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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

No data are available on the toxicity to reproduction or development of sodium and potassium methanolates. Methanolates are classified as corrosive to the skin according to Annex I of the Dangerous Substance Directive (67/548/EEC) and according to Annex VI of the CLP regulation (EC 1272/2008). In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided, as pointed out in the introductory sections to Annexes VII-X of the REACH regulation. Furthermore, under normal handling and use conditions human exposure by any route is unlikely or not significant, as the necessary RMM are in place.

The abiotic hydrolysis of sodium and potassium methanolates with tissue water results in the formation of sodium and potassium ions respectively, hydroxide ions and methanol. For hazard assessment of methanolates at potentially non-irritating concentration/dose levels, information on the hydrolysis/dissociation products was taken into account. Thus, considering the hydrolysis/dissociation products as structurally related substances, read-across was conducted following a category approach.

The major health hazard (and the mode of action) of sodium and potassium hydroxides(CAS No. 1310-73-2 and 1310-58-3, respectively) is local irritation and/or corrosion. Both sodium and potassium hydroxides are classified as corrosive to the skin according to Annex I of the Dangerous Substance Directive (67/548/EEC) and according to Annex VI of the CLP regulation (EC 1272/2008). At concentrations between 0.5 and 2%, they are classified as skin and eye irritants. Repeated exposure to Na+or K+ions and OH- ions at non-irritant concentrations is unlikely to produce systemic toxic effects by any route and under normal handling and use conditions (European Commission, 2007; OECD, 2001, 2002). Moreover, sodium hydroxide is not expected to be systemically available under normal handling and use conditions. Therefore, it can be stated that the substance will not reach the foetus nor reach male and female reproductive organs. It can be concluded that a specific study to determine the developmental toxicity or the toxicity to reproduction is not necessary (European Commission, 2007). Similarly, for potassium hydroxide effects in non-irritating doses/concentrations to reproduction or development are not expected (OECD, 2001). Therefore, hazard assessment is mainly focused on the repeated dose toxicity of methanol (CAS No.67-56-1).

No impairment of fertility and reproductive performance was found in male and female rats (parent and daughter generations) exposed to methanol (NEDO, 1987). In a two generation reproduction study, rats were exposed to methanol by inhalation for 19-20 hours/day (NEDO, 1987). No treatment-related alterations in general observations and reproductive parameters were found. None of the fertility indices including sexual cycle, days needed for insemination, insemination rate and pregnancy rate showed statistically significant differences. There were no differences for body weight, food consumption and water consumption during gestation and lactation period, either. No abnormalities were observed in findings on delivery and nursing behaviour and necropsy data of F0 animals. No firm conclusions can be drawn about fertility of either sex, as the copulation time of 21 days was comfortably long for successful insemination and gametogenesis was not considered. In the F1 and F2 progeny (both sexes), no histological changes and no effects on testes or ovaries were reported. However, a decrease in brain weights was evident at 1.3 mg/L methanol, but without noticeable histological changes and functional impairments. This phenomenon is believed to represent a change occurring during the prenatal period (Takeda and Katoh, 1988). However, no quantitative data and statistical level were documented for organ weights. The meaning of an apparent shift of testis descent in male offspring in relation to body weight development of the pups in the two following generations is unclear and was not directly addressed by Takeda and Katoh (1988), but detailed by NEDO (1987) and considered a significant difference from untreated controls. Furthermore, it is obvious that this parameter showed considerable variation also between the control groups of both generations.

Although there was no obvious pathological effect in the progeny of 1.3 mg/L exposed groups, the effects observed may be considered as biologically relevant under these test conditions and, therefore, 1.3 mg/L is established as LOAEC and 0.13 mg/L as NOAEC for post-natal development while for parental effects, the NOAEC is 1.3 mg/L.

In a one generation reproduction study in monkeys (Burbacher et al., 1999), adult female monkeys were exposed to methanol vapour (2.5 hours/day) during prebreeding, breeding and pregnancy. Methanol exposure had no effects on the tested reproductive performance, including menstrual cycles, conception rate, and live-birth delivery rate. However, all methanol-exposed animals had a decrease of about 6 to 8 days in duration of pregnancy compared to control animals. It is not clear whether this decrease in duration of pregnancy was related to methanol exposure. Prenatal exposure to methanol had no effect on infant growth and physical development for the first 9 months. However, results of the study were confounded by the normal variance and the low number of animals. The NOAEC for reproductive effects can be determined to be 2.39 mg/L.

In another study which investigated reproductive effects, there was an insignificant increase in morphological anomalies in spermatozoa in male mice 5 weeks after oral dosing at 1000 mg/kg bw/day for 5 days (Ward et al., 1984).

It is also pointed out that in repeated dose toxicity studies ovarian and testicular tissues have not been adversely affected by methanol administration.

Short description of key information:
Methanolates are classified as corrosive to the skin according to Annex I of the Dangerous Substance Directive (67/548/EEC) and according to Annex VI of the CLP regulation (EC 1272/2008). In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided, as pointed out in the introductory sections to Annexes VII-X of the REACH regulation. Furthermore, under normal handling and use conditions human exposure by any route is unlikely or not significant, as the necessary RMM are in place.
At non-irritant concentration/dose levels, no effects on fertility are expected after exposure to methanolates via any route as indicated by the available information on structurally related substances (hydrolysis/dissociation products: methanol, NaOH or KOH). It is unlikely that exposure to methanolates at non-irritant concentration/dose levels would result in exposure to toxic doses of the hydrolysis/dissociation products, in particular methanol.

Effects on developmental toxicity

Description of key information
Methanolates are classified as corrosive to the skin according to Annex I of the Dangerous Substance Directive (67/548/EEC) and according to Annex VI of the CLP regulation (EC 1272/2008). In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided, as pointed out in the introductory sections to Annexes VII-X of the REACH regulation. Furthermore, under normal handling and use conditions human exposure by any route is unlikely or not significant, as the necessary RMM are in place.
At non-irritant concentration/dose levels, no developmental toxicicty/teratogenicity effects are expected after exposure to methanolates via any route as indicated by the available information on structurally related substances (hydrolysis/dissociation products: methanol, NaOH or KOH). It is unlikely that exposure to methanolates at non-irritant concentration/dose levels would result in exposure to toxic doses of the hydrolysis/dissociation products, in particular methanol.
Additional information

Animal data

Developmental toxicity has been observed in many rodent studies which resulted in a variety of effects in offspring due to prenatal and/or postnatal dosing.

In a developmental study, rats were exposed to 0.27, 1.33, 6.65 mg/L methanol by whole body inhalation from gestation days 7 through 17 for 23 hours/day (NEDO, 1987). In the top dose, maternal toxicity was recorded. In the progeny, there was foetal malformation, increased perinatal mortality and developmental delay. Teratogenic effects occurred only at the maternally toxic exposure concentration. Exposure levels of 1.33 mg/L or less did not induce toxic symptoms in maternal animals, structural abnormalities or delay in growth or functional development in the F1-generation. Therefore, the NOAEC for maternal and developmental toxicity is considered to be 1.33 mg/L.

In a second whole-body inhalation developmental study rats were exposed whole in chambers from gestation days 1 through 19 at 6.65 and 13.3 mg/L and from gestation days 7 through 15 towards 26.6 mg/L for 7 hours/day (Nelson et al., 1985). In the high dose group, significantly reduced food consumption without adverse effect on body weight gain was noted in maternal animals. No signs of maternal toxicity were observed in the lower dose groups. No influence on the number of corpora lutea and of implantations. No effects on foetal lethality and resorption were found. There was no evidence of embryotoxic/teratogenic activity of methanol at 6.65 mg/L. At the highest concentration, an increased number of litters with skeletal and visceral malformations was noted. These included in particular rudimentary and extra cervical ribs and exencephaly and encephalocele, and, to minor extent, cardiovascular and urinary-tract defects. In this study a NOAEC for maternal and developmental toxicity of 6.65 mg/L was obtained.

In a developmental whole body inhalation study, mice were exposed to methanol (1.33, 2.66, 6.65, 9.97, 13.3, 19.94 mg/L) on gestation days 6 to 15 for 7 hours/day. Additionally, an orally exposed group was included for comparison (Rogers et al., 1991, 1993). There were no signs of maternal toxicity. Developmental effects occurred after inhalation of 2.66 mg/L (Rogers et al., 1991, 1993). The dose related increase in cervical ribs or ossification sites lateral to the seventh cervical vertebra was significant at 2.66 mg/L. Significant increases in the incidence of exencephaly and cleft palate were observed at 6.65 mg/L. At the highest dose, almost complete resorption of embryos in most litters occurred. Reduced foetal weight was noted at 13.3 mg/L and above. In this study, NOAECs for maternal and developmental toxicity were 19.94 and 1.33 mg/L, respectively.

A study employing a single intraperitoneal injection of mice on gestation day 7 resulted in craniofacial malformations and malformations of the holoprosencephaly spectrum at 1700 mg/kg bw (LOAEL), while no NOAEL could be identified (Fu et al., 1995).

In another study of Fu et al. (1996) pregnant female mice were orally administered 5000 mg/kg methanol on gestation days 6 to 10. The influence of folate in the diet on the incidence of developmental defects in the offspring was investigated. Methanol had no marked influence on maternal folate levels, irrespective of folate supplementation, except in maternal plasma where there was some evidence of a reduction of about 20%. Methanol treatment was slightly foetotoxic (reduced mean foetal weight and reduced mean crown-rump length), but had no impact on other reproductive parameters. There was some evidence of a teratogenic effect (increased incidences of cleft palate and exencephaly) under folate-adequate supply, but this was hardly statistically significant: cleft palate (2/222 vs. 0/282) and exencephaly (5/222 vs. 1/282 in the respective high-folate control). Likewise, folate deficiency failed to produce significant malformations (in accordance with Heid et al., 1992): cleft palate (5/215 vs. 0/282) and exencephaly (2/215 vs. 1/282 in the respective high-folate control). However, cleft palate, but not exencephaly was significantly increased in the presence of methanol: 39/235 vs. 5/215 and 8/235 vs. 2/215 of folate-poor control, respectively.

In pregnant CD-1 mice given methanol (5000 mg/kg/d) from gestation days 6 to 15, in one group receiving folate-deficient and the other folate-supplemented diet, there were no pronounced differences in the formate blood levels between both groups: 5.13 ± 0.68 mmol/L (folate-def.) and 3.90 ± 0.94 mmol/L (folate-suppl.) vs. 0.36 ± 0.13 mmol/L (untreated control). Developmental toxicity, however, was significantly higher in folate-deficient dams (Hong et al., 1997). On balance, the results indicate that developmental toxicity of methanol in mice on low dietary folate is not linked to increased formic acid levels (Hong et al., 1997); however, folate deficiency may enhance the teratogenic effects of methanol in mice.

It is unlikely that concentrations associated with serious developmental effects in rodents could be reached by administration of sodium or potassium methanolate to experimental animals, as those dose levels would be in the acute toxic dose range and associated with massive local irritation at the site of first contact. The maximum tolerated dose in such studies is therefore likely to be below the dose that would result in methanol mediated developmental effects. In addition for animal welfare reasons it is not recommended to perform further animal studies with sodium and potassium methanolate.

 

Human data

There are no relevant epidemiological studies or case reports which describe an increase in the incidence of malformations in children of mothers exposed to methanol during pregnancy. However, the limited data available on methanol exposure on reproductive and developmental effects do not show an association (NTP, 2003).

In an epidemiological study, the reproductive effects of various occupations and associated exposures to complex mixtures were examined in women who gave birth to infants with and without cleft lip or cleft palate (Lorente et al., 2000). No association was found between methanol exposure and oral clefts. The small number of subjects exposed to methanol, the lack of individual exposure data, and confounding factors by other chemical exposures did not allow drawing firm conclusions as to the role of methanol on these outcomes.

NTP (2003) reviewed several studies that investigated the association between the periconceptional use of multivitamins containing folic acid and birth defects (e. g. neural tube defects and orafacial clefts). These studies suggest that folate deficiency in humans may lead to greater susceptibility to such effects. However, in all of theses reviewed studies, the association between methanol and these effects was not directly investigated. Therefore no conclusion can be drawn regarding causality between methanol and birth defects based on human data.

NTP (2003) stated that the rodent data on reproductive and developmental toxicity are of relevance for an assessment of the situation in humans even in the light of the known differences in methanol metabolism between rodents and humans. Rodents are adequate models for human exposure as long as formate levels do not accumulate. However, the blood methanol concentrations associated with serious teratogenic effects and reproductive toxicity occur in a dose range which is associated with formate accumulation in humans, metabolic acidosis and visual and clinical effects in humans (NTP, 2003) and far above the European OEL (200 ppm = ca. 260 mg/m³).

In humans, transient central nervous system effects generally appear at blood methanol levels higher than 200 mg/L, ocular symptoms appear at blood levels of > 500 mg/L and fatalities haven often occurred in untreated patients with initial blood methanol concentrations in the range of 1500 – 2000 mg/L. Other effects (e.g. marginal, not yet definitive neurological effects observed in primates) may be exhibited at lower inhalation doses and lower methanol blood levels.

 

Conclusion

No data are available on reproductive or developmental toxicity of sodium and potassium methanolate. The abiotic hydrolysis of sodium and potassium methanolates with tissue water results in the formation of sodium and potassium ions respectively, hydroxide ions and methanol. For hydroxide ions, sodium and potassium ions no relevant reproductive toxicity potential has been identified. For methanol reproductive and developmental toxicity effects have been described in rats, mice and monkeys. Blood methanol concentrations associated with serious developmental effects and reproductive toxicity in rodent studies are in the range associated with formate accumulation. It is unlikely that concentrations associated with serious developmental effects in rodents could be reached by administration of sodium or potassium methanolate to experimental animals, as those dose levels would be in the acute toxic dose range and associated with massive local irritation at the site of first contact. The maximum tolerated dose in such studies is therefore likely to be below the dose that would result in methanol mediated developmental effects. In addition for animal welfare reasons it is not recommended to perform further animal studies with sodium and potassium methanolate.

Justification for classification or non-classification

The health hazard of sodium methanolate is dominated by its corrosive properties.The abiotic hydrolysis of sodium methanolate with tissue water results in the formation of sodium ions, hydroxide ions and methanol. At non-irritant concentrations, exposure to sodium methanolate via any route will not result in exposure to toxic doses of any of its hydrolysis/dissociation products, in particular methanol.

Based on read-across from the hydrolysis/dissociation products (category approach), the available information on reproductive/developmental toxicicty of sodium methanolate is conclusive but not sufficient for classification according to DSD (67/548/EEC) and CLP (1272/2008/EC).