2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl}ethyl hydrogen phosphate

Endpoint summary

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

Reference

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

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.