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

Effects on fertility

Description of key information

Oral, rat (no guideline followed): NOAEL (maternal, systemic) ≥ 9 mg/kg bw/d; NOAEL (maternal, fertility) ≥ 9 mg/kg bw/d

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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

Description (incidence):

Control: 1/12 females died.

Key result

Dose descriptor:

NOAEL

Remarks:

calculated

Effect level:

9 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed at 75 mg/kg of diet.

Remarks on result:

other: Source: CAS 67-03-8

Remarks:

a default factor of 0.12 for rats was used for converting test substance concentrations in feed (mg/kg) into daily dose (mg/kg bw per day) as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579).

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

calculated

Generation:

F1

Effect level:

9 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed in F1 generation

Remarks on result:

other: Source: CAS 67-03-8

Remarks:

a default factor of 0.12 for rats was used for converting test substance concentrations in feed (mg/kg) into daily dose (mg/kg bw per day) as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579).

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

The source substance had no effect on reproductive performance. Based on the analogue approach, the same results were expected for the target substance.

Effect on fertility: via oral route

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 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.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data available assessing the potential for 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0) to cause toxicity to reproduction. Read-across from a source substance 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, 8.7. 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).

In vivo animal data

CAS 67-03-8

A non-guideline study investigating the effects of thiamine hydrochloride (CAS 67-03-8) on the reproduction in the rat was published by Morrison and Sarett (1959). Groups of 12 female rats were fed a basal diet containing 1.5 mg thiamine hydrochloride per kg of feed (control group) or a diet supplemented with 50 times this level of thiamine hydrochloride resulting in a thiamine hydrochloride content of 75 mg/kg of feed (treatment group). After a 12-week treatment period, the animals were mated with untreated males. The dams were sacrificed after the young were weaned on lactation day 21. In the control group, 1/12 females died. This is considered to be an incidental occurrence. Treatment-related clinical signs were not observed in the treatment group. In addition no adverse effects on body weight, food and water consumption, food efficiency and organ weights (liver, kidneys and adrenals) were noted following the treatment. Gross pathological examination revealed no abnormalities in the treated rats. No significant differences on the number of litter and number of pups were observed between the groups. No other fertility parameters were investigated. Based on the results of this study the NOAEL for systemic effects was considered to be 75 mg/kg diet which is equivalent to 9 mg/kg bw/day for female rats (based on a default factor of 0.12 for rats as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579)). The NOAEL for fertility was considered to be 75 mg/kg diet which is equivalent to 9 mg/kg bw/day for female rats.

Additional information

The Select Committee on GRAS Substances (SCOGS) prepared the report "Evaluation of the health aspects of thiamine hydrochloride and thiamine mononitrate as food ingredients" as an independent evaluation of the safety of thiamine hydrochloride and thiamine mononitrate when used in foods (FDA, 1978). The report included summaries of studies assessing the toxicity to reproduction of the above-mentioned substances:

During a three-generation study, thiamine did not reveal adverse effects on fertility when mice were exposed to 50-75 g/kg bw/day, or on lactation when thiamine intake in mice was about 100 mg/kg bw/day (FDA, 1978).

A three-generation study was performed in male and female rats with findings comparable to those for the mouse, as described above. Weaning rats were fed a diet supplemented with thiamine hydrochloride or mononitrate corresponding to approximately 30 mg/kg bw/day. Growth, reproductive performance and necropsy findings do not differ when treatment and control animals were compared (FDA, 1978).

In a feeding study, 5 female rats were exposed to thiamine at doses of approximately 10 mg/kg bw/day for 2 weeks following mating. The dams were maintained on this diet throughout gestation and lactation. The average birth weight, number of young per litter and average weight of the offspring at weaning did not differ significantly from the controls (FDA, 1978).

The resorption rate in pregnant rats following oral administration of 10 g thiamine hydrochloride per kg body weight was similar to those observed in the control animals.

 

Conclusion for reproduction toxicity

Based on the results obtained in the study from Morrison et al. (1957) the source substance thiamine hydrochloride (CAS 67-03-8) did not cause adverse effects on reproductive performance. The NOAEL for systemic effects and for fertility were considered to be 9 mg/kg bw/day for female rats. Similar findings were described in the evaluation report on the safety of thiamine hydrochloride and thiamine mononitrate by SCOGS (FDA, 1978). The available data on several species from a number of studies did not indicate any adverse effects on reproduction (fertility) in mice at 75 mg/kg bw/day, and in rats at 10 mg/kg bw/day. Therefore, no hazard for toxicity to reproduction/fertility was identified for the target substance.

Based on common functional groups and structural similarities, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0) is not predicted to show hazardous properties for reproduction toxicity (fertility).

Effects on developmental toxicity

Description of key information

Oral, rat (no guideline followed): NOAEL (offspring, developmental) ≥ 9 mg/kg bw/d

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no data available assessing the potential for 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]-thiazolium (CAS 10023-48-0) to cause developmental toxicity. Read-across from a source substance 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, 8.7. 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).

CAS 67-03-8

A non-guideline study investigating the effects of thiamine hydrochloride (CAS 67-03-8) on the reproduction in the rat was published by Morrison and Sarett (1959). Groups of 12 female rats were fed a basal diet containing 1.5 mg thiamine hydrochloride per kg of feed (control group) or a diet supplemented with 50 times this level of thiamine hydrochloride resulting in a thiamine hydrochloride content of 75 mg/kg of feed (treatment group). After a 12-week treatment period, the animals were mated with untreated males. The dams were sacrificed after the young were weaned on lactation day 21. No adverse effects on body weight and survival of offspring on Day 5 and 21 after weaning were noted. The survival rate was 98 and 96% on Day 5 for the control and treatment group, respectively, and 73 and 76% on Day 21 for the control and treatment group, respectively. Based on the results of this study the NOAEL values for developmental toxicity was considered to be 75 mg/kg diet, which is equivalent to 9 mg/kg bw/day for the offspring (based on a default factor of 0.12 for rats as described in a scientific opinion from EFSA (EFSA Journal 2012;10(3):2579)).

 

Conclusion for reproduction toxicity

Based on the results obtained in the study from Morrison et al. (1957) the source substance thiamine hydrochloride (CAS 67-03-8) did not show adverse effects on the development of the offspring. Therefore, no hazard for developmental toxicity was identified for the target substance.

Based on common functional groups and structural similarities, Thiazolium, 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-4-methyl-5-[2-(phosphonooxy)ethyl]- (CAS 10023-48-0) is not predicted to show hazardous properties in the developmental endpoint.

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 available source substance data on toxicity to reproduction do not meet the criteria for classification according to Regulation (EC) No 1272/2008, and are therefore conclusive but not sufficient for classification.