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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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was performed on the read-across substance Choline chloride similar to OECD 452 with minor deviations and not all details are given. However, the available information is sufficient to consider the results as reliable.
Data source
Reference
- Reference Type:
- publication
- Title:
- Effect of methionine and choline on liver tumor promotion by phenobarbital and DDT in diethylnitrosamine-initiated rats.
- Author:
- Shivapurkar N, Hoover KL, Poirier LA
- Year:
- 1 986
- Bibliographic source:
- Carcinogenesis 7: 547-550
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Deviations:
- yes
- Remarks:
- only male rats used
- GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Choline chloride
- EC Number:
- 200-655-4
- EC Name:
- Choline chloride
- Cas Number:
- 67-48-1
- Molecular formula:
- C5H14NO.Cl
- IUPAC Name:
- 2-hydroxy-N,N,N-trimethylethanaminium chloride
- Test material form:
- not specified
- Details on test material:
- - Name of test material (as cited in study report): Choline chloride
- Other: Supplier: Fisher Chemical Company
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: no data
- Weight at study initiation: 50 - 60 g
- Fasting period before study: no
- Housing: three per cage in plastic shoebox cages
- Diet (e.g. ad libitum): ad libitum a natural ingredient ground chow (Wayne Laboratory Blox Allied Mills, Inc., Chicago, IL)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
chow diet was supplemented with 1.0 % Choline chloride - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- five days of non-supplemented chow, i.p. injection of saline (since the choline group served as a control group in a tumor promoting study), five days of non-supplemented chow.
72 weeks of treatment with supplemented chow, followed by 31 weeks post-observation with non-supplemented chow - Frequency of treatment:
- continuously, i.e. application via feed which was available ad libitum
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 other: percent (nominal) in diet
- Remarks:
- Doses / Concentrations: 1%
Basis: nominal in diet
- Dose / conc.:
- 10 000 ppm
- Remarks:
- calculated from the above mentioned dosage of 1 % in diet
- No. of animals per sex per dose:
- 30 males / dose
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: Choline treated rats served as controls in a tumor promoting study on Phenobarbital (PhB) and 1,1 bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), the levels of Choline chloride was based on previous experiments wherein these levels were shown to inhibit the drop in hepatic S-adenosylmethionine levels due to PhB and DDT
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable - Positive control:
- Due to original study aim (tumor promoting effects), results will be given derived from animals which were initiated with i.p. injection of 200 mg/kg bw of diethylnitrosamine dissolved in sterile normal saline followed by a diet supplemented with 0.05 % 1,1 bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT)
Examinations
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS: No data, only body weight denoted
BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were taken at weekly intervals for 16 weeks and biweekly thereafter
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not applicable
OTHER: Gross pathology performed - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 1)
HISTOPATHOLOGY: Yes, but no results provided - Other examinations:
- Growth and survival
- Statistics:
- The comparisons between the incidences of tumors in different groups were analysed by Fischer's exact test. The survival data were analysed by the computer program developed by Thomas el al. (Thomas CG, Breslow N and Gart JJ (1977) Trend and homogeneity analyses of proportions and life table data. Computers Biomed. Res., 10, 373-381.). Kaplan-Meier survival curves were derived by using this procedure. Comparison among survival of different experimental groups were made by Cox's test and P value based on the chi-square test from Cox's analysis. The incidences of liver and lung tumors and of leukemias in each group were based upon the number of animals surviving at 1 year since the first instance of each of the tumors occurred between weeks 55 and 60.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- mortality: no difference compared to control animals
- Mortality:
- no mortality observed
- Description (incidence):
- mortality: no difference compared to control animals
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- no difference compared to control animals
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- relative liver weight: no difference compared to control animals
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- performed, but limited data given; Liver and lung tumor formation: no difference compared to control animals
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- Various lung, liver and other tumors, leukemia: no difference compared to control animals
- Details on results:
- CLINICAL SIGNS AND MORTALITY - no difference compared to control animals
BODY WEIGHT AND WEIGHT GAIN - no difference compared to control animals
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study) no data
FOOD EFFICIENCY no data
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study) not applicable
OPHTHALMOSCOPIC EXAMINATION no data
HAEMATOLOGY no data
CLINICAL CHEMISTRY no data
URINALYSIS no data
NEUROBEHAVIOUR no data
ORGAN WEIGHTS - relative liver weight: no difference compared to control animals
GROSS PATHOLOGY - performed, but limited data given; Liver and lung tumor formation: no difference compared to control animals
HISTOPATHOLOGY: NON-NEOPLASTIC no data
HISTOPATHOLOGY: NEOPLASTIC (if applicable) - various lung, liver and other tumors, leukemia: no difference compared to control animals
HISTORICAL CONTROL DATA (if applicable) controls see table 1
OTHER FINDINGS See table 1
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- > 10 000 ppm
- Based on:
- test mat.
- Remarks:
- Choline chloride
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: originally reported as 1 % in diet
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 200 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Remarks:
- Choline chloride
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 040 mg/kg bw/day (nominal)
- Based on:
- other: Choline hydroxide, amount recalculated from choline chloride
- Sex:
- male
- Basis for effect level:
- other: Basis for effects: overall effects; mortality; body weight; gross pathology; organ weights Recalculated value from NOAEL > 1200 mg/kg bw choline chloride regarding the molecular weight of each compound.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Results – Comparison of rats fed 1% choline chloride in diet to control group (plain diet)
Endpoint |
Treatment Group (1 % Choline chloride in diet) |
Control Group (plain diet) |
Positive Control Group (i.p. 200 mg/kg bw of diethylnitrosamine, 0.05 % DDT in diet) |
|
Survival at week |
52 |
28 |
28 |
28 |
78 |
28 |
28 |
21 |
|
102 |
24 |
23 |
3 |
|
Body weight at week / g |
10 |
258 |
253 |
262 |
50 |
406 |
408 |
394 |
|
Relative liver weight (%) |
3.4 |
3.60 |
13.42 |
|
Number of animals bearing liver tumors |
Neoplastic nodules |
2 |
2 |
1 |
Hepatocellular carcinomas |
0 |
1 |
28 |
|
Cholangiomas + cholangiocarcinomas |
0 |
0 |
6 |
|
Lung metastases |
0 |
0 |
13 |
|
Number of animals with tumors / extrahepatic lesions |
Lung |
1 |
2 |
4 |
Leukemia |
2 |
8 |
4 |
|
Others |
4 |
7 |
8 |
Applicant's summary and conclusion
- Conclusions:
- The present study was classified as reliable with restrictions due to the limited information provided. However, since the available information is sufficient to consider the study as reliable, the results obtained can be used to assess the repeated dose toxicity of choline chloride and hence, choline base. The study duration was 103 weeks, wherein the animals were dosed the first 72 weeks with 1 % Choline chloride (10,000 ppm) in diet. Consequently, considering the total life span of a rat of approx. 1.5 - 2 years, the study duration was chosen long enough to detect all possible effects arising from Choline chloride.
The read-across from choline chloride to choline base is justified because the absorption after oral application is very likely to have remained unchanged, information gained from choline chloride for this endpoint can be used as weight-of-evidence information without modification. This is due to the fact that, if ingested orally, the contact time of the basic solution to the oesophagus is rather short for causing severe chemical burns which will be necessary to enlarge the oral uptake. Once reaching the stomach, the basic pH of the choline base solution will be immediately neutralized by the gastric acid. Only when ingesting large amounts of choline base, the neutralization capacity of the stomach acid will be used up. However, this scenario is unlikely due to expected pain in the oral cavity and pharynx caused by hydroxide. Also, in case it would have been decided to neutralize the test compound in order to avoid diminished food intake due to the undesired taste and pain, chlorous acid would be the recommended one, resulting in choline chloride anyway.
Hence, only effects of the choline cation have to be regarded and the results gained from choline chloride can be used without modifications.
No adverse effects were detected compared to control. In fact, although not statistically significant, Choline chloride treated animals developed less tumors than control animals. Also, no effects were seen regarding body weight gain, and the relative liver weight was also slightly, but not significantly decreased compared to control. This could be due to the fact that Choline chloride, which is also used as a feed additive, is an effective methyl donor, which does not require extensive metabolic pathways, which could possibly lead to additional liver damage due to hazardous degradation products. Hence, it is likely that CC does not only exhibit no adverse effects but also liver-protecting effects. Most likely effects for an increased liver weight can be (non)-neoplastic lesions, fatty liver or scar formation / cirrhosis due to necrosis already on only single cellular level, and also an increased requirement of metabolic enzymes. These effects are diminished by an additional gavage of Choline chloride. Furthermore, the positive control (i.p. 200 mg/kg bw of diethylnitrosamine, 0.05% DDT in diet) led to a decreased body weight and increased relative liver weight and tumor formation compared to control, which is an additional reason why the study, and so the results, can be considered as valid.
So, taking further into account the average food consumption of 120 g/kg bw/day of a male rat as given in ECHAs guidance document R.8, and the fact that no adverse effects were denoted compared to control at an average choline chloride (CC) consumption of 1 % in diet (10,000 ppm), the NOAEL was determined to be > 1 % CC in diet, which corresponds to > 1200 mg/kg bw/day (nearly life time duration). This NOAEL can be recalculated for choline hydroxide to 1040 mg/kg bw/day, regarding the molecular weight of each compound.
In conclusion, it can be stated that choline chloride and hence choline base does not induce any adverse effects and can be considered as non-toxic when administered chronically to rats, and no classification, neither as carcinogenic or STOT-RE, is required. - Executive summary:
In a chronic toxicity study equivalent to OECD Guideline 452, the read-across substance choline chloride was administered orally 1 % (10,000 ppm) in feed to male Fischer 344 rats, 30 animals per group, over 72 weeks with 31 weeks post-observation period.
There were no compound-related adverse effects denoted compared to control regarding the observed endpoints, i.e. body weight and body weight gain, relative liver weight, tumor formation in liver and lung, leukemia and other tumors. So the NOAEL is > 1 % Choline chloride (10,000 ppm) in food, based on all observed effects, which corresponds to NOAEL > 1200 mg/kg bw/day choline chloride or a NOAEL > 1040 mg/kg bw/day for choline hydroxide.
This chronic toxicity study in rats is acceptable with restrictions, satisfies the guideline requirements for a chronic oral toxicity study (OECD 452) in rats, and allow to draw the conclusion that Choline chloride and hence choline hydroxide is practically non-toxic.
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