(6R,7R)-7-[((2Z)-2-[({2-[(1,1-dimethylethyl)oxy]-1,1-dimethyl-2-oxoethyl}oxy)imino]-2-{2-[(triphenylmethyl)amino]-1,3-thiazol-4-yl}acetyl)amino]-8-oxo-3-(1-pyridiniumylmethyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Endpoint summary

Description of key information

The skin irritation potential of the test substance has been determined using a weight of evidence approach combining the results of two historical studies. Exposure of rats to 1 g/animal (3400 mg/kg bw) in an acute dermal toxicity study did not result in any visible effects to the skin. A supporting study where guineas pigs (n=3) were exposed to the test substance on shaved and abraded skin resulted in negligible irritation when assessed at 24 and 48 hours.

In a historical study, application of 100mg/eye to white New Zealand rabbits resulted in significant conjunctival effects 1 hour post exposure, with effects remaining at 24 hours. All effects were reversed by 72 hours; there were no effects noted on the cornea or iris at any timepoint. One component of the solvate ,N,N-dimethylformamide (Index Number 616-001-00-X) has a harmonised classification which includes serious eye irritation (H319). Given that the solvent is present at significant concentrations in the substance (~18% w/w) , it was decided to apply the precautionary principle and the classification criteria for mixtures in accordance with 1272/2008/EC, resulting in a hazard classification for eye irritation for the solvant preparation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

groups of three rats were dermally exposed to 1g/rat of the test substance to assess dermal acute toxicity and irritation potential.

GLP compliance:

no

Remarks:

GLP not implemented at the time of study

Specific details on test material used for the study:

Batch RJ1173

Species:

rat

Strain:

Sprague-Dawley

Remarks:

glaxo colony

Details on test animals or test system and environmental conditions:

Male rats
weights 290-413g
housed singly

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

3.4 g/kg (1g/rat)

Duration of treatment / exposure:

24 hours

Observation period:

7 days

Number of animals:

3 animals per test group

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Interpretation of results:

GHS criteria not met

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

May 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

No test guideline is mentioned in the study report. The study intended to provide evidence on the potential hazards of human skin contact with the test compound. The compound was tested for potential skin irritancy in the guinea pig which is frequently used for the evaluation of chemicals for dermal irritancy.

GLP compliance:

no

Remarks:

The study was conducted priorto the adoption of GLP for such studies

Species:

guinea pig

Strain:

Dunkin-Hartley

Type of coverage:

occlusive

Preparation of test site:

other: clipped and depilated, then either left intact or abraded

Vehicle:

other: suspended in soft paraffin

Controls:

yes, concurrent vehicle

yes, concurrent positive control

Amount / concentration applied:

The test compounds and the positive control substance (sodium carbonate, AnalaR-grade) were suspended at a concentration of 50% 2/2 in soft paraffin B.P.

Both flanks of the test animals were clipped and depilated and the skin on one flank abraded using a disposable hypodermic needle. 0.25g of compound/soft paraffin suspension confined within a fibre washer (area 2.25cm2) was applied to each flank and occluded with polythene sheeting, secured by Elastoplast adhesive bandage for 21 hours.

Duration of treatment / exposure:

21 hours

Observation period:

24 and 48 hours

Number of animals:

3 per group

Details on study design:

Irritant reactions were graded subjectively on a 0-5 scale at 24 and 48 hours. Group means of these scores were calculated and the overall irritancy produced by the compounds classified as negligible (0-0.9), slight (1.0-1.9), moderate (2.0-3.4) or severe (3.5-5.0).

Irritation parameter:

overall irritation score

Basis:

mean

Remarks:

intact and abraded

Time point:

24/48 h

Score:

ca. 0.3

Reversibility:

fully reversible

Remarks on result:

other: none guideline study used as weight of evidence, no 72 hour time point recorded, results reported as mean of 3 animals.

Remarks:

negligible irritation potential

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48 h

Score:

0.3

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

reported as overall mean of timepoints and animals

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48 h

Score:

0.3

Reversibility:

fully reversible

Remarks on result:

probability of weak irritation

Remarks:

reported as overall mean of timepoints and animals

Interpretation of results:

GHS criteria not met

Conclusions:

The substance produced negligible irritancy.

Executive summary:

CQ intermediate (1132/4 DMF solvate) was suspended at a concentration of 50% w/w in soft paraffin and applied to intact and abraded guinea-pig skin under occlusive dressing for 21 hours. Irritant reactions were assessed at 24 and 48 hours. The compound produced negligible irritancy.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: read-across from component repsonsible for classification

Reason / purpose for cross-reference:

read-across source

Reference 2

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the substance is classified as skin irritation and the available information indicates that it should be classified as eye irritation (Category 2)

other:

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based upon the weight of evidence from two older non-guideline studies conducted in rabbits and guinea pigs, there is insufficient evidence to classify the substance for skin irritation.

One component of the solvate ,N,N-dimethylformamide (Index Number 616-001-00-X) has a harmonised classification which includes serious eye irritation (H319). Given that the solvent is present at significant concentrations in the substance (~18% w/w) , it was decided to apply the precautionary principle and the classification criteria for mixtures in accordance with 1272/2008/EC, resulting in a hazard classification for eye irritation for the solvant preparation.