5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[[2-(1,1-dimethylethoxy)-1,1-dimethyl-2-oxoethoxy]imino]acetyl]amino]-3-(chloromethyl)-8-oxo-, (4-methoxyphenyl)methyl ester, (6R,7R)-

Endpoint summary

Description of key information

Oral NOEL at 13 weeks on rats: 4 mg/kg bw/day. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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

There are no experimental nor literature toxicological data available on TATD-CLE. Therefore the read across approach with the analogue Cefalonium (EC: 226-948-7; CAS: 5575-21-3) was considered in order to trace a complete toxicological profile of the substance.

 

In the 4-week study, dietary cefalonium intake in males was 0, 43, 234, 1194 and 6014 mg/kg bw/day, respectively. At all dose levels increased water and food intake were found. However, since no other adverse effects were observed at the two lowest dose levels, the increases at these levels were considered not relevant for human safety.

In the 13-week study, dietary intake of cefalonium in males was 0, 4, 39, 440 and 4434 mg/kg bw/day and 0, 4, 44, 462 and 4674 mg/kg bw/day in females. An increase in the size of caecum was observed in males and females receiving more than 440 and 462 mg/kg bw/day. Blood urea nitrogen levels were decreased in males at the two highest dose levels. Serum ketone bodies were increased in males and females at the highest dose. Serum globulin levels were decreased in males at the two highest dose levels (no difference in effect between two levels) and in females at the three highest dose levels (dose related). Water and food intake were increased at all dose levels, however, since no other adverse effects were observed at the lowest dose level, these increases at this level were considered not relevant for human safety.

Although the 47 week and 13 week rat studies were pre-GLP and no raw data were available, they do indicate that no toxic effects are reported at 4 mg/kg bw/day and therefore the dose of 4 mg/kg bw/day could be accepted as a toxicological NOEL.

 

Two oral repeated dose toxicity studies of 7 and 13 weeks were done in beagle dogs.

In the 7-day study, 2 dogs per sex per dose group received 10, 50, 100 and 1000 mg cefalonium/kg bw/day as cefalonium dehydrate by gavage. In this dose-range finding study, the small intestine of high-dose animals exhibited pathological changes probably resulting from the administration of large amounts of a relative insoluble suspension. The oral NOEL was 100 mg/kg bw/day.

In the 13 -week study, two dogs per sex per dose group received 0, 10 or 1000 ma cefalonium (as the dehydrate)/kg bw/day. In this study, no treatment related effects were observed up to the highest tested dose of 1000 mg/kg bw/day. However the number of dose levels and test animals were too low, to allow any conclusion.

Applying a precautionary approach, the worst case reported for the structural analogue has been used as representative for the TADT-CLE.

No data for both dermal and inhalation route are available.

 

Reference

EMEA, Committee for veterinary medicinal products. Cefalonium. Summary report. EMEA/MRL/646/99-Final.August 1999.

Justification for classification or non-classification

According to CLP regulation (EC1272/2008), 3.9 Specific target organ toxicity - repeated exposure section, substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement, on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed.

The dose/concentration guidance values reported to assist the category 1 classification are C ≤ 10 mg/kg bw/day and they are referred to effects seen in a standard 90-day toxicity study conducted in rats. A NOEL of 4 mg/kg bw/day, that was resulted from an oral repeated dose toxicity test of 13 weeks on rats, has been considered for TADT-CLE, therefore a consequent classification is proposed.

 

In conclusion, according to CLP regulation (EC1272/2008), TADT-CLE is classified for Specific Target Organ Toxicity-Repeated Exposure in the category 1 (STOT RE 1, H372).