Registration Dossier

Administrative data

Description of key information

Oral, male rats: LD50 = 3710 mg/kg bw (RA CAS 67-03-8)

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:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
3 710 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Source: CAS 67-03-8, Sprince et al., 1974.
Remarks:
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
Based on the analogue approach, same results are expected for the target substance.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
3 710 mg/kg bw
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 substances 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 regarding acute toxicity for 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazoniol-5-yl]ethyl dihydrogen diphosphate (CAS 136-09-4). Read-across from an appropriate 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 analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Acute oral toxicity

CAS 67-03-8

Acute toxicity of thiamine hydrochloride was tested in male CFE albino rats (Sprince et al., 1974). In this study several doses of 4, 6, 8, 10, 11, 12, 14 and 16 mM/kg bw were tested in 15 animals per dose. Marked tremors developed within 5 - 10 minutes, persisting for another 5 - 10 minutes and were followed by a characteristic jumping behavior for about 1 - 3 minutes. Soon thereafter, 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

Haley et al. (1948) investigated the source substances thiamine hydrochloride and thiamine mononitrate on its potential to exhibit toxicity after intravenous and intraperitoneal administration in mice, respectively. The determined LD50 values in mice were 329.8 mg/kg bw intraperitoneal for thiamine hydrochloride, and 387.3 mg/kg bw intraperitoneal and 84.24 mg/kg bw intravenous for thiamine mononitrate, respectively. 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. Symptoms by i.v. injections are hypotonia due to vasodilatation, bradycardia and respiratory arrhythmia leading to general neuromuscular inhibition. Death is caused by depression of the respiratory centre (Haley, 1948).

 

Besides these publications, further information was taken from the reports "Evaluation of the health aspects of thiamin hydrochloride and thiamin 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, LD50 levels of a study from Bitsch (1997; as cited in SCF, 2001) were described to be 0.07-0.125 g/kg bw intravenous, 0.317-0.500 g/kg bw intraperitoneal and 3-15 g/kg bw orally in mice for thiamine hydrochloride. Lang (1979; as cited in SCF, 2001) quoted an oral LD50 of vitamin B1 of 3.0 g/kg bw for mice. The lethal i.v. for mice were 0.125 g/kg bw, for rats 0.25 g/kg bw, for rabbits 0.30 g/kg bw and dogs 0.35 g/kg bw (McCormick, 1988; as cited in SCF, 2001). In monkeys up to 0.60 g/kg bw was required to produce toxic symptoms (Gubler, 1991; as cited in SCR, 2001). According the FDA report, the oral LD50 values of thiamin were considered to be 2450 and 5000 mg/kg bw for mice, respectively, and 9500 mg/kg bw for rats. After oral administration with thiamin hydrochloride LD50 values of 3000, 5000, 6000 and 8224 mg/kg bw for mice were determined, respectively. The administration with thiamin mononitrate revealed LD50 values of 7000 mg/kg bw in mice.

 

Overall conclusion

The thiamine derivates thiamin hydrochloride (CAS 67-03-8) and thiamin mononitrate (CAS 532-43-4) did not exhibit acute oral toxicity. Therefore based on the analogue approach, 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazoniol-5-yl]ethyl dihydrogen diphosphate (CAS 136-09-4) 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 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazoniol-5-yl]ethyl dihydrogen diphosphate, 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.

The available data on acute oral toxicity from the source substances thiamin hydrochloride (CAS 67-03-8) and thiamin mononitrate (CAS 532-43-4) do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.

Therefore, applying the RA-A approach, the target substance 2-[3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazoniol-5-yl]ethyl dihydrogen diphosphate is also considered no to meet the classification criteria for acute oral toxicity.