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EC number: 600-039-9 | CAS number: 10023-48-0
- 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
Endpoint summary
Administrative data
Description of key information
Oral, male rats: LD50 = 3710 mg/kg bw
Key value for chemical safety assessment
Acute toxicity: via oral route
Link to relevant study records
- Endpoint:
- acute toxicity: oral
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- refer to analogue justification provided in IUCLID section 13
- Reason / purpose for cross-reference:
- read-across source
- Key result
- Sex:
- male
- Dose descriptor:
- LD50
- Effect level:
- 3 710 mg/kg bw
- Based on:
- test mat.
- Remarks on result:
- other: 3710 mg/kg bw, calculated from 11.0 mM/kg bw (according to Sprince et al., 1974)
- Interpretation of results:
- other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008
- Conclusions:
- CLP: not classified
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- The available information comprises an adequate and reliable study from a reference substance with similar structure and intrinsic properties. The target and the source substance are thiamine derivatives with similar structure. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Acute toxicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Acute toxicity: via dermal route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification for read-across
There are no reliable data available, assessing the acute toxicity potential for 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0). Read-across from a source substance Thiamine, hydrochloride (CAS 67-03-8) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5. in order to fulfil the standard data requirements defined in Regulation (EC) No 1907/2006, Annex VII, 8.5. Common functional groups, structural similarities and comparable toxicological properties (according to the joint consideration in Annex VI to CLP) of the source and target substance are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).
In vivo animal data
Acute oral toxicity
CAS 67-03-8
The acute oral toxicity potential of thiamine hydrochloride was assessed in a non-guideline study in which male CFE albino rats were administered the test substance by gavage (Sprince et al., 1974). In this study doses of 4, 6, 8, 10, 11, 12, 14 and 16 mM/kg bw were administered to 15 animals per dose. In the animals that died, death occurred within 15-45 minutes after administration from respiratory failure (no further details were given). Marked tremors developed within 5-10 minutes, persisted for 5-10 minutes, and were followed by a characteristic “jumping” behaviour for 1-3 minutes. Following this reaction, the animals became limp. Based on the results of this study a LD50 value of 11 mM/kg bw, corresponding to 3701 mg/kg bw was derived.
Other routes (intravenous)
Haley et al. (1948) investigated the source substances thiamine hydrochloride and thiamine mononitrate for their potential to cause toxicity in mice and rabbits after intravenous administration, respectively. The determined LD50 values in mice were 84.24 mg/kg bw for thiamine mononitrate. Death occurred within 30 s after intravenous administration in mice. In rabbits the intravenous lethal dose was determined to be 112.58 mg/kg bw for thiamine mononitrate and 117.45 mg/kg for thiamine hydrochloride. Death occurred within 10 min in rabbits. Gross pathological examination in mice and rabbits revealed cardiac arrhythmias in all animals after opening the thoracic cage. Signs of toxicity, such as restlessness, labored respiration, vasodilatation, cynosis, muscular twitching, clonic convulsions and death by respiratory paralysis occurred. In addition, visual signs of anoxia, gradually deepening bluish coloration of the ears and all other body areas where the fur was thin enough to permit direct observation, were observed.
Other routes (intraperitoneal)
Haley et al. (1948) investigated the source substances thiamine hydrochloride and thiamine mononitrate for their potential to cause toxicity in mice after intraperitoneal administration, respectively. The LD50 values were < 310 mg/kg bw for thiamine hydrochloride and 387.3 mg/kg bw for thiamine mononitrate. Death occurred within 5 min after intraperitoneal administration in mice. Symptoms of toxicity, such as restlessness, labored respiration, vasodilatation, cynosis, muscular twitching, clonic convulsions and death by respiratory paralysis occurred. In addition, visual signs of anoxia, gradually deepening bluish coloration of the ears and all other body areas where the fur was thin enough to permit direct observation, was observed. In addition, in all animals cardiac arrhythmias were seen after opening the thoracic cage. The same signs of toxicity and the same gross pathological findings after intraperitoneal administration were described as after intravenous administration.
Based on the results from Haley et al. (1948), there is little difference in the toxic potential of either thiamine hydrochloride or thiamine mononitrate and the signs of toxicity are the same for both vitamin derivates. After intravenous administration death occurred within 30 s in mice and within 10 min in rabbits, respectively, indicating that mice are the more sensitive species.
Human data
Wrenn et al. (1989) monitored 989 subjects that received in total 1070 thiamine hydrochloride doses by rapid IV push technique over a 6-month period. 94 patients were incidentally on a cardiac monitor at the time of the study. Adverse reactions were observed in 12 cases (1.1%). In 11 of these 12 cases, transient burning occurred immediately after injection in the arm with the IV line and lasted from seconds to minutes. The authors considered this a minor reaction with no allergic or immune component. Of these 11 patients, seven were men and four were women (1.75:1 ratio). In the 12th case, transient generalized pruritus without any other associated symptoms was observed in the subject; the authors considered this a potentially major reaction. The rates of minor and major reactions, therefore, were 1.02 and 0.093%, respectively. Arrhythmias were not observed in any of the subjects.
The death of a subject who received four intravenous injections of thiamine hydrochloride over a period of about one month each in a dose of 100 mg/cc, due to anaphylaxis, was reported (Haley, 1946). As no further information was given on the dose administered and the general condition of the subject, this information is not considered to be relevant.
Additional information
Information available in the public literature was summarised in the reports "Evaluation of the health aspects of thiamine hydrochloride and thiamine mononitrate as food ingredients" (FDA, 1978) and "Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B1" (SCF, 2001).
In the SCF Opinion, oral LD50 levels in mice were reported to be 3-15 g/kg for thiamine hydrochloride bw and 3.0 g/kg bw for vitamin B1 (thiamine) (SCF, 2001). The oral LD50 values of thiamine were described to be 2450 and 5000 mg/kg bw for mice, respectively, and 9500 mg/kg bw for rats (FDA, 1978). After oral administration with thiamine hydrochloride LD50 values of >3000 mg/kg bw for mice were determined. The administration via oral administration with thiamine mononitrate revealed LD50 values of 7000 mg/kg bw in mice (FDA, 1978).
Overall conclusion
Based on the results of an acute oral toxicity study a LD50 value of 3701 mg/kg bw was derived for thiamine hydrochloride in rats (Sprince et al., 1974). Human data by Wrenn et al. (1989) indicate only minor reactions with no allergic or immune component in 989 subjects that received in total 1070 thiamine hydrochloride doses by rapid IV push technique over a 6-month period. Since there is no data on inhalation and dermal exposure available the information on the i.v. and i.p. routes was taken into account. The LD50 values for i.p. and i.v. exposure are relatively high and indicate low acute toxicity via the relevant route of exposure.
Overall, the thiamine derivates thiamine hydrochloride and thiamine mononitrate did not exhibit acute oral toxicity. Therefore based on the analogue approach, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium is not considered to exhibit hazardous properties after single exposure.
Justification for classification or non-classification
According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0), data will be generated from information on reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.
Therefore the available source substance data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.
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