Choline hydroxide

Endpoint summary

Description of key information

1) BASF, 1963 - Read across from choline chloride, key, acute oral toxicity, rats, recalculated LD50 ca. 3040 mg/kg bw

2) BASF, 1969 - Read across from choline chloride, supporting, acute oral toxicity, rats, recalculated LD50 ca. 4770 mg/kg bw
3) Salazar-Rodriguez/Sosa, 2004 - Read across from choline chloride, supporting, acute oral toxicity, rats, recalculated LD0 ≥ 2.42 g/kg bw, recalculated intermittent total dose LD0 ≥ 7.26 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

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 040 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) on the read-across substance choline chloride are available to cover the endpoint "Acute Toxicity: oral". Furthermore, the study on acute toxicity generally does not need to be conducted asthe substance is classified as corrosive to the skin.
Hence, the available information meets fully the tonnage-driven data requirements of REACH. Additionally, all available studies revealed equivalent result, 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:

the study does not need to be conducted because the substance is classified as corrosive to the skin

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:

the study does not need to be conducted because the substance is classified as corrosive to the skin

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

There is no reliable information available for acute toxicity for Choline hydroxide. Therefore, the data on the source substance Choline chloride (CAS 67-48-1) have been considered.

 

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 ca. 4770 mg/kg bw choline hydroxide, 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 also 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 an approximative LD50 of ca. 5450 mg/kg bw (referring to a 70 % Choline chloride solution). This corresponds to approximately 3500 mg/kg bw of 100 % Choline chloride or 3040 mg/kg bw Choline hydroxide, respectively.

 

These results are obtained from two studies which were classified as reliable with restrictions and is can therefore be justified to used them to assess the hazard of choline hydroxide. With a recalculated LD50 of 3040 mg/kg bw and 4770 mg/kg bw, respectively, Choline hydroxide is practically nontoxic and does therefore not need to be classified as hazardous according to Regulation 1272/2008/EC. 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 ≥ 2.42 mg/kg bw resp. LD0 ≥ 7.26 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 240 mg/kg bw of choline hydroxide. Clinical signs were ventral position, myoclonus and tremor, exophthalmos, dyspnoea 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 (4x), elsewise organs with negative results (killed animals), respectively.

The acute toxicity of the read-across substance choline chloride after intraperitoneal injection was also 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 230 mg/kg bw choline hydroxide.

 

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 recalculated LD50 (i.p.) values of 240 mg/kg bw and 230 mg/kg bw, resp., nevertheless relatively high values, the classification of choline hydroxide as non-hazardous regarding acute toxicity is still justified.

Justification for selection of acute toxicity – oral endpoint
Data waiving: According to REACH Annex VII and VIII column 2 the study acute toxicity does not generally need to be conducted if the substance is classified as corrosive to the skin. However, acute toxicity data is available for the read-across substance choline chloride (CAS 67-48-1), and will be mentioned within this chapter, because this information is still relevant to show that choline hydroxide does not need to be classified as acute toxic.
The chosen study is 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 (3040 instead of 4770 mg/kg bw) was chosen out of precautionary principles.

Justification for selection of acute toxicity – inhalation endpoint
Data waiving: According to REACH Annex VII and VIII column 2 the study on acute toxicity does generally not need to be conducted if the substance is classified as corrosive to the skin. The latter is evident because of the high pH-value of the test item (pH = 14.9 (45 % solution, Struyvelt E, 2012), pH = 13.1 – 14.2 (10 - 90 % (w/w) of 45 % solution in water, Intertek, 2013) and pKb value (pKb = 5.06 for 0.0064-0.0403 M solutions (Seidel A (ed.) 2004. Kirk-Othmer Encyclopedia of Chemical Technology, Fifth edition, Wiley-Interscience, John Wiley & Sons, Inc., Publication)). Hence, the test does not need to be conducted due to ethical reasons and animal welfare.
Additionally, the test substance has very low vapor pressure (1.43xE-7 Pa, pure choline hydroxide, EPIWIN / Intertek, 2013), 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 VII and VIII column 2 the study on acute toxicity does generally not need to be conducted if the substance is classified as corrosive to the skin. The latter is evident because of the high pH-value of the test item (pH = 13.1 – 14.9 (10-100 % of a 45 %choline hydroxide solution in water) and pKb value (pKb = 5.06 for 0.0064-0.0403 M solutions (Seidel A (ed.) 2004. Kirk-Othmer Encyclopedia of Chemical Technology, Fifth edition, Wiley-Interscience, John Wiley & Sons, Inc., Publication)). Hence, the test does not need to be conducted due to ethical reasons and animal welfare.
However, skin contact during use and production cannot be completely excluded. In general, the neutral choline cation is not favoured for absorption.
Nevertheless, the absorption will be enhanced due to the corrosive properties of choline base, and so the toxicity via the dermal route cannot be disregarded. The test cannot be performed due to ethical reasons and animal welfare, and an estimated absorption of 50 % is considered reasonable which is equal to the estimated absorption rate via the oral route. Hence, the available information gained from choline chloride via the oral route can be transferred without modifications to choline base (dermal route). So, corrected for choline base, LD50 values for the dermal route can be assumed to be 4770 mg/kg bw (BASF, 1969), 3040 mg/kg bw (BASF, 1963), the LD0 as LD0 ≥ 2.42 g/kg bw resp. LD0 ≥ 7.26 g/kg (three consecutive days, intermittent gavage) (Salazar-Rodriguez/Sosa, 2004). Due to safety reasons, the lowest LD50 value will be taken for risk assessment, but the value of 3040 mg/kg bw is still above the boundary value of 2000 mg/kg bw for classification.
Hence, testing can be waived, choline hydroxide can be considered to practically nontoxic and does not need to be classified as hazardous (acute toxicity) according to Regulation 1272/2008/EC.

Justification for classification or non-classification

For Choline hydroxide, an LD50 of 3040 mg/kg bw was recalculated based on the value obtained in the most relevant study with its structural analogue Choline chloride (BASF, 1963), and therefore the substance does not need to be classified as hazardous (acute toxicity) according to Regulation 1272/2008/EC.

The recalculated LD0 ≥ 2.42 g/kg bw resp. LD0 ≥ 7.26 g/kg (three consecutive days, intermittent gavage) - based on the value obtained in the study by Salazar-Rodriguez/Sosa with Choline chloride can be used to support the classification of being practically nontoxic as stated above.

Nevertheless, due to the corrosive properties of the test item, a classification as corrosive to the skin / eye is required for Choline hydroxide according to Regulation 1272/2008/EC.