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

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data available regarding repeated dose toxicity for 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0). Read-across from appropriate substances 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 VIII, 8.6. Structural similarities and similarities in properties and/or activities 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).

 

Animal data

Oral

No oral repeated dose toxicity data were available for the target substance. Therefore data cited in the report "Evaluation of the health aspects of thiamine hydrochloride and thiamine mononitrate as food ingredients" (FDA, 1978) was assessed.

In the first study summarised, the oral administration for several weeks of thiamine (CAS ‎59-43-8) to animals caused few deleterious effects. Rats were given 500 to 1500 mg/kg bw/day by gavage 5 days/week for 6 weeks. Examination of organs, urinary sediments and various haematological and liver function parameters revealed no significant changes. Clinical signs were not observed. The growth was slightly reduced in the high dose animals of both sexes, although the growth in females was reduced more at the lower dose. No further details were given in the report.

The FDA report also includes a brief summary of a study performed in male rats: the basal diet of male rats was supplemented for 2 to 6 weeks with 12 to 10,000 µg thiamine per g of diet (corresponding to 1.2 to 1000 mg/kg bw/day). No adverse effects were detected with regard to the growth of the animals (FDA, 1978).

 

Other routes

Thiamine monophosphate disulfide (CAS 992-46-1) was administered intraperitoneally for 6 months to male Wistar rats (Hori et al., 1965). 20 animals per dose were administered thiamine monophosphate disulfide in doses equivalent to 50 and 100 mg/kg bw/day thiamine hydrochloride (CAS 67-03-8). A negative control receiving the vehicle 1.5% sodium bicarbonate was included in the study. The effects on body weight, organ weights and food intake were investigated and the animals were observed for clinical signs. Haematological findings (number of erythrocytes, number of leucocytes and haemoglobin value), gross pathology (liver, heart, spleen, kidney, adrenal gland and testes) and histopathological findings (no further details given) were recorded. 4 animals of the low dose and the control group, respectively, and 5 animals of the high dose group died due to dosing errors during injection or infection catarrh. The gross pathological and histopathological examinations showed a parasitic infection of Cysticerus fasciolaris and pathological changes due to infection catarrh in all animals. A case of hypertrophy in the perihepatic membrane was seen in the high-dose group, but no degeneration of hepatic parenchyma was found, therefore this effect was considered by the authors to be caused by the mechanical stimulation during the injection. Based on the results of the study, a NOAEL ≥ 100 mg/kg bw/day was derived, since no adverse effects were observed at the highest administered dose.

 

In a brief abstract, the toxicity of thiamine (CAS 67-03-8) in rabbits was described. A total intravenous dose of 200 to 300 mg thiamine hydrochloride corresponding to 66.67 to 100 mg/kg bw, respectively, usually resulted in collapse and/or death in most of the animals. If the injection was stopped before respiration ceased, the animals usually recovered within five min and apparently suffered no ill effects. The animals were exposed an unknown number of times during a period of 8 months (Haley and Flesher, 1946).

 

Human data

During a double-blind, placebo-controlled, randomized study, subjects were administered thiamine hydrochloride to assess the effect of the substance on cognitive parameters related to Alzheimer’s disease. In the first experiment 18 patients diagnosed with probable Alzheimer’s disease according to the standard criteria, with a mean age of 71 years, received 3 g thiamine hydrochloride per day for 28 days. In the second experiment, 17 patients diagnosed with probable Alzheimer’s disease and with a mean age of 69 years, received 4 to 8 g thiamine hydrochloride per day over a period of 13 months. It has been reported, that the patients of the first experiment tolerated the thiamine dose well, and no adverse systemic effects were noted. In the second experiment, the subjects that were treated with doses up to 8 g/day tolerated these well without weakness or side effects except for two subjects who developed nausea and indigestion at doses of 7.0 and 7.5 g/day, respectively. These two subjects were subsequently treated at their highest tolerated dose without side effects in the latter months (i.e., 6.5 and 7.0 g/day) (Meador, 1993).

Furthermore, it was reported by Haley and Flesher (1946) that death occurred due to anaphylaxis after administration of four intravenous injections of the test substance each in a dose of 100 mg/cc equivalent to a 10% solution over a period of about one month to one subject. No further information about the dose volume, the patient's health and condition was given. Therefore, this information was disregarded.

The allergic potential of thiamine hydrochloride was assessed in a study by Wrenn et al. (1989). In this study, adverse reactions were observed in 12 cases (1.1%) when administered to 989 consecutive patients as a total of 1070 doses. In 11 of the 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). However, in the 12th case transient generalized pruritus without any other associated symptom was observed in the subject; the authors considered this a potential allergic reaction. The rates of minor and major reactions, therefore, were 1.02 and 0.093%, respectively. No adverse systemic effects were observed.

Additional information

Royer-Morrot (1991) measured the plasma thiamine concentrations after intramuscular and oral administration in healthy male volunteers. In this study, 10 men were given 500 mg thiamine i.m. once a day for 11 days and ten were given 250 mg of the test substance orally twice daily for 11 days. The times to reach steady-state were not different for the two administration routes. The mean elimination half-life was 1.8 days. No information on side effects was given. A randomised, double-blind, placebo-controlled study by Gokhale (1996) was conducted to prove the efficacy for the treatment with thiamine hydrochloride of primary dysmenorrhoea. The study was carried out on 556 girls aged 12 to 21 years, who received thiamine hydrochloride in a dose of 100 mg orally, daily for 90 days. The authors reported that the treatment was without any side effects. According to a BfR report “Application of vitamins in food” (2004), thiamine is considered to exhibit a low toxicity and did not result in side effects after oral intake. In humans side effects such as headache, dizziness, increased perspiration and itching after thiamine administration in high doses of 50 mg/kg bw/day or more than 3 g per day can occur (Bässler et al., 2002 as cited in BfR, 2004).

 

Overall conclusion

Repeated oral dose toxicity studies which were summarized in a FDA report revealed low toxicity in rats. In humans, oral doses up to 8 g/day were tolerated well without weakness or side effects except for individual cases who developed nausea and indigestion. Overall, thiamine and the thiamine derivate thiamine hydrochloride did not to show hazardous properties to human health following repeated dose exposure via the relevant route of exposure. Therefore based on the analogue approach, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium is also not considered to exhibit hazardous properties after repeated oral exposure.

References:

BfR (2004). Domke A., Großklaus R., Niemann B., Przyrembel H., Richter K., Schmidt E., Weißenborn A., Wörner B., Ziegenhagen R.: Verwendung von Vitaminen in Lebensmitteln. Toxikologische und ernährungsphysiologische Aspekte, Teil I. ISBN 3-931675-87-4

FDA (1978). Evaluation of the health aspects of thiamin hydrochloride and thiamin mononitrate as food ingredients. Contract No. FDA 223-75-2004.

Gokhale LB (1996). Curative treatment of primary (spasmodic) dysmenorrhea. Indian J. Mec. Res.103, 227-231.

Royer-Morrot MJ, Zhiri A, Paille F, Royer RJ (1992). Plasma thiamine concentrations after intramuscular and oral multiple dosage regimens in healthy men. Eur J Clin Pharmacol 42:219-222.

SCF (2001). Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B1.

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 repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.