Sodium methanolate

Endpoint summary

Description of key information

Oral: LD50 (rat) in water or water soluble solvents: 800 - 1687 mg/kg bw
Dermal: LD50 (rat): > 2000 mg/kg bw (50% aqueous solution)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Interfauna (UK) Limited, Wyton, Huntingdon
- Age at study initiation: five to eight weeks old
- Weight at study initiation: 122 - 145 g males; 120 - 142 g females
- Fasting period before study: overnight
- Housing: in groups of up to five by sex in solid-floor polypropylene cages with sawdust bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): 50-68
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 100-200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw

Doses:

1000, 1260, 1587 and 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
observations: 1 and 4 hours after dosing and subsequently once daily for 14 days
weighing: on the day of treatment (day 0), day 7 and 14, or at death
- Necropsy of survivors performed: yes

Statistics:

Probit Analysis

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 687 mg/kg bw

95% CL:

>= 1 464 - <= 2 406

Sex:

male

Dose descriptor:

LD50

Effect level:

1 844 mg/kg bw

95% CL:

>= 1 395 - <= 2 437

Sex:

female

Dose descriptor:

LD50

Effect level:

1 682 mg/kg bw

95% CL:

>= 1 218 - <= 2 323

Mortality:

One animal was found dead one hour after treatment. All other deaths were noted one to six days after treatment.

Clinical signs:

other: All animals: hunched posture, pilo-erection, decreased respiration rate (1 to 4 h after dosing). Some of the symptoms were observed up to days 6 to 9 in surviving animals of the 1587 mg/kg bw group and up to day 11 in those of the high dose group. Additio

Gross pathology:

Common abnormalities of animals that died during the study: red lungs, pale or dark or patchy pallor of livers. At 1587 and 2000 mg/kg bw: severe haemorrhage and rugae of the glandular gastric epithelium. Occasional adherence of stomach to the liver. In the surviving animals killed at termination occasional findings were white foci in the non-glandular gastric epithelium and adherence of the stomach to the liver.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral median lethal dose (LD50) and the 95% confidence limits of the test material in the Sprangue-Dawley CFY strain rat were calculated by the probit method to be:
All animals: 1687 (1464 - 2406) mg/kg bodyweight
Males only: 1844 (1395 - 2437) mg/kg bodyweight
Females only: 1682 (1218 - 2323) mg/kg bodyweight

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 687 mg/kg bw

Quality of whole database:

The available information comprises adequate, reliable (Klimisch score 1 or 2) and consistent studies, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Principles of method if other than guideline:

Rats (3/sex/dose) were exposed dermally to the test substance for 24 hours under occlusive conditions. The animals were observed for 14 days and the LD50 was calculated.

GLP compliance:

no

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hagemann, Extertal
- Weight at study initiation: mean males: 220 g, mean females: 190 g
- Diet: ad libitum
- Water: ad libitum

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: backs and flanks of the animals
- % coverage: 50 cm²
- Type of wrap if used: occlusive, impermeable


REMOVAL OF TEST SUBSTANCE
- Washing (if done): with warm water oder warm water/lutrol
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): not reported
- Concentration (if solution): 50%
- Constant volume or concentration used: not reported

Duration of exposure:

24 hours

Doses:

1000, 2000 mg/kg

No. of animals per sex per dose:

3

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: not specified
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, gross pathology

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

no deaths occured

Clinical signs:

other: Irregular breathing and bad general condition Skin: necrosis after the 24 hour application

Gross pathology:

No macroscopic organ changes apart from skin necrosis were observed.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute dermal median lethal dose (LD50) in all animals was determined to be > 2000 mg/kg bodyweight. Skin necrosis was observed after the 24-h exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

Oral

An aqueous solution of sodium methanolate (10 to 20%) was tested for its acute toxicity according to OECD guideline 401 and GLP in male and female Sprague-Dawley rats. Animals were given the test substance by gavage at 1000, 1260, 1587 and 2000 mg/kg bw. The LD50 was 1687 mg/kg bw as calculated by the probit method. Animals of all dose groups showed symptoms of hunched posture lethargy and decreased respiration rate. Macroscopic findings at necropsy in animals that died during the study included red lungs, pale dark or patchy pale discoloration of the liver and at doses from 1587 mg/kg bw severe haemorrhage and rugae of the glandular gastric epithelium as well as occasional adherence of the stomach to the liver. In animals killed at termination occasional white foci in the nonglandular stomach and adherence of the stomach to the liver was also observed (Evonik, 1988).

Sodium methanolate was administered as a 2.15 to 10% aqueous solution (volume administered 10 mL/kg) to male and female Sprague-Dawley rats by gavage at dose levels between 215 and 1000 mg/kg bw. All animals of the 1000 mg/kg dose group died while animals dosed up to 681 mg/kg bw survived. Clinical symptoms of dyspnoea and apathy were observed in all dose groups, at 316 mg/kg bw yellow discoloration of the urine was observed and disturbances of posture and gait were observed from 681 mg/kg bw on. Macroscopic findings were only observed in the animals that died during the study and included dilatation and discoloration of the right heart, acute congestive hyperaemia, atonic stomach and intestines, fluid stomach and intestinal content and diffuse reddening and vascular injection of the forestomach. The study was well documented, but non-GLP (BASF SE, 1979).

As both studies mentioned above were performed with aqueous solutions of sodium methanolate, in fact the hydrolysis products (sodium hydroxide, CAS No. 1310-73-2; methanol, CAS No. 67-56-1) have been tested.

Two other studies tested the acute oral toxicity to rats of suspensions of solid sodium methanolate in non-aqueous solutions. An LD50 value of 800 mg/kg bw was reported in a study using Lutrol as a solvent. No characteristic symptoms were observed in this study. Macroscopic findings were only reported in the animals that died during the study and included acute dilatation of the right heart and congestive hyperaemia as well as ulcerating gastritis, bleeding in the forestomach, thickened walls of the glandular stomach, adhesions between stomach and liver atonic intestine with bloody content, hydrothorax and partly blood coloured ascites (BASF SE, 1979). This study is a well documented non-GLP study.

In another well documented non-GLP study a suspension of sodium methanolate in corn oil was administered to male and female Sprague Dawley rats. This study is not included in the IUCLID, but taken from the OECD SIDS of sodium and potassium methanolate (2006) as secondary source for discussion in this endpoint summary. In this study an LD50 of 2037 mg/kg bw was obtained. Laboured breathing, weakness, wet and stained perianal area as well as chromodacryorrhea and ruffled fur were observed in all animals. Macroscopic findings were not reported in the reference (Dupont de Nemours, 1982; cited in OECD SIDS of sodium and potassium methanolate, 2006).

In the OECD SIDS of sodium and potassium methanolate (2006) is discussed that:

-       the difference between the two studies in non-aqueous solvents is probably due to their different lipophilicity. Lutrol is hydrophilic and readily dissolved in the aqueous gastric fluid liberating the dispersed test substance that will hydrolyse immediately delivering the hydrolysis products at a relative high concentration to the stomach tissue. This leads to the relative severe signs of irritation and corrosivity. The lipophilic corn oil on the other hand can be expected to release the test substance more slowly from the administered bolus leading to a lower tissue concentration of the hydrolysis products and less damage to the gastric mucosa.

-       The symptomatology and macroscopic findings in all studies are consistent with the corrosive nature of the substance and sodium hydroxide as the corrosive hydrolysis product. The differences in toxicity can probably be explained with the different concentrations and dose rates of the delivery of the substance and its degradation products to the tissues of the gastrointestinal tract. The order of magnitude of the LD50 is consistent with that of sodium hydroxide for which LD50 values between 325 and higher than 500 mg/kg bw have been reported (OECD, 2002; European Commission, 2007). It is unlikely that methanol contributes much to the acute toxicity observed in the above studies as in most of the studies in rodents methanol toxicity was approximately one order of magnitude lower (OECD, 2004). With regard to a possible methanol toxicity in humans through oral uptake of sodium methanolate, it should be considered that doses that would lead to deaths in humans (300 to 1000 mg methanol/kg bw) correspond to sodium methanolate doses between 507 to 1690 mg/kg bw. Such dose levels would already cause considerable irritation of the mucous membranes in the oral cavity, pharynx and gastrointestinal tract and humans are unlikely to be exposed orally to such dose levels.

 

Dermal

A non-GLP, but well documented acute dermal toxicity study with 50% aqueous sodium methanolate in rats revealed a low acute toxicity (> 2000 mg/kg bw) via the dermal route. As the study was performed in aqueous solution, in fact the hydrolysis products have been tested. No deaths occurred at 1000 and 2000 mg/kg bw. Clinical signs reported included irregular breathing and bad general condition. Skin necrosis was observed after the 24 hour application period. This finding is in accordance with the corrosivity of the test substance (BASF SE, 1979). Due to the severe corrosivity of sodium methanolate it is very unlikely that dermal exposure of humans to sodium methanolate would lead to an uptake of methanol that would be sufficiently high to cause acute methanol toxicity.

 

Inhalation

A study on the acute toxicity by inhalation is not necessary according to Annex VIII, Section 8.5, Column 2 of the REACH regulation, as methanolates are classified as corrosive to the skin.

The available data on this endpoint was, however, taken into account. Only limited inhalation toxicity studies are available and were also disregarded for assessment due to major methodological deficiencies. In the first study, rats were exposed for 8 hours to an enriched atmosphere of the volatile components of a 30% solution of sodium methanolate in methanol at 20 °C. 200 L air/hour was pumped through a 5 cm layer of the product at 20 °C. No effects were observed in the animals following the exposure (BASF SE, 1978; unsuitable test system, documentation insufficient for assessment, non-GLP). It is likely that the animals in this study were exposed to methanol rather than to sodium methanolate. After exposure of rats to a dust enriched atmosphere (200 L air per hour were piped through a 5 cm layer of the product) for 8 hours no mortality, no clinical symptoms and no macroscopic organ changes were observed (BASF SE, 1979; unsuitable test system, documentation insufficient for assessment, non-GLP). As no signs of irritation were observed, it is likely that irritant exposure levels could not be reached using this method. It is very unlikely that through inhalation exposure to sodium methanolate air concentrations could be reached that would be in the range of causing methanol toxicity. The tolerable exposure will be limited by the highly corrosive properties of the substance.

 

Other routes

The LD50 of sodium methanolate was determined to be 130 mg/kg bw in mice, after intraperitoneal administration of a sodium methanolate (30% in methanol) solution in Lutrol (BASF SE, 1978). No further information was available for this study. In another study, mice were administered sodium methanolate as a 0.43-14.7% suspension in Lutrol. Symptoms were reported as uncharacteristic. In the beginning of the observation period, body weight reduction was noted. No macroscopic findings at necropsy were reported. Deaths occurred within the first week of the experiment. The LD50 was determined to be 40 mg/kg bw (BASF SE, 1979).

 

Conclusion

No signs of toxicity were reported in rats exposed to a dust enriched atmosphere of sodium methanolate for 8 hours, the dermal LD50 of a 50% aqueous solution was > 2000 mg/kg bw in rats. Skin necrosis was observed in this study. After oral administration the acute toxicity is dependent on the local tissue concentration and the dose rate of the substance and its degradation product sodium hydroxide. The rat LD50 in water or water-soluble solvents was between 800 and 1687 mg/kg bw, when administered in corn oil the LD50 was 2037 mg/kg bw. The acute toxicity is consistent with that of sodium hydroxide and it can be assumed that the primary mode of action is local irritation/corrosion at the site of first contact.

 

References not included as study summaries in IUCLID:

OECD SIDS Initial Assessment Report for SIAM 22 (2006): Category of Methanolates: Sodium Methanolate, Potassium Methanolate (CAS No: Sodium Methanolate: 124-41-4; Potassium Methanolate: 865-33-8).

OECD SIDS Initial Assessment Report for SIAM 14 (2002): Sodium Hydroxide (CAS No: 1310-73-2).

European Union Risk Assessment Report (2007): Sodium Hydroxide (CAS No: 1310-73-2).

OECD SIDS Initial Assessment Report for SIAM 19 (2004): Methanol (CAS No: 67-56-1).

Justification for classification or non-classification

Based on the available acute oral toxicity data, sodium methanolate is harmful if swallowed and fulfils the CLP/UN-GHS criteria for classification:

CLP/UN-GHS: Acute toxicity - oral, Category 4 (H302)

The available data on the acute dermal toxicity of sodium methanolate is conclusive but not sufficient for classification.

The available data on the acute inhalation toxicity of sodium methanolate is not reliable, but as sodium methanolate is classified as corrosive to skin and eyes, no further data is needed. Based on the corrosive properties of sodium methanolate and the absence of acute inhalation test data in combination with possible inhalation exposure, the substance should be labelled as "corrosive to the respiratory tract" (EUH071).