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EC number: 204-625-1 | CAS number: 123-41-1
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicological Summary
- Administrative data
- Workers - Hazard via inhalation route
- Workers - Hazard via dermal route
- Workers - Hazard for the eyes
- Additional information - workers
- General Population - Hazard via inhalation route
- General Population - Hazard via dermal route
- General Population - Hazard via oral route
- General Population - Hazard for the eyes
- Additional information - General Population
Administrative data
Workers - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 194.54 mg/m³
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 1
- Dose descriptor starting point:
- other: Al
- Value:
- 6.67 mg/kg bw/day
- Modified dose descriptor starting point:
- other: Al
- Value:
- 194.54 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The Adequate Intake (AI) of 6.67 mg/kg bw/day corresponding to a corrected AI of 194.54 mg/m³ derived from the EFSA Panel on Dietetic Products, Nutrition and allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation.
Derivation of corrected AI: 6.67 mg/kg bw/day * (1/0.096 m³ / kg bw/day) * (6.7 m³ / 10 m³) * (50 % / 25 %) * (7 d/ 5d) = 194.54 mg/m³
In detail, an oral absorption of 50 % and absorption by inhalation of 25 %, the sRV (standard respiratory volume of humans during 8 hours) of 0.096 m³/kg/day and a factor of 0.67 (derived of the standard respiratory volumes for workers under normal conditions and by light activity: 6.7 m³ and 10 m³) and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. general population (7 days continuous exposure) have been used.
Please also refer to argumentation stated below.
- AF for dose response relationship:
- 1
- Justification:
- default
- AF for differences in duration of exposure:
- 1
- Justification:
- no Assessment factor for differences in duration of exposure needs to be applied, as the AI applies to an oral chronic lifetime intake
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No allometric scaling should be applied in case of oral-to-inhalation extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- no Assessment factor for other interspecies differences needs to be applied, as the AI is a human derived value and is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for intraspecies differences:
- 1
- Justification:
- no Assessment factor for intraspecies differences needs to be applied, as the AI is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for the quality of the whole database:
- 1
- Justification:
- default (database is of high quality)
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
Workers - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 9.34 mg/kg bw/day
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 1
- Dose descriptor starting point:
- other: Al
- Value:
- 6.67 mg/kg bw/day
- Modified dose descriptor starting point:
- other: corr. Al
- Value:
- 9.34 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The Adequate Intake (AI) of 6.67 mg/kg bw/day corresponding to 9.34 mg/kg bw/day derived from the EFSA Panel on Dietetic Products, Nutrition and allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation.
Derivation of corrected AI: 6.67 mg/kg bw/day * (50 % / 50 %) * (7 d / 5 d) = 9.34 mg/kg bw/day
In detail, an oral absorption of 50 %, a dermal absorption of 50 % taking the corrosive properties of the substance into account, and a correction factor of 1.4 for differences in human and experimental exposure conditions: workers (5 working days) vs. general population (7 days continuous exposure) have been used.
Please also refer to argumentation stated below.
- AF for dose response relationship:
- 1
- Justification:
- default
- AF for differences in duration of exposure:
- 1
- Justification:
- no Assessment factor for differences in duration of exposure needs to be applied, as the AI applies to an oral chronic lifetime intake
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- no Assessment factor for interspecies differences needs to be applied, as the AI is already a human derived value
- AF for other interspecies differences:
- 1
- Justification:
- no Assessment factor for other interspecies differences needs to be applied, as the AI is a human derived value and is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for intraspecies differences:
- 1
- Justification:
- no Assessment factor for intraspecies differences needs to be applied, as the AI is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for the quality of the whole database:
- 1
- Justification:
- default (database is of high quality)
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Workers - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - workers
- NOAEL/NOEL from chronic animal study (rats, oral, feed) (Shivapurka et al, 1986):
- Upper limit -> 3.5 g choline/d for adults (50 mg/kg bw/d) (EFSA, 2016)
- Summary
The calculation of the DNELs is in general performed in accordance with the principles given in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”
The available dose descriptors are based on the Adequate Intake (AI) derived from the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline.
Hazard via inhalation route
Long-term exposure – systemic effects:
No route specific data is available. However, such studies are not considered necessary, due to exposure or other considerations regarding the unlikeliness of absorption as the oral route is considered to be the most likely one for humans, because the test substance has a very low vapour pressure and a high melting point, 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.
There is a chronic oral rat study available (Shivapurkar N, 1986) in which a NOAEL > 1200 mg/kg bw is reported for Choline chloride (highest /only dose tested). In this study male Fischer 344 rats were exposed for 72 weeks + 31 weeks post-observation) orally via feed to choline chloride. The study was conducted similar to OECD guideline 452. The NOAEL value of > 1200 mg Choline chloride corresponds to a value of 1040 mg/kg bw for Choline hydroxide. Furthermore, there is a subchronic (3 – 4 months) study (Hodge, 1945), in which male and female rats were exposed orally via feed and drinking water (similar to OECD Guideline 408). A NOAEL of 1300 – 2900 mg/kg bw/day and a LOAEL of 3400 – 5000 mg/kg bw/day were reported for Choline chloride. Moreover, a subacute (28 day) study is available (Mehta et al., 2009), in which male and female mice (Balb/c) were exposed to choline chloride either orally via gavage, intraperitoneally and intranasaly (GLP, OECD guideline 407 / no guideline available). Here a NOEL > 200 mg/kg bw/day (highest / only dose tested) was reported. All available studies revealed equivalent, plausible and consistent results over all three durations including a nearly lifetime exposure with an NOAEL > 1200 mg Choline chloride/kg bw, i.e. all studies give no rise to concern of compound-related toxic effects when applying choline chloride repeatedly and trigger no classification as STOT-RE. NOAEL > 1200 was obtained for choline chloride, which was transformed into a NOAEL > 1040 mg/kg bw for choline base by recalculation from choline chloride, by performing route-to-route extrapolations.
However, the (oral) Adequate Intake (AI) derived from the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation for the following reasons:
The AI of 400 mg/day, equivalent to an intake of 6.67 mg/kg bw/day, for adults is considered the recommended average daily intake which is assumed to be adequate for lifetime exposure of adult human subjects. Moreover, as even higher AI of 480 and 520 mg/day were set for pregnant and lactating women, respectively, the AI of 400 mg/day is considered safe regarding reproduction and pre-/perinatal development as well. Furthermore, it should be noted that the AI of 400 mg/day has been set based on the average observed choline intake in healthy populations in the European Union and in consideration of the amounts of choline needed to replete about 70 % of depleted subjects who showed signs of organ dysfunction in a depletion/repletion study. Thus, the DNELs derived from this AI should be considered as very conservative and highly protective.
This is clearly supported by a chronic toxicity study on choline chlorine in rats (Shivapurkar, 1986), showing no signs for adverse effects in the observed endpoints even at a considerably high dose level yielding a NOAEL of > 1,200 mg/kg bw/day, equivalent to a NOAEL > 1040 mg/kg bw for choline base.
The AI is then converted into a corrected AI by route-to-route extrapolation as described in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”. No further Assessment factor is needed. The DNEL is calculated to be 194.54 mg/kg bw.
Acute short-term exposure – systemic effects:
Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are normally not required. It is specified: "For some toxic substances, for which there may be peak exposures, a DNELacute needs to be set and assessed in relation to the human peak exposure levels". This would be the case for substances with classification & labelling for acute hazards.
Based on available data on the read-across substance choline chloride, choline hydroxide is not classified for acute systemic hazard. Furthermore, choline hydroxide has a low vapour pressure, thus the generation of inhalable forms is low and an acute exposure hazard via inhalation is unlikely for humans. Therefore, according to ECHA's Guidance Part E (v3, May 2016) the hazard Assessment Conclusion "No hazard is identified” has been derived.
Acute short-term and Long-term exposure - local effects
Due to 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), choline hydroxide was classified as Skin corrosive 1A (H314) and Eye damage 1 (H318).
Based on the skin corrosive 1A (H314) classification, choline hydroxide is allocated to the high hazard band for local effects via all routes (inhalation, dermal and oral) according to the ECHA Guidance Part E (v3, May 2016).
Exposure to such extreme corrosive substances should be strictly contained.
Hazard via dermal route
Long-term exposure – systemic effects:
No data needed to be derived for dermal exposure, because of the corrosive properties due to 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 the fact that the subchronic or chronic NOAELs can be sufficiently derived from test via oral route.
There is a chronic oral rat study available (Shivapurkar N, 1986) in which a NOAEL > 1200 mg/kg bw is reported (highest /only dose tested). In this study male Fischer 344 rats were exposed for 72 weeks + 31 weeks post-observation) orally via feed to choline chloride. The study was conducted similar to OECD guideline 452. The NOAEL value of > 1200 mg Choline chloride corresponds to a value of 1040 mg/kg bw for Choline hydroxide. Furthermore, there is a subchronic (3 – 4 months) study (Hodge, 1945), in which male and female rats were exposed orally via feed and drinking water (similar to OECD Guideline 408). A NOAEL of 1300 – 2900 mg/kg bw/day and a LOAEL of 3400 – 5000 mg/kg bw/day were reported for Choline chloride. Moreover, a subacute (28 day) study is available (Mehta et al., 2009), in which male and female mice (Balb/c) were exposed to choline chloride either orally via gavage, intraperitoneally and intranasaly (GLP, OECD guideline 407 / no guideline available). Here a NOEL > 200 mg/kg bw/day (highest / only dose tested) was reported. All available studies revealed equivalent, plausible and consistent results over all three durations including a nearly lifetime exposure with an NOAEL > 1200 mg/kg bw. (equivalent to a NOAEL > 1040 mg/kg bw for choline base), i.e. all studies give no rise to concern of compound-related toxic effects when applying choline hydroxide repeatedly and trigger no classification as STOT-RE.
However, the (oral) Adequate Intake (AI) derived from the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation for the following reasons:
Choline hydroxide, similar to choline chloride, as a quaternary alkylammonium salt dissociates readily into the respective ions when getting into contact with water and the choline cation is what is left to be considered (US EPA, 2010). This can plausibly also be expected to occur upon contact with biological fluids after systemic uptake. Thus, the toxicological profile of both choline compounds for systemic endpoints is similar and related toxicological data on both choline salts are used for their hazard assessment. Based on this, the Adequate Intake (AI) derived from the EFSA Panel on Dietetic Products, Nutrition and Allergies is considered relevant for choline hydroxide as well.
The AI of 400 mg/day, equivalent to an intake of 6.67 mg/kg bw/day, for adults is considered the recommended average daily intake which is assumed to be adequate for lifetime exposure of adult human subjects. Moreover, as even higher AI of 480 and 520 mg/day were set for pregnant and lactating women, respectively, the AI of 400 mg/day is considered safe regarding reproduction and pre-/perinatal development as well. Furthermore, it should be noted that the AI of 400 mg/day has been set based on the average observed choline intake in healthy populations in the European Union and in consideration of the amounts of choline needed to replete about 70 % of depleted subjects who showed signs of organ dysfunction in a depletion/repletion study. Thus, the DNELs derived from this AI should be considered as very conservative and highly protective.
This is clearly supported by a chronic toxicity study on choline chlorine in rats (Shivapurkar, 1986), showing no signs for adverse effects in the observed endpoints even at a considerably high dose level yielding a NOAEL of > 1,200 mg/kg bw/day, equivalent to a NOAEL > 1040 mg/kg bw for choline base.
The AI is then converted into a corrected AI by route-to-route extrapolation as described in ECHA (2012) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health.”, No further Assessment factor is needed. The DNEL is calculated to be 9.34 mg/kg bw.
Acute short-term exposure – systemic effects:
Chapter 8.7.3 of the REACH TGD (R.8) indicates that acute exposure DNEL values are normally not required. It is specified: "a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified".
However, for choline hydroxide, according to ECHA's Guidance Part E (v3, May 2016) the hazard Assessment Conclusion "No hazard is identified” has been derived, as the substance is not classified for acute systemic hazards based on available data on the read-across substance choline chloride.
Acute short-term and long-term exposure - local effects
Due to 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), choline hydroxide was classified as Skin corrosive 1A (H314) and Eye damage 1 (H318).
Based on the skin corrosive 1A (H314) classification, choline hydroxide is allocated to the high hazard band for local effects via all routes (inhalation, dermal and oral) according to the ECHA Guidance Part E (v3, May 2016).
Exposure to such extreme corrosive substances should be strictly contained.
Modification of the starting point:
From all available data for the different human health endpoints it is clear that choline hydroxide exerts its effect by a threshold mode of action. Thus, DNELs can be calculated for the different threshold endpoints based on the most relevant dose descriptors per endpoint. DNELs are derived based on the available toxicity data for the substance, reflecting the routes, duration and frequency of exposure.
Bioavailability (absorption)
No data needed to be derived for dermal exposure, because of the corrosive properties due to 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 the fact that the subchronic or chronic NOAELs can be sufficiently derived from test via oral route.
Also, no data is needed for the application of choline hydroxide via inhalation, because choline hydroxide has a very low vapor pressure and is expected to have a high melting point, so the potential for the generation of inhalable forms is low and no dust with inhalable particles will be formed.
Hence, it is sufficient to derive the DNELs from the most sensitive / relevant endpoint, which would normally be the chronic (72 weeks) oral feeding study in rats (Shivapurkar N, 1986), were a NOAEL > 1200 was obtained for choline chloride, which was transformed into a NOAEL > 1040 mg/kg bw for choline base by recalculation from choline chloride, by performing route-to-route extrapolations. However, in this case a different approach was pursued - please refer to the details below.
In any case, the respective absorption rates via all three application routes need to be taken into account in order to derive the adjusted dose descriptor starting point, which are:
- 50 % absorption by oral application, taking into account the ionic structure, specific transport mechanisms and partial metabolism of the compound by the intestinal microflora.
- 25 % absorption after inhalation, taking into account the limited absorption due to the ionic structure, and the poorer expression of specific transport mechanisms.
- 50 % absorption after dermal exposure, taking into account the corrosive properties and hence, penetration-enhancing effects of choline base compared to the poor ability of choline chloride to penetrate the stratum corneum.
So, the DNELs for long-term systemic effects via inhalation or dermal route were determined via oral-to-inhalation resp. oral-to-dermal extrapolations.
Route-to-route extrapolation:
Oral-to-inhalation extrapolation is performed to obtain a long-term inhalation AI for systemic effects from the oral human AI from the Scientific opinion "Dietary Reference Values for choline" (NDA, 2016; doi: 10.2903/j.efsa.2016.4484). According to "Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012), in case of oral-to-inhalation extrapolation a default factor of 2 for absorption should be introduced.
The following formula was used: corrected inhalative AI = oral AI x (1/sRVhuman) x (ABSoral-human) x (ABSinhalation-human) x (6.7 m³/ 10 m³) x 7/5);
where sRV is standard respiratory volume of humans during 8 hours (= 0.096 m³/kg/day); ABS-absorption and 6.7 m³ and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, and 7d/5d is the different exposure duration in humans (general population) and human workers - workers (5 working days) vs. general population (7 days continuous exposure)
Oral-to-dermal extrapolation is performed to obtain long-term dermal AI for systemic effects from the oral human AI from the Scientific opinion "Dietary Reference Values for choline" (NDA, 2016; doi: 10.2903/j.efsa.2016.4484). The following formula was used:
corrected dermal AI = oral AI x (ABS oral-human/ABS dermal-human) x 7d/5d;
where ABS is absorption, and 7d/5d is the different exposure duration in humans (general population) and human workers - workers (5 working days) vs. general population (7 days continuous exposure)
Exposure conditions and respiratory volumes:
Differences in the respiratory volumes between experimental animals and humans were used when an oral human AI from the Scientific opinion "Dietary Reference Values for choline" (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) was used to assess inhalation exposure in humans. 0.096 m³/kg/day is the standard respiratory volumes in humans during 8h exposure. 6.7 and 10 m³ (each referring to a duration of 8 hours) are standard respiratory volumes for workers under normal conditions and by light activity, respectively. Furthermore, the different exposure condition in human workers and general population was taken into account (workers - 5 working days - versus - general population - 7 days continuous exposure).
Applying of assessment factors and calculation of DNELs:
No assessment factors have been applied to the corrected AI to obtain the endpoint specific DNELs. As this value applies for humans - including vulnerable population groups such as pregnant women - and for a life-time exposure duration, no Assessment factors (AFs) to correct uncertainties and variability within and between species in the effect data are necessary.
Calculation of DNELs:
Long-term exposure by inhalation – systemic effects:
The oral human AI of 6.67 mg/kg bw was converted into the inhalation AI:
Modification of the starting point: corrected NOAEC = 6.67 mg/kg bw x (1/0.096 m³) *(6.7/10)m³ * (50 % / 25 %) * (7 d/ 5 d) = 194.54 mg/m³.
Derivation of DNEL = corr. AI = 194.54 mg/m³
(No Assessment factors)
Long-term dermal exposure – systemic effects:
The oral human AI of 6.67 mg/kg bw was converted into the dermal AI:
corrected dermal AI = 6.67 x (50 % / 50 %) * (7 d / 5 d)
corr. dermal AI = 9.34 mg/kg bw
DNEL: corr. AI = 9.34 mg/kg bw/days
(No Assessment factors)
Justification for DNEL Derivation:
As outlined above, DNELs were derived using the Adequate Intake (AI) for non-pregnant adults (400 mg/day) published by EFSA Panel on Dietetic Products, Nutrition and Allergies (2016, doi: 10.2903/j.efsa.2016.4484). This recommended average daily intake level corresponds to 6.67 mg/kg/day, based on an adequate intake of 400 mg/kg and a reference body weight of 60 kg and is considered adequate for lifetime exposure of adult human subjects.
Moreover, as even higher AI of 480 and 520 mg/day were set for pregnant and lactating women, respectively, the AI of 400 mg/day is considered safe regarding reproduction and pre-/perinatal development as well. Furthermore, it should be noted that the AI of 400 mg/day has been set based on the average observed choline intake in healthy populations in the European Union and in consideration of the amounts of choline needed to replete about 70 % of depleted subjects who showed signs of organ dysfunction in a depletion/repletion study. Thus, the DNELs derived from this AI should be considered as very conservative and highly protective.
In the following, for the purpose of comparability the DNELs derived using the standard approach as explained in the respective guidance documents are given.
The DNEL calculation, based on a NOAEL of a chronic oral feeding study in rats (Shivapurka et al., 1986) on choline chloride, is shown under point 1.
Under point 2, the DNEL calculation based on the value of upper limit of choline for human adults, which correlates with hypotensive effect, nausea and diarrhoea, is shown.
As demonstrated in the summary table under point 3, the standard DNEL calculations using descriptors based on adversity observed in animal or human studies lead to significantly higher limit values than the DNEL calculation using the EFSA AI for choline.
Following the precautionary principle the EFSA AI for choline is considered as the most critical value resulting in the most conservative dose descriptor for DNEL derivation.
No systemic effects, treatment for 72 weeks, observation 31 weeks: NOAEL = NOEL: >1200 mg/kg bw/d, equivalent to a NOAEL of 1040 mg/kg bw for choline hydroxide.
- DNEL systemic, worker inhalation (long term):
Corrected NOAEL: 1040 mg/kg bw x (1/0.38 m³/kg/day) x (50 %/25 %) x (6.7/10) = 3667.37 mg/m³
Applied AFs: DNEL = 3667.37 mg/m³/(2.5 x 5 x 1 x 1 x 1 x 1 x 1) = 293.39 mg/m³
AFs are: 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration, 1 – allometric scaling (No allometric scaling should be applied in case of oral-to-inhalation extrapolation), 1 – dose response (clear dose response), 1 – quality of data base (default), 1 – remaining uncertainties (even though using read-across data, no additional AF for remaining uncertainties was applied because the NOAEL based on choline chloride was modified to a NOAEL for choline hydroxide and substance-specific differences in physicochemical properties between choline hydroxide and choline chloride were already taken into account by modification of absorbance values).
- DNEL systemic, worker dermal (long term):
Corrected NOAEL: 1040 mg/kg bw x (50 %/50 %) = 1040 mg/kg bw
Applied AF: DNEL = 1040 mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1) = 20.8 mg/kg bw.
AFs are: 4 – interspecies (default, rat to human), 2.5 – remaining interspecies differences, 5 – intraspecies, 1 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default), 1 – remaining uncertainties (even though using read-across data, no additional AF for remaining uncertainties was applied because the NOAEL based on choline chloride was modified to a NOAEL for choline hydroxide and substance-specific differences in physicochemical properties between choline hydroxide and choline chloride were already taken into account by modification of absorbance values).
LOAEL 7.5 g/d of choline for adults (70 kg) (US Institute of Medicine, 1998): correlated with hypotensive effect, nausea and diarrhoea; Uncertainty factor 2: Upper limit -> 3.5 g choline/d for adults (50 mg/kg bw/d)
- DNEL systemic, worker inhalation (long term): 50 mg/kg bw/day * (1/0.096 m³ / kg bw/day) * (6.7 m³ / 10 m³) * (50 % /25 %) * (7 d/ 5d) = 977 mg/m³
- DNEL systemic, worker dermal (long term): 50 mg/kg bw/day * (50 % / 50 %) * (7 d / 5 d) = 70 mg/kg bw/day
Systemic DNELs | Rodent data | AI | UL |
worker inhalation | 293.39 mg/m³ | 194.54 mg/m³ | 977 mg/m³ |
worker dermal | 20.8 mg/kg bw/day | 9.34 mg/kg bw/day | 70 mg/kg bw/day |
Based on these calculations, it is clear that the EFSA approach based on the AI reveals the lowest value. This value was chosen in a worst-case-approach as it represents the most conservative approach for DNEL derivation.
General Population - Hazard via inhalation route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 46.64 mg/m³
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 1
- Dose descriptor starting point:
- other: Al
- Value:
- 6.67 mg/kg bw/day
- Modified dose descriptor starting point:
- other: corr. AL
- Value:
- 46.64 mg/m³
- Explanation for the modification of the dose descriptor starting point:
The Adequate Intake (AI) of 6.67 mg/kg bw/day corresponding to a corrected AI of 46.64 mg/m³ derived from the EFSA Panel on Dietetic Products, Nutrition and allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation.
Details on derivation of corrected AI: 6.67 mg/kg bw/day * (1/0.286 m³ / mg/kg bw/day) * (50 % / 25 %) = 46.64 mg/m³
(the standard respiratory volume of humans during 24 hours of 0.286 m³/kg/day has been used.
Please also refer to argumentation stated below.
- AF for dose response relationship:
- 1
- Justification:
- default
- AF for differences in duration of exposure:
- 1
- Justification:
- no Assessment factor for differences in duration of exposure needs to be applied, as the AI applies to an oral chronic lifetime intake
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- No allometric scaling should be applied in case of oral-to-inhalation extrapolation
- AF for other interspecies differences:
- 1
- Justification:
- no Assessment factor for other interspecies differences needs to be applied, as the AI is a human derived value and is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for intraspecies differences:
- 1
- Justification:
- no Assessment factor for intraspecies differences needs to be applied, as the AI is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for the quality of the whole database:
- 1
- Justification:
- default (database is of high quality)
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
DNEL related information
General Population - Hazard via dermal route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6.67 mg/kg bw/day
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 1
- Dose descriptor starting point:
- other: Al
- Value:
- 6.67 mg/kg bw/day
- Modified dose descriptor starting point:
- other: corr. Al
- Value:
- 6.67 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The Adequate Intake (AI) of 6.67 mg/kg bw/day corresponding to 6.67 mg/kg bw/day derived from the EFSA Panel on Dietetic Products, Nutrition and allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation.
Derivation of corrected AI: 6.67 mg/kg bw/day * (50 % / 50 %) = 6.67 mg/kg bw/day
In detail, an oral absorption of 50 %, a dermal absorption of 50 % taking the corrosive properties of the substance into account has been used
Please also refer to argumentation stated below
- AF for dose response relationship:
- 1
- Justification:
- default
- AF for differences in duration of exposure:
- 1
- Justification:
- no Assessment factor for differences in duration of exposure needs to be applied, as the AI applies to an oral chronic lifetime intake
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- no Assessment factor for interspecies differences needs to be applied, as the AI is already a human derived value
- AF for other interspecies differences:
- 1
- Justification:
- no Assessment factor for other interspecies differences needs to be applied, as the AI is a human derived value and is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for intraspecies differences:
- 1
- Justification:
- no Assessment factor for intraspecies differences needs to be applied, as the AI is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for the quality of the whole database:
- 1
- Justification:
- default (database is of high quality)
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
Local effects
Long term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
Acute/short term exposure
- Hazard assessment conclusion:
- high hazard (no threshold derived)
General Population - Hazard via oral route
Systemic effects
Long term exposure
- Hazard assessment conclusion:
- DNEL (Derived No Effect Level)
- Value:
- 6.67 mg/kg bw/day
- Route of original study:
- Oral
DNEL related information
- DNEL derivation method:
- ECHA REACH Guidance
- Overall assessment factor (AF):
- 1
- Dose descriptor starting point:
- other: Al
- Value:
- 6.67 mg/kg bw/day
- Modified dose descriptor starting point:
- other: corr. Al
- Value:
- 6.67 mg/kg bw/day
- Explanation for the modification of the dose descriptor starting point:
The Adequate Intake (AI) of 6.67 mg/kg bw/day derived from the EFSA Panel on Dietetic Products, Nutrition and allergies (NDA, 2016; doi: 10.2903/j.efsa.2016.4484) for Choline is considered as the most conservative dose descriptor for the DNEL derivation.
Derivation of corrected AI: 6.67 mg/kg bw/day = 6.67 mg/kg bw/day (no correction necessary)
Please also refer to the argumentation stated below.
- AF for dose response relationship:
- 1
- Justification:
- default
- AF for differences in duration of exposure:
- 1
- Justification:
- no Assessment factor for differences in duration of exposure needs to be applied, as the AI applies to an oral chronic lifetime intake
- AF for interspecies differences (allometric scaling):
- 1
- Justification:
- no Assessment factor for interspecies differences needs to be applied, as the AI is already a human derived value
- AF for other interspecies differences:
- 1
- Justification:
- no Assessment factor for other interspecies differences needs to be applied, as the AI is a human derived value and is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for intraspecies differences:
- 1
- Justification:
- no Assessment factor for intraspecies differences needs to be applied, as the AI is applicable for all adult human subjects and is also considered safe regarding reproduction and pre-perinatal development as well
- AF for the quality of the whole database:
- 1
- Justification:
- default (database is of high quality)
- AF for remaining uncertainties:
- 1
- Justification:
- no remaining uncertainties
Acute/short term exposure
- Hazard assessment conclusion:
- no hazard identified
DNEL related information
General Population - Hazard for the eyes
Local effects
- Hazard assessment conclusion:
- medium hazard (no threshold derived)
Additional information - General Population
- NOAEL/NOEL from chronic animal study (rats, oral, feed) (Shivapurka et al, 1986):
- Upper limit -> 3.5 g choline/d for adults (50 mg/kg bw/d) (EFSA, 2016)
- Summary
The principles of the DNEL calculation for the general population are the same as already described for workers. However, there are additional considerations or deviations for:
Modification of the starting point:
Bioavailability (absorption):
The oral, dermal and inhalation absorption values used are the same as done for workers.
Respiratory volumes:
Adaptions in the respiratory volumes under normal conditions in humans were taken into account. A default respiratory volume of 0.286 m³/kg bw for humans (general population) was used to convert oral AI into inhalation AI, referring to 24h exposure instead of 8h (worker).
Additional explanation: the sRV (standard respiratory volume of humans during 24 hours) of 0.286 m³/kg/day has been used.
Applying of assessment factors:
No assessment factors have been applied to the corrected AI to obtain the endpoint specific DNELs. As this value applies for humans - including vulnerable population groups such as pregnant women - and for a life-time exposure duration, no Assessment factors (AFs) to correct uncertainties and variability within and between species in the effect data are necessary.
Calculation of endpoint-specific DNELs for general population
Long-term exposure - systemic effects (oral):
The oral AI of 6.67 mg/kg bw was not modified for differences in absorption by oral route since no substance- and route specific information is available:
DNEL = 6.67 mg/kg bw.
(No Assessment factors).
Long-term exposure - systemic effects (dermal):
For the oral AI of 6.67 mg/kg bw, the following conversion was necessary:
dermal AI = oral AI x (50 % / 50 %) = 6.67 mg/kg bw
(an oral absorption of 50 % and a dermal absorption of 50 %)
DNEL = 6.67 mg/kg bw
(No Assessment factors)
Long-term exposure - systemic effects (inhalation):
The oral AI of 6.67 mg/kg bw was converted into the inhalation AI:
Corrected inhalation AI = oral AI x (1/0.286 m³/kg bw/day) x (ABS oral-humanABS inhal-human), where 0.286 is the standard respiratory volume (m³/kg bw) of humans during 24 h exposure, ABS is absorption (values are the same as described for workers).
Corrected Inhalation AI = 6.67 mg/kg bw x (1/0.286 m³/kg/day) x (50 %/25 %) = 46.64 mg/m³
DNEL = 46.64 mg/m³
(No Assessment factors)
Selected DNELs
DNEL systemic oral = 6.67 mg/kg bw
DNEL systemic dermal = 6.67 mg/kg bw
DNEL systemic inhalation = 46.64 mg/m³
Justification for DNEL Derivation:
As outlined above, DNELs were derived using the Adequate Intake (AI) for non-pregnant adults (400 mg/day) published by EFSA Panel on Dietetic Products, Nutrition and Allergies (2016, doi: 10.2903/j.efsa.2016.4484).
This recommended average daily intake level corresponds to 6.67 mg/kg/day, based on an adequate intake of 400 mg/day and a reference body weight of 60 kg and is considered adequate for lifetime exposure of adult human subjects.
Moreover, as even higher AI of 480 and 520 mg/day were set for pregnant and lactating women, respectively, the AI of 400 mg/day is considered safe regarding reproduction and pre-/perinatal development as well. Furthermore, it should be noted that the AI of 400 mg/day has been set based on the average observed choline intake in healthy populations in the European Union and in consideration of the amounts of choline needed to replete about 70 % of depleted subjects who showed signs of organ dysfunction in a depletion/repletion study. Thus, the DNELs derived from this AI should be considered as very conservative and highly protective.
In the following, for the purpose of comparability the DNELs derived using the standard approach as explained in the respective guidance documents are given.
The DNEL calculation based on a NOAEL of a chronic oral feeding study in rats (Shivapurka et al., 1986) on choline chloride is shown under point 1. Under point 2, the DNEL calculation based on the value of the upper limit (UL) of choline for human adults, which correlates with hypotensive effect, nausea and diarrhoea, is shown.
As demonstrated in the summary table under point 3, the standard DNEL calculations using descriptors based on adversity observed in animal or humans studies lead to significantly higher limit values than the DNEL calculation using the EFSA AI for choline.
Following the precautionary principle, the EFSA AI for choline is considered as the most critical value resulting in the most conservative dose descriptor for DNEL derivation.
No systemic effects, treatment for 72 weeks, observation 31 weeks: NOAEL = NOEL: >1200 mg/kg bw/d, equivalent to a NOEAL of 1040 mg/kg bw for choline hydroxide.
- DNEL systemic, general population inhalation (long term):
Corrected NOAEL: 1040 mg/kg bw x (1/1,15 m³/kg/day) x (50 %/25 %) = 1808.70 mg/m³
Applied AFs: DNEL = 1808.70 mg/m³ / (2.5 x 10 x 1 x 1 x 1 x 1*) = 72.34 mg/m³.
AFs are: 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration, 1 – allometric scaling (No allometric scaling should be applied in case of oral-to-inhalation extrapolation), 1 – dose response (clear dose response), 1 – quality of data base (default), 1 – remaining uncertainties (even though using read-across data, no additional AF for remaining uncertainties was applied because the NOAEL based on choline chloride was modified to a NOAEL for choline hydroxide and substance-specific differences in physicochemical properties between choline hydroxide and choline chloride were already taken into account by the modified absorbance value).
- DNEL systemic, general population dermal (long term):
Corrected NOAEL: 1040 mg/kg bw x (50 % / 50 %) = 1040 mg/kg bw
Applied AF: DNEL = 1040 mg/kg bw/(4 x 2.5 x 10 x 1 x 1 x 1) = 10.4 mg/kg bw/d
AFs are: 4 – interspecies (default, rat to human), 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration, 1 – dose response (clear dose response), 1 – quality of data base (default), 1 – remaining uncertainties (even though using read-across data, no additional AF for remaining uncertainties was applied because the NOAEL based on choline chloride was modified to a NOAEL for choline hydroxide and substance-specific differences in physicochemical properties between choline hydroxide and choline chloride were already taken into account by the modified absorbance value).
- DNEL systemic, general population oral = 1040 mg/kg bw / (4 x 2.5 x 10 x 1 x 1 x 1) = 10.4 mg/kg bw
AFs are: 4 – interspecies (default, rat to human), 2.5 – remaining interspecies differences, 10 – intraspecies, 1 – study duration (no time extrapolation factor in case of local effects), 1 – dose response (clear dose response), 1 – quality of data base (default), 1 – remaining uncertainties (even though using read-across data, no additional AF for remaining uncertainties was applied because the NOAEL based on choline chloride was modified to a NOAEL for choline hydroxide and substance-specific differences in physicochemical properties between choline hydroxide and choline chloride were already taken into account by the modified absorbance value).
LOAEL 7.5 g/d of choline for adults (70 kg) (US Institute of Medicine, 1998): correlated with hypotensive effect, nausea and diarrhoea; Uncertainty factor 2: Upper limit -> 3.5 g choline/d for adults (50 mg/kg bw/d)
- DNEL systemic, general population inhalation (long term): 50 mg/kg bw/day * (1/0.286 m³ / mg/kg bw/day) * (50 % / 25 %) = 350 mg/m³
- DNEL systemic, general population dermal (long term): 50 mg/kg bw/day * (50 % / 50 %) = 50 mg/kg bw/day
- General population oral (long term): 50 mg/kg bw/d
Systemic DNELs | Rodent data | AI | UL |
General population, inhalation | 72.34 mg/m³ | 46.64 mg/m³ | 350 mg/m³ |
General population, dermal | 10.4 mg/kg bw | 6.67 mg/kg bw/day | 50 mg/kg bw/day |
General population, oral | 10.4 mg/kg bw/day | 6.67 mg/kg bw | 50 mg/kg bw/day |
Based on these calculations, it is clear that the EFSA approach based on the AI reveals the lowest value. This value was chosen in a worst-case-approach as it represents the most conservative approach for DNEL derivation.
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