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EC number: 201-137-0 | CAS number: 78-73-9
- 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
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Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1966
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: well documented study result, which meets basic scientific principles, conducted on the read-across substance Choline chloride
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 966
- Report date:
- 1966
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- In the feeding studies the animals (16 / 12 / 11 or 7 pregnant mice, gestation day 1 -18) were treated daily via the diet with Choline chloride (1 %, 2.5 %, 5 % and 10 % in feed). The rats ingested daily approximately 5 g of food. On gestation day 19 all animals were subjected to necropsy and the uteri and fetuses were examined.
- GLP compliance:
- not specified
- Remarks:
- study was performed prior to implementation of GLP
- Limit test:
- no
Test material
- Reference substance name:
- Choline chloride
- EC Number:
- 200-655-4
- EC Name:
- Choline chloride
- Cas Number:
- 67-48-1
- IUPAC Name:
- 2-hydroxy-N,N,N-trimethylethanaminium chloride
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report): N-Trimethyl-ß-hydroxyäthyl-ammoniumchlorid
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Ivanova Kisslegg, Germany
- Housing: single in glasses
- Diet (e.g. ad libitum): every second day one piece of bread per animal per day. Thus about 5 grams of food were taken in.
- Water (e.g. ad libitum): ad libitum (out of drinking bottles)
For the investigations, NMRI mice of the company Ivanova Kisslegg in Germany, were used. Their fertility, rate of spontaneous foetal resorptions
and rate of anomalies are known through extensive testing. The methodology corresponded to the one described in the laboratories previous reports.
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Feeding trials:
Food preparation:
For the preparation of feed with 1 %, 2.5 %, 5 % and 10 % of Choline chloride (= 10 000 ppm - 100 000 ppm), 5 g, 12.5 g, 25 g or 50 g of Choline chloride were finely distributed in 300 mL of a 1 % aqueous traganth suspension in the Ultra-Turrex, then finely ground with 500 g of rats bread (Lab Blox from Allied Mills, Chicago) in the Star-mix and mixed with a special machine, divided in 50 approximately equal pieces and dried for 14 - 15 hours at +80 ° C. The pieces of bread weighed 9.5 to 11 g.
Experiment:
The choline containing bread was given to all experimental animals (pregnant mice from 1 - 18 day of gestation). The number of pregnant mice in the individual test groups was in the "1 % - group" 16, in the "2.5 % group" 12, in the "5 % group" ~ 11, and the "10 % - group" 7 animals.
All mice were housed singly in glases and provided with 1 peice of bread every second day and water ad libitum. Of the bread thus were taken in about 5 grams of food per day. On gestation day 19, all animals were sacrifices and the uteri and fetuses wer e examined. - Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- no data
- Duration of treatment / exposure:
- between the 1st and 18th day of gestation
- Frequency of treatment:
- via the feed (rat bread), the feed for 2 days was given at once every second days
- Duration of test:
- 19 days
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
1 %
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
2.5 %
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
5 %
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
10 %
Basis:
nominal conc.
- No. of animals per sex per dose:
- 1 % in rat bread - 16 animals
2.5 % in rat bread - 12 animals
5 % in rat bread - 11 animals
10 % in rat bread - 7 animals - Control animals:
- yes, historical
Examinations
- Maternal examinations:
- On the 19th day of gestation, all animals were sacrificed and the uteri and fetuses examined in the manner described earlier.
- Ovaries and uterine content:
- On the 19th day of gestation, all animals were sacrificed and the uteri and fetuses examined in the manner described earlier.
- Fetal examinations:
- mean number of offsprings, the mean foetal body weight, mean foetal length, the foetal resportion rate and the number of anomalies
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Decrease in body weight gain with increasing dose of Choline chloride, see table 2.
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 4 160 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 4 921 mg/kg bw/day (nominal)
- Based on:
- other: Choline bicarbonate
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 10 000 ppm (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 1 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 1 479 mg/kg bw/day (nominal)
- Based on:
- other: Choline bicarbonate
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 1 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOEL
- Effect level:
- 1 479 mg/kg bw/day (nominal)
- Based on:
- other: Choline bicarbonate
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 4 160 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: other:
- Dose descriptor:
- LOAEL
- Effect level:
- 4 921 mg/kg bw/day (nominal)
- Based on:
- other: Choline bicarbonate
- Basis for effect level:
- other: other:
- Dose descriptor:
- LOAEL
- Effect level:
- 10 800 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- LOAEL
- Effect level:
- 12 777 mg/kg bw/day (nominal)
- Based on:
- other: choline bicarbonate
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes. Remark: Observed adverse effects are not related to teratogenic effects of Choline chloride but maternal toxicity.
Details on embryotoxic / teratogenic effects:
See table 3
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
The amount of Choline chloride uptake is given per animal and day; per kg mouse/day and within the whole time of experimental treatment as well as per kg intake of Choline chloride in table 1.
Table 1 | |||||
Amount of Choline chloride uptake | |||||
Choline chloride concentration in feed (%) | mean body weight during experiment | mean amount of Choline chloride uptaken | |||
per day | total | ||||
per mouse | per kg mouse | per mouse | per kg mouse | ||
1,0 % | 40 g | 0,05 g | 1,25 g | 0,90 g | 22,5 g |
2.5 % | 30 g | 0,125 g | 4,16 g | 2,25 g | 74,8 g |
5,0 % | 30 g | 0,250 g | 10,80 g | 4,50 g | 194,4 g |
10,0 % | 25 g | 0,5 g | 20,00 g | 9,00 g | 360,0 g |
The average body weight gain between day 1.-19. of gestation was in the "1 %" Choline chloride group 25.2 g. The average body weight gain was reduced in a dose-dependent manner with the increased Choline chloride concentration. The reduced body weight gain in mice, as shown in table 2, is only partly due to the abortion, because in the "2.5 -group", and even more in the "5 % group" dams, which did not abort, had a significantly lower body weight gain, as the mice which received the feed with 1 % Choline chloride.
Table 2 | ||
mean body weight gain of pregnant mice from day 1-19 of gestation | ||
Choline concentration in feed (%) | number of pregnant mice | mean body weiht gain (g) |
1 %= 10 000 ppm | total 16 | + 25,2 |
without abortion 16 | + 25,2 | |
with abortion 0 | - | |
2.5 % = 25 000 ppm | total 12 | + 11,9 |
without abortion 8 | + 16,6 | |
with abortion 4 | + 2,7 | |
5 % = 50 000 ppm | total 11 | + 3,7 |
without abortion 3 | + 12,6 | |
with abortion 8 | + 0,2 | |
10 % = 100 000 ppm | total 7 | - 5,2 |
with abortion 7 | - 5,2 |
In all 7 animals receiving the Choline chloride 10% solution (= 100,000 ppm) in the diet and in 8 of 11 mice receiving the bread with 5 % (=50 000 ppm) it resulted in expulsion of all fetuses, so that in these animals after the death at the 19th day of gestation in the uterus only the implantation sites were detected. Even in the mice fed 2.5 % Choline chloride, 4 of the 12 mice aborted. Moreover, the 32 surviving fetuses of the " 5 % group" were well behind in development. The administration of food with a content of 1 % (=10,000 ppm) Choline chloride did not affect the development of the offsprings (Table 3).
Table 3 | ||||||||||
Testing of Choline chloride for teratogenic effects in mice (feeding-experiments) - on day 1-18 of gestation | ||||||||||
Choline chloride concentration in feed (%) | number of pregnant mice | mean fetus - | Foetal resportion | Abortions | Number of fetus with anomalies / total number of living fetus | |||||
with fetus with anomalies | total | number | weight (g) | length (cm) | absolute | % | absolute | % | ||
1 % = 10,000 ppm | 3 | 16 | 10,3 | 1,4 | 2,4 | 7 | 4,0 | - | 3/166 (2 cleft palate 1 confused ribs) | |
2,5 % = 25,000 ppm | 0 | 12 | 5,8 | 1,2 | 2,2 | 4 | 3,6 | 39 | 34,8 | 0/69 |
5 % s» 50,000 ppm | 1 | 11 | 2,9 | o,9 | 2,0 | 2 | 1,8 | 77 | 69,4 | 1/32 (confused ribs) |
10 % = 100,000 ppm | 0 | 7 | - | - | = | - | 68 | 100,0 | - | |
control mice without treatment | ||||||||||
0 % | 50 | 414 | 9,5 | 1,3 | 2,2 | 343 | 7,99 | 12 | 0,28 | 40/3918 (cleft palate) |
6/3918 (exencephaly) | ||||||||||
2/3918 (mikrocephaly) | ||||||||||
1/ " " (mikrognathie) | ||||||||||
4/ " " (hypo- or -aplasia of throcic vertebra) | ||||||||||
1/ " " (aplasia of vertebra of ripps) | ||||||||||
6/ " " (ripp-anomalies) |
Even after 5 repeated intraperitoneal injections, Choline chloride (in a dose corresponding to half LD50/kg) on gestation days 11 -15 did not affect of foetal development of NMRI mice. The feeding of Choline chloride over the entire period of gestation, in concentrations of 2.5 %, 5 % and 10 % (25 000 ppm to 100000 ppm) on the other hand, resulted in expulstion of all fetuses and thus to complete abortion in the majority of animals.This "abortion effect"' is not an expression of a specific embryotoxic toxicity but sign of a general toxicity, because not only the mice with abortion but also the animals without abortion had a significantly reduced body weight than any untreated pregnant mice. This thesis - the lack of a specific embryotoxic effect of Choline chloride - is also supported by the fact that the gavage of food with1 % (= 10,000 ppm) Choline chloride over the entire period of gestation was well tolerated by the dams without symptoms and the foetal development was not disturbed.
Choline chloride thus had under the given experimental conditions, no teratogenic effect, since the product caused only altered development in the foetuses at doses, which also had toxic effects on the dams.
Applicant's summary and conclusion
- Conclusions:
- The study on the read-across substance Choline chloride was classified as reliable with restrictions (Klimisch 2) and meets the requirements for a developmental toxicity study. Hence, the results can be considered as reliable and be used for the assessment of possible developmentally toxic effects.
The read-across from Choline chloride to Choline hydrogen carbonate (CbiC) is justified because the absorption after oral application is very likely to remained unchanged, since the toxicologically relevant choline cation is identical in both salt, its transport mechanisms in the body are only relevant for the cation, too, and no absorption-enhancing irritating effects are expected from the anion.
The expected most relevant exposure route is the oral route. Once dissociated in the aqueous acidic environment in the stomach, the bicarbonate anion will be transformed. In an aqueous solution, hydrogen carbonate is in an equilibrium with the anhydrate of the carbonic acid, carbon dioxide (CO2):
CO2 + 2 H2O ⇌ H3O+ + HCO3- with a pKs = 6.4 referring to carbon dioxide (Riedel E (1999) “Anorganische Chemie”, 4th edition, Berlin; New York, de Gruyter).
Due to the strongly acidic environment of the stomach, the equilibrium will be furthermore shifted to the side of CO2, which is a regular product of cell respiration, is so ubiquitous present in the body anyway and subject of effective excretion processes.
So, information gained from choline chloride for this endpoint can be used to cover it without regarding the bicarbonate anion or modification except adjusting the dose regarding the molecular weight of both choline salts.
The feeding of choline chloride (CC) over the entire period of gestation, in concentrations of 2.5 %, 5 % and 10 % (25 000ppm to 100000 ppm), resulted in expulsion of all fetuses and thus to complete abortion in the majority of animals, beginning with 34.8 % abortions (4,160 mg/kg bw/d CC ≙ 4,921 mg/kg bw/day CbiC) to complete loss of all fetuses (20,000 mg/kg bw/d CC ≙ 23,661 mg/kg bw/day CbiC). This "abortion effect"' is not an expression of a specific embryotoxic toxicity but sign of a general toxicity, because not only the mice with abortion but also the animals without abortion had a significantly reduced body weight compared to untreated pregnant mice. This thesis - the lack of a specific embryotoxic effect of choline chloride - is also supported by the fact that the gavage of food with 1 % Choline chloride (= 10,000 ppm ≙ 1,250 mg/kg bw/d CC ≙ 1,479 mg/kg bw/day CbiC) over the entire period of gestation was well tolerated by the dams without symptoms and the fetal development was not disturbed.
The only reason to determine the NOAEL to be 4160 mg/kg bw/d choline chloride (2.5 % in feed, ≙ 4,921 mg/kg bw/day CbiC) and to take this dose level for further risk assessment, was because the IUCLID5 software requires a numeric value and the first effects on the fetal development were seen in the next higher dose (5 % in feed), although they are not related to possible developmentally toxic effects of the compound itself but to maternal toxicity.
Choline chloride thus had under the given experimental conditions no teratogenic effect, since the product caused only altered development in the fetuses at doses, which also had toxic effects on the dams.
As a consequence, choline chloride and so choline bicarbonate does not need to be classified as toxic to reproduction, neither according to Regulation 1272/2008/EC nor Directive 67/548/EEC. - Executive summary:
- In the feeding studies the animals (16 / 12 / 11 or 7 pregnant mice, gestation day 1 -18) were treated daily via the diet with Choline chloride (1 %, 2.5 %, 5 % and 10 %, BASF, 1966). The choline containing bread was given to all experimental animals (pregnant mice from 1 - 18 day of gestation). The number of pregnant mice in the individual test groups was in the "1 % - group" 16, in the "2.5 % group" 12, in the "5 % group" ~ 11, and the "10 % - group" 7 animals. All mice were housed singly in glases and provided with 1 piece of bread every second day and water ad libitum. Thus about 5 grams od food per day were taken in. On gestation day 19, all animals were sacrificed and subject to necropsy and the uteri and fetuses were examined and the mean number of offsprings, the mean foetal body weight, mean foetal length, the foetal resportion rate and the number of anomalies were noted.The average body weight gain between day 1.-19. of gestation was in the "1 %" Choline chloride group 25.2 g. The average body weight gain was reduced in a dose-dependent manner with the increased Choline chloride concentration. The reduced body weight gain in mice, was only partly due to the abortion, because in the "2.5 -group", and even more in the "5 % group" dams, which did not abort, had a significantly lower body weight gain, as the mice which received the feed with 1 % Choline chloride.In all 7 animals receiving the Choline chloride 10% solution (= 100,000 ppm)in the diet and in 8 of 11 mice receiving the bread with 5 % (= 50 000 ppm) it resulted in expulsion of all fetuses,so that in these animals after the death at the 19th day of gestation in the uterus only the implantation sites were detected. Even in the mice fed 2.5 % Choline chloride, 4 of the 12 mice aborted. Moreover, the 32 surviving fetuses of the "5 % group" were well behind in development. The administration of food with a content of 1 % (=10,000 ppm) Choline chloride did not affect the development of the offsprings.
Choline chloride thus had under the given experimental conditions, no teratogenic effect, since the product caused only altered development in the foetuses at doses, which also had toxic effects on the dams. The study was classified as reliable with restrictions and meets the requirements for a developmental toxicity study. Choline chloride does not need to be classified as toxic to reproduction, neither according to Regulation 1272/2008/EC nor Directive 67/548/EEC.
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