Pyridinium, 1-[[(6R,7R)-7-[[(2Z)-(2-amino-4-thiazolyl)[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-, chloride, hydrochloride (1:1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: predictions from Basic Data set

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: A qualitative assessment of the toxicokinetics of the substance has been performed, based upon its physical properties and the results of toxicological studies.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 2.0 November 2014

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

73547-70-3

Molecular formula:

C22-H22-N6-O7-S2.2 H-Cl

Radiolabelling:

no

Results and discussion

Metabolite characterisation studies

Metabolites identified:

not specified

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

key physical properties:

Molecular weight: 619.51
Water solubility: >1000 g/L
Partition co-efficient log Pow: -3.36
Particle size distribution: 90% (<89 µm), 50% (<5.7 µm), 10% (<0.147 µm)
Dissociation constant: not determined
pH (10% suspension ): 1.2
Hydrolysis: not determined inherently biodegradable

Any other information on results incl. tables

acute oral toxicity: discriminating dose 2000 mg/kg.

Reproductive Toxicity Screen (OECD422): No toxicologically significant effects on fertility, reproductive performance or pup development were noted up to the maximum dose tested (750 mg/kg bw/day).

28 day repeat dose oral toxicity (OECD422) :

The oral administration of Ceftazidime dihydrochloride to rats by gavage, at dose levels of

50, 200 and 750 mg/kg bw/day, resulted in reduced body weight gains in males treated with

750 mg/kg bw/day and microscopic liver changes in animals of either sex treated with

750 mg/kg bw/day and in males treated with 200 mg/kg bw/day.  The ‘No Observed Effect

Level’ (NOEL) for systemic toxicity was therefore considered to be 200 mg/kg bw/day for

females and 50 mg/kg bw/day for males.  

The increased cytoplasmic rarefaction in the liver of males was most likely due to variation in

glycogen storage within the cells and is generally considered to be an adaptive response,

therefore, a No Observed Adverse Effect Level (NOAEL) for males was considered to be

200 mg/kg bw/day.

Males treated with 750 mg/kg bw/day showed statistically significant increases (p<0.05) in

cholesterol, alanine aminotransferase and albumin/globulin ratio and a statistically significant

reduction (p<0.05) in total protein.

Males from all treatment groups showed statistically significant reductions (p<0.05-0.01) in

alkaline phosphatase and bile acids.  With the exception of one individual alkaline

phosphatase value at 750 and 200 mg/kg bw/day, all remaining values were within the

historical control ranges and therefore were considered not to be of toxicological importance.

Males treated with 750 and 200 mg/kg bw/day also showed a statistically significant increase

(p<0.05) in potassium concentration and a statistically significant reduction (p<0.05) in

calcium concentration.  The majority of individual values were within the historical control

ranges and in the absence of a true dose related response, the intergroup differences were

considered not to be of toxicological importance.

Females treated with 750 and 200 mg/kg bw/day showed a statistically significant reduction

in bile acids.  Females treated with 750 mg/kg bw/day also showed statistically significant

increases (p<0.05-0.01) in albumin and albumin/globulin ratio.  All of the individual values

were within the historical control ranges, therefore, the intergroup differences were

considered not to be of toxicological importance.        

skin exposure: The substance is considered to be corrosive given the pH of 1.2

eye exposure: The substance is considered to be corrosive given the pH of 1.2

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
oral: clinical signs witnessed in the repeat dose oral toxicity study indicates that the substance is absorbed following administration in polyethylene glycol with systemic effects noted: clinical chemistry and liver following exposure to all dose levels. NO toxicologically significant effects were observed on reproductive or developmental parameters in the exposed animals.
The water solubility, partition coefficient and molecular mass all indicate that this substance will be bioavailable via the oral route.

Inhalation: The particle size distribution indicates that there is potential for exposure by this route.

Dermal absorption: the physical parameters of the substance:pH, molecular weight and log Pow, indicate that the substance will disrupt the stratum corneum and underlying epidermis/dermis and be systemically available from dermal exposure.

Metabolism: There is some evidence from the 28 day study to indicate that the substance is undergoing hepatic metabolism (increases in serum cholesterol and ALAT).


Excretion: There is limited evidence from the oral toxicity studies conducted ( increase (p<0.05) in potassium concentration and a statistically significant reduction (p<0.05) in
calcium concentration. ,and increases in absolute and relative kidney weights in males in repeat dose studies) that the substance may interact with the kidneys.