Choline hydrogen carbonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

200.29 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Modified dose descriptor starting point:

NOAEC

Value:

5 007.37 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans and hence, repeated dose toxicity testing viathe inhalation route was not done. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

NOAEL derived from chronic study, no additional AF required

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:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default (workers)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

2

Justification:

Remaining uncertainties because of read-across from Choline chloride to Choline hydrogen carbonate. No other remaining uncertainties, especially because the NOAEL corresponds to the highest dose tested.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

71 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Value:

7 100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Long-term systemic DNEL for dermal route has been derived from the NOAEL > 1420 mg/kg bw/day established in the oral chronic study in rats (Shivapurkar N, 1986). A repeated dose toxicity testing via dermal route was not performed because the oral route is the most likely route of exposure for humans, the dermal route is not required and omitted due to animal welfare. When applied orally, no neoplasms or carcinomas were seen in the first targeted organs which could possibly indicate proliferating effects due to irritation. Also, no irritating or other adverse effects were reported in IUCLID chapters 7.3 and 7.4 indicating a high local tolerance towards the substance when applied dermally. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case, is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

NOAEL derived from chronic study, no additional AF required

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

5

Justification:

default (workers)

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, especially because the NOAEL corresponds to the highest dose tested

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The calculation of the DNELs is performed in accordance with the principles given in ECHA (2008) “Guidance of Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health”.

In general, for workers only the derivation of the DNELs for long-term systemic effects (Hazard via inhalation / dermal route) were considered necessary. Besides the DNELs for long-term systemic effects on the general population (Hazard via inhalation / dermal / oral route) t

hese are the only mandatory DNELs; the other DNELs (local effects / short-term exposure) were not considered necessary because first, no local effects were seen in all available studies and the substance is not classified as irritating to the skin and eyes. Second, the substance is not classified as acute toxic (LD50 > 2000 mg/kg bw), which rises no concern for adverse effects by a short-term peak exposure. Also, for Choline bicarbonate, the most relevant exposure for humans is via the oral route. This is the standard application route to explore systemic effects and is furthermore the route resulting in the highest absorption of the substance. The generation of inhalable forms is low, due to the low vapour pressure and the fact that Choline bicarbonate is only distributed as an aqueous solution. Also, due to the ionic structure, the absorption via the dermal route can be neglected. Hence, relevant points to consider when deriving the DNELs for choline hydrogen carbonate were:

 

Mode of action:

From all available data for the different human health endpoints it is clear that Choline bicarbonate 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.

For the non-threshold endpoints (mutagenicity and carcinogenicity) no DNELs can be derived, because a No-Effect Level could not be established from the relevant studies. Hence, the hazard characterization is based on a qualitative approach.

 

Local effects:

The derivation of the DNELs for local effects is not needed because the substance is neither classified as a skin nor an eye irritant nor as a skin sensitizer, and, in combination with the fact that the generation of inhalable forms is low, choline bicarbonate is not expected to be irritating or sensitizing to the respiratory system. There is no data indicating a dose-response and route-specific effects for inhalation or dermal application. Hence, local effects are covered sufficiently by the long-term DNEL for systemic effects.

 

Modification of the starting point:

There is no indication that the bioavailability via the oral route in rats in not relevant for humans. Diffusion is a physico-chemical phenomenon and not species-specific. Also, the responsible transporters for choline are expressed in the tissues of both human and rat.

No study needed to be conducted for dermal exposure, because the physicochemical and toxicological properties do not suggest a potential for a significant rate of absorption through the skin. Also, no data is needed for the application of choline bicarbonate via inhalation, because Choline bicarbonate 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.

No relevant differences in human and experimental exposure conditions are expected. Even if a high peak exposure via the oral route is not expected in humans, effective clearance mechanisms take hold to eliminate additional choline.

Hence, it is sufficient to derive the DNELs from the most sensitive / relevant endpoint, which is the chronic (72 weeks) oral feeding study in rats (Shivapurkar N, 1986), were a NOAEL > 1420 mg/kg bw was obtained, by performing route-to-route extrapolations.

Here, 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

- 10 % absorption after dermal exposure, taking into account the negligible ability of choline bicarbonate 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.

 

Respiratory volumes:

Differences in the respiratory volumes between experimental animals and humans were used when an oral rat NOAEL from the chronic feed study in rats was used to assess inhalation exposure in humans. 0.38 m³/kg/day is the standard respiratory volumes in rats during 8h exposure. 6.7 and 10 m³ are standard respiratory volumes for workers under normal conditions and by light activity, respectively.

Exposure duration:

No modifications concerning the exposure duration were considered necessary. The selected dose descriptor starting point was a NOAEL derived from a chronic study in rats (2 years), which corresponds to the average lifetime of rats. Hence, no modification need to be made when assessing the risk of a lifetime exposure in humans.

Assessment factors to cover uncertainties and variations:

- Duration of exposure: No additional uncertainty was detected, because the available NOAEL was already derived from a chronic study covering the life span of the test species, hence, an AF of 1 was applied.

- Allometric scaling: In general, no allometric scaling should be applied in case of oral-to-inhalation extrapolation. For oral-to-dermal extrapolation, the species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the chronic oral toxicity study, which was used to derive the dermal long-term DNEL.

- Other Interspecies differences: A default assessment factor of 2.5 was applied for remaining interspecies differences in toxicodynamics between rat and human in all cases.

- Intraspecies differences: A default assessment factor of 5 was applied for workers for all endpoints and for all exposure routes.

- Dose response: A default assessment factor of 1 was applied because no variations in dose-response were detected (clear dose response).

- Quality of whole database: The relevant dose descriptor, an oral chronic study, was obtained from a database of high quality, and so an AF of 1 was applied because no additional uncertainties are arising.

An additional assessment factor of 2 was applied, as the available NOAEL was derived from read-across; no further uncertainties were detected, which is reflected in a total AF of 2 for remaining uncertainties.

The oral chronic study in rats (Shivapurkar N, 1986) with a NOAEL > 1420 mg/kg bw served as the starting point for the DNEL derivation.

The study with the longest test duration was chosen as this is the likeliest study to detect all possible substance-related effects with repeated application, which is the actual purpose of the testing for repeated dose toxicity. Also, all available studies on repeated dose toxicity revealed equivalent, plausible and consistent results over all three durations, i.e. give all no rise to concern of compound-related toxic effects and hence the most significant study (i.e. longest duration) was chosen.

 

Taking all the above mentioned factors into account, the relevant DNELs were derived to:

Long-term exposure - systemic effects (inhalation): DNEL = 200.29 mg/m³

(1^st step: Conversion of oral NOAEL to inhalatory NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) x (6.7 m³/10 m³) = 1420 mg/kg bw x (1/0.38 m³/kg/day) x (50 %/25 %) x (6.7/10) = 5007.37 mg/m³

2^nd step: DNEL derivation under application of assessment factors, according:

DNEL = 5007.37 mg/m³/(2.5 x 5 x 1 x 1 x 1 x 1 x 2) = 200.29 mg/m³.

Assessment factors 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), 2 - read-across.

 

Long-term exposure - systemic effects (dermal): DNEL = 71 mg/kg bw/day

(1^st step: Conversion of oral to dermal NOAEL:

Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1420 mg/kg bw x (50 %/10 %) = 7100 mg/kg bw

2^ndstep: DNEL derivation under application of assessment factors, according:

DNEL = 7100 mg/kg bw/(4 x 2.5 x 5 x 1 x 1 x 1 x 2) = 71 mg/kg bw.

Assessment factors 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), 2 - read-across

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

49.39 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Value:

2 469.57 mg/m³

Explanation for the modification of the dose descriptor starting point:

Due to the low vapour pressure of the test substance acute exposure hazard via inhalation is unlikely for humans and hence, repeated dose toxicity testing via inhalation route was not done. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

NOAEL derived from chronic study, no additional AF required

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:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

2

Justification:

Remaining uncertainties because of read-across from Choline chloride to Choline hydrogen carbonate. No other remaining uncertainties, especially because the NOAEL corresponds to the highest dose tested.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

35.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

7 100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The long-term systemic DNEL for the dermal route has been derived from the NOAEL > 1420 mg/kg bw/day established in the oral chronic study in rats (Shivapurkar N, 1986). A repeated dose toxicity testing via the dermal route was not performed, because the oral route is the most likely route of exposure for humans, the dermal route is not required and omitted due to animal welfare. When applied orally, no neoplasms or carcinomas were seen in the first targeted organs which could possibly indicate proliferating effects due to irritation. Also, no irritating or other adverse effects were reported in IUCLID chapters 7.3 and 7.4, indicating a high local tolerance towards the substance when applied dermally. Therefore a route-to-route extrapolation from an oral repeated dose study, as a worst case, is justified.

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

NOAEL derived from chronic study, no additional AF required

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

2

Justification:

Remaining uncertainties because of read-across from Choline chloride to Choline hydrogen carbonate. No other remaining uncertainties, especially because the NOAEL corresponds to the highest dose tested.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.1 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Value:

1 420 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

not applicable

AF for dose response relationship:

1

Justification:

default

AF for differences in duration of exposure:

1

Justification:

NOAEL derived from chronic study, no additional AF required

AF for interspecies differences (allometric scaling):

4

Justification:

default (rat to human)

AF for other interspecies differences:

2.5

Justification:

default

AF for intraspecies differences:

10

Justification:

default (general population)

AF for the quality of the whole database:

1

Justification:

default (database is of high quality)

AF for remaining uncertainties:

2

Justification:

Remaining uncertainties because of read-across from choline chloride to choline hydrogen carbonate. No other remaining uncertainties, especially because the NOAEL corresponds to the highest dose tested.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The principles of the DNEL calculation for the general population are the same as already described for workers. However, besides the DNELs for long-term systemic effects (Hazard via inhalation / dermal route), also the DNEL for long-term systemic effects via the oral route needs to be derived. There are additional considerations or deviations to take into account:

 

Route of exposure / Bioavailability (absorption):

The oral absorption in rats and in humans is assumed to be the same. The minor part contributing to absorption, passive diffusion, is a rather physico-chemical phenomenon and species-independent. Also, the microintestinal flora, which is responsible for the partial metabolism to trimethylamine prior to absorption, can be considered to have the same metabolic capacity due to wide distribution of all possibly present bacteria with a negligible species selectivity.

The major part of choline absorption is due to transport mechanisms. Here, the possibly involved transporters are for gastrointestinal absorption the three organic cation transporters OTC1, OTC2 and OTC3, facilitating the low-affinity transport, and the CTL1-5 genes (choline-specific transporter-like proteins), facilitating the intermediate-affinity sodium-independent transport. These transporters are expressed in both human and rat tissues and hence, also in this case no differences are expected.

 

Respiratory volumes:

No differences in the respiratory volumes under normal conditions and by light activity in humans were taken into account. A default respiratory volume of 1.15 m³/kg bw for rats was used to convert oral NOAEL into inhalation NOAEC.

 

Assessment factors to cover uncertainties and variations:

- Intraspecies variations: A higher assessment factor of 10 (instead of 5 for workers) for intraspecies variation/differences of the human population was used. This default factor needs to be enlarged because of the wider variations present in the general population. Here not only healthy adults need to be taken into consideration, but also children, elder or non-healthy humans.

- Allometric scaling: In case of the derivation of an oral DNEL for humans from animal data, a species specific allometric scaling factor is necessary, too. The species-specific default assessment factor of 4 for allometric scaling for rats was applied in the case of employment of the oral NOAEL from the chronic oral toxicity study, which was used to derive the dermal long-term DNEL.

 

Taking all the above mentioned factors into account, the relevant DNELs were derived to:

 

Long-term exposure - systemic effects (inhalation): DNEL = 49.39 mg/m³

(1^st step: Conversion of oral NOAEL to inhalatory NOAEC:

Inhalation NOAEC = oral NOAEL x (1/sRVrat) x (ABS oral-rat/ABS inhal-human) = 1420 mg/kg bw x (1/1,15 m³/kg/day) x (50 %/25 %) = 2469.57 mg/m³

2^nd step: DNEL derivation under application of assessment factors, according:

DNEL = 2469.57 mg/m³ / (2.5 x 10 x 1 x 1 x 1 x 1 x 2) = 49.39 mg/m³.

Assessment factors 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), 2 - read-across.

 

Long-term exposure - systemic effects (dermal): DNEL = 35.5 mg/kg bw/day

(1^st step: Conversion of oral to dermal NOAEL:

Dermal NOAEL = oral NOAEL x (ABS oral-rat/ABS dermal-human) = 1420 mg/kg bw x (50 %/10 %) = 7100 mg/kg bw

2^nd step: DNEL derivation under application of assessment factors, according:

DNEL = 7100 mg/kg bw / (4 x 2.5 x 10 x 1 x 1 x 1 x 2) = 35.5 mg/kg bw.

Assessment factors 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), 2 - read-across.

 

Long-term exposure - systemic effects (oral): DNEL = 7.1 mg/kg bw/day

The oral NOAEL of 1420 mg/kg bw was not modified for differences in absorption by oral route species-specific differences are to be expected:

Oral NOAEL rat = oral NOAEL human = 1200 mg/kg bw.

DNEL = 1420 mg/kg bw / (4 x 2.5 x 10 x 1 x 1 x 1 x 2) = 7.1 mg/kg bw.

Assessment factors 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), 2 - read-across.