 16000, or 20000 ppm from GD 1 - 19. No definite evidence of malformations due to the ethanol exposure were seen although the incidence of abnormal changes at the highest concentration was of borderline significance. The NOAEC for maternal toxicity was found to be 16000 ppm and the NOAEC for teratogenicity was found to be 20000 ppm.

Randall and Taylor (1979) reported about the prenatal ethanol exposure in mice. The animals were offered concentrations of 17, 25 and 30 % via the diet from GD 5 - 10.  The incidence of fetal resorptions and congenital malformations increased in a dose-related manner. Anomalies included skeletal, neurological, urogenital and cardiovascular systems. These data indicate, that in mice alcohol diet which is adequate in vitamins and protein results in increased fetal wastage and birth defects. The NOAELs found were 17% in the diet for maternal toxicity and teratogenicity.

In a study published by Wier et al. (1987), pregnant mice were exposed to ethanol at 2200, 3600, 5000, 6400 and 7800 mg/kg/day by gavage from GD 8 to 14. Maternal mice treated at concentrations of 3600 mg/kg ethanol and higher were lethargic, showed staggered gait and/or laboured breathing and mortality increased dose dependently from 3600 mg/kg up to the highest dose group. At 5000 mg/kg, resorption of litters was increased and live foetuses/litters were decreased. No other fetal effects were seen. The NOAEL was set at 3600 mg/kg ethanol for embryotoxicity and 2200 mg/kg for maternal toxicity.  No teratogenic effects were seen even at the highest dose tested. In a study published by Schwetz et al. (1978), pregnant rats were exposed to 15 % ethanol in drinking water from GD 6 to 15. Mean food and water consumption was significantly reduced. As a result, reduced body weight gain occurred between GD 6 and 16. Ethanol ingestion did not affect fetal survival but mean fetal body weight was significantly reduced. 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 compared to the control litters. It was suggested to be an expected manifestation of the decreased fetal body weight.

Schwetz et al. (1978) published a study where pregnant CD-1 mice were exposed to 15 % ethanol in drinking water from GD 6 to 15. 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 after ethanol-treatment. It was suggested that this increase was an expected manifestation of the decreased fetal body weight observed.

Schwetz et al. (1978) reported about a study where pregnant New Zealand rabbits received 15 % ethanol in drinking water from GD 6 to 18. 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.

In a study published by Anderson et al. (1981), male mice received 6.3% ethanol in drinking water (providing 32 % ethanol derived calories). Males were mated with untreated females. Pregnancy rates were reduced by ethanol treatment but resorption rates were unaffected. Litter size, weights, and viability were unaffected by ethanol treatment. There was a decrease in male/female ratio in the experimental group. There was no increase in frequency of gross abnormalities resulting from ethanol treatment.

Female CBA and C3H mice were exposed to liquid ethanol diet providing 15 %, 20 %, 25 %, 30 % and/or 35 % ethanol derived calories for a period of at least 30 days before mating untreated males, and throughout gestation (Chernoff 1977a,b). For CBA mice, at 15 % and higher doses, an increase in resorptions and significant number of abnormalities were noted, namely deficient occiput ossification, missing sternebra, rib abnormalities, dilated brain ventricles, open eyelids, heart defects, exencephaly and gastroschisis. In C3H mice, at 25 % and higher doses an increase in resorptions was observed whereas a significant number of the same abnormalities as described in CBA mice were noted at 20 % levels and higher. The high doses used in both studies make it difficult in predicting the effects from non-oral consumption of ethanol.

Ethanol clearly can cause developmental toxicity.  However, the doses required to cause such effects in animals are exceeding highly those concentrations that are 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, due to the caustic properties of sodium ethanolate, a secondary exposure to ethanol is considered to be low and developmental toxicity from ethanol to be absent.

Justification for classification or non-classification

No data/information are available for sodium ethanolate regarding toxicity to reproduction/developmental toxicity. Data are available for reaction product ethanol which gave an indication for developmental toxicity at very high concentrations simultaneously being accompanied by maternal toxicity. In regard to the caustic properties of sodium ethanolate, secondary exposure to ethanol is considered to be low and reproductive toxicity from ethanol to be absent.

For that reason, no classification is proposed.