Choline hydrogen carbonate

Endpoint summary

Description of key information

1) BASF, 1969 - acute oral toxicity, rats, LD50 ca. 6500 mg/kg bw
2) BASF, 1963 - acute oral toxicity, rats, LD50 ca. 4140 mg/kg bw
3) Salazar-Rodriguez/Sosa, 2004 - acute oral toxicity, rats, LD0 >= 3.30 g/kg bw, intermittent total dose LD0 >= 9.90 g/kg bw (3 consecutive days)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented study result, which meets basic scientific principles, but test was performed on the read-across substance Choline chloride.

Qualifier:

no guideline followed

Principles of method if other than guideline:

A Choline chloride solution (30 % in aqua dest.) was adminstered to rats via the oral route.

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

no data available

Route of administration:

oral: unspecified

Vehicle:

other: aqua dest.

Details on oral exposure:

The substance was administered orally to rats

Doses:

5 mL of a 70 % solution of Choline chloride, applied as a 30 % solution in aqua dest.

No. of animals per sex per dose:

no data

Control animals:

not specified

Details on study design:

no specific information available

Sex:

not specified

Dose descriptor:

approximate LD50

Effect level:

ca. 5 450 mg/kg bw

Based on:

test mat.

Remarks:

70% Choline chloride

Remarks on result:

other: refering to a 70 % Choline chloride solution

Sex:

not specified

Dose descriptor:

approximate LD50

Effect level:

ca. 3 500 mg/kg bw

Based on:

act. ingr.

Remarks:

pure Choline chloride

Remarks on result:

other: converted that corresponding to Choline chloride 100 %

Sex:

not specified

Dose descriptor:

approximate LD50

Effect level:

ca. 4 140 mg/kg bw

Based on:

other: Choline bicarbonate

Remarks on result:

other: re-calculated from LD50 of pure Choline chloride

Mortality:

none reported

Clinical signs:

other: restlessness, staggering, cramps and laboured breathing

Gross pathology:

no significant findings

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: other: EU-GHS

Conclusions:

The study was considered to be of high quality (reliability Klimisch 2). The substance did not show a high toxicity after a single oral application to rats. The LD50 was identified to be ca. 3500 mg/kg bw of the read-across substance choline chloride, which corresponds to 4140 mg/kg bw Choline hydrogen carbonate.

Executive summary:

The acute oral toxicity of the read-across substance choline chloride was investigated in rats (BASF, 1963). The rats received doses of ca. 5 mL of a 70 % Choline chloride solution (applied as a 30 % solution in water). No mortality was reported. The main clinical symptoms of intoxications were restlessness, staggering, cramps and laboured respiration. Therefore the oral toxicity can be characterised by a approximative LD50 of ca. 5450 mg/kg bw (refering to a 70 % Choline chloride solution). This corresponds to approximately 3500 mg/kg bw of 100 % Choline chloride or 4140 mg/kg bw Choline hydrogen carbonate, respectively. Choline bicarbonate does not need to be classified as hazardous, neither according to Regulation 1272/2008/EC nor Directive 67/548/EEC.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 140 mg/kg bw

Quality of whole database:

Two equivalent studies assessed with Klimisch 2 and one supporting study (Klimisch 4 because only abstracts could be retrieved) are available, all on the read-across substance Choline chloride, to cover the endpoint "Acute Toxicity: oral", hence, the available information meets fully the tonnage-driven data requirements of REACH. Additionally, all available studies revealed equivalent results, i.e. are all above the boundary value of 2000 mg/kg bw for classification, and so the outcomes of the studies are consistent.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute toxicity - oral:

In an acute oral toxicity study with a 7 d post-observation period, rats were given 11000 mg/kg bw of the read-across substance Choline chloride 50 %, applied as a 30 % aqueous suspension with tragacanth. The oral LD50 was determined to be ca. 11000 mg/kg of the test item, which corresponds to ca. 5500 mg/kg of pure choline chloride or 6500 mg/kg bw Choline hydrogen carbonate, respectively. Clinical signs were apathy, dyspnoe, calm behavior, accelerated respiration, individually chewing constraint, huddled posture and wet, dirty and shaggy fur, necropsy findings were more or less serous smeared snout (5 x), particularly ani, diarrhoea, elsewise sepsis (dead animals) and pneunomia in the right upper half of lungs (2 x), reduced body weight (1 x), bronchopneumonia, elsewise organs with negative results (killed animals), respectively.

The acute oral toxicity of the read-across substance Choline chloride was investigated in rats (BASF, 1963). The rats received doses of ca. 5 mL of a 70 % Choline chloride solution (applied as a 30 % solution in water). No mortality was reported. The main clinical symptoms of intoxications were restlessness, staggering, cramps and laboured respiration. Therefore the oral toxicity can be characterised by a approximative LD50 of ca. 5450 mg/kg bw (refering to a 70 % Choline chloride solution). This corresponds to approximately 3500 mg/kg bw of 100 % Choline chloride or 4140 mg/kg bw Choline hydrogen carbonate, respectively.

These results are obtained from two studies which were classified as reliable with restrictions, and can therefore be justifiedly used to assess the hazard of Choline hydroxide. With an LD50 of 4140 mg/kg bw and 6500 mg/kg bw, respectively, choline hydrogen carbonate is practically nontoxic and does therefore not need to be classified as hazardous, neither according Regulation 1272/2008/EC nor Directive 67/548/EEC. Although only abstracts are available and hence the reliability is not assessable, the results of the study by Salazar-Rodriguez/Sosa are consistent with the data provided in both the studies mentioned above, so the LD0 ≥ 3.30 mg/kg bw resp. LD0 ≥ 9.90 mg/kg (three consecutive days, intermittent gavage) obtained in this study can be used to support the classification of being practically nontoxic / non- hazardous regarding acute toxicity.

 

Acute toxicity - other routes:

In an acute toxicity study with i.p. injection and a 7 d post-observation period, mice were given a 4 % aqueous solution of the read-across substance choline chloride (50 %) with tragacanth. The i.p. LD50 was determined to be ca. 550 mg/kg of the test item applied in a 4 % solution, which corresponds to ca. 275 mg/kg of the pure Choline chloride and hence 325 mg/kg bw of Choline hydrogen carbonate. Clinical signs were ventral position, myoclonus and tremor, exophthalmos, dispnoea or accelerated and precussive respiration, cyanosis, huddled posture, sunken flanks, clotted eyes and fluffed fur, necropsy findings were sepsis (dead animals) and bracket-formed adhesions on the liver (4 x), elsewise organs with negative results (killed animals), respectively.

The acute toxicity of the read-across substance choline chloride after intraperitoneal injection was investigated in mice (BASF, 1963). The mice received doses of ca. 0.35 mL of a 70 % Choline chloride solution (applied as a 8 % solution in water). No mortality was reported. The main clinical symptoms of intoxications were restlessness, staggering, cramps and laboured respiration. The intraperitoneal toxicity with an approximative LD50 of ca. 266 mg/kg bw of 100 % Choline chloride was found, which corresponds to 315 mg/kg bw Choline hydrogen carbonate.

Since this route of application (intraperitoneal) is not relevant for human risk assessment, the results are not used to assess the need for classification and represent with consistent LD50(i.p.) values of 325 mg/kg bw and 315 mg/kg bw, resp., nevertheless relatively high values, the classification of Choline bicarbonate as non-hazardous regarding acute toxicity is still justified.

Justification for selection of acute toxicity – oral endpoint
One of two equally well-documented acute toxicity studies on the read-across substance Choline chloride, assessed with Klimisch 2. The LD50 values of both oral studies can be considered as equivalently reliable and both above the boundary value of 2000 mg/kg bw for classification. However, the lower LD50 (4140 instead of 6500 mg/kg bw) was chosen due to safety reasons.

Justification for selection of acute toxicity – inhalation endpoint
The test substance has a very low vapor pressure (9.13xE-10 Pa, pure Choline hydrogen carbonate, EPIWIN), so the potential for the generation of inhalable forms is low. Furthermore, the substance is distributed as an aqueous solution, so no dust with inhalable particles will be formed and therefore no acute inhalation test was performed.

Justification for selection of acute toxicity – dermal endpoint
Data waiving: According to REACH Annex VIII column 2 Testing by the dermal route is appropriate if (1) inhalation of the substance is unlikely and (2) skin contact in production and/or use is likely and (3) the physicochemical and toxicological properties suggest the potential for a significant rate of absorption through the skin. Although inhalation of choline bicarbonate is unlikely and skin contact may possibly occur when using choline bicarbonate, the latter condition does not apply. Skin absorption is influenced by several factors, i.a.:
- Molecular weight: With a molecular weight of 165.2 g/mole, absorption is possible, but not highly favoured
- LogPow: Since Choline bicarbonate, due to its ionic structure and rather small molecular weight, has a negative logPow (approx. -3.77 to -2.25), dermal absorption may practically not occur because poor lipophilicity will limit penetration into the stratum corneum.
- Water solubility: Water solubility is very high, i.e. >750 g/L. Also here, dermal absorption may practically not occur due to the high hydrophilicity of the compound.
- Skin irritation / corrosion: If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. Choline bicarbonate was not classified as irritant to the skin, therefore, no additional penetration enhancement must be considered.
Hence, based on the physico-chemical properties of Choline bicarbonate, a dermal absorption is very hindered and so unlikely. Consequently, no additional testing is required and the testing for acute toxicity via dermal route for Choline bicarbonate can be waived.

Justification for classification or non-classification

For choline hydrogen bicarbonate, an LD50 of 4140 mg/kg bw was obtained in the most relevant WoE study, and therefore the substance does not need to be classified as hazardous, neither according Regulation 1272/2008/EC nor Directive 67/548/EEC.

The LD0 ≥ 3.30 g/kg bw resp. LD0 ≥ 9.90 g/kg (three consecutive days, intermittent gavage) obtained in the study by Salazar-Rodriguez/Sosa can be used to support the classification of being practically nontoxic as stated in the WoE studies.