Registration Dossier

Administrative data

Description of key information

Beta-lactam compounds are know to elicit skin and respiratory sensitisation in sensitive individuals, the substance in question is a non-penicillin betalactam drug intermediate where the beta-lactam ring structure is intact. All non-penicillin beta-lactams have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions in some patients. Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam classes can be lower than the risk within a class, the hazard posed is present and potentially lifethreatening.

The potential health hazard of non-penicillin beta-lactams therefore is similar to that of penicillins. Further similarities between non-penicillin beta-lactams and penicillins are as follows:

• It is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans.

• There is a lack of suitable animal or receptor testing models that are predictive of human sensitivity.

• The threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods.

Non-Penicillin Beta-Lactam Drugs:

A CGMP Framework for Preventing Cross Contamination: US Food and Drug Administration, April 2013

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in chemico
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
All non-penicillin beta-lactams have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions in some patients. Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam classes can be lower than the risk within a class, the hazard posed is present and potentially lifethreatening. The potential health hazard of non-penicillin beta-lactams therefore is similar to that of penicillins. Further similarities between non-penicillin beta-lactams and penicillins are as follows:
• It is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans.
• There is a lack of suitable animal or receptor testing models that are predictive of human sensitivity.
• The threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods.

Non-Penicillin Beta-Lactam Drugs:
A CGMP Framework for Preventing Cross Contamination: US Food and Drug Administration, April 2013
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
other: Guinea pig topical sensitisation test
GLP compliance:
no
Type of study:
other: guinea pig topical sensitisation test
Justification for non-LLNA method:
Study was carried out before LLNA was considered a requirement. It is considered sufficient for the endpoint, so there was no need for an additional LLNA study, which would involve more animals.
Specific details on test material used for the study:
Batch No: RJ1173
Species:
guinea pig
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
Five male and five female guinea pigs, initially weighing 250-300 g.
Route:
other: epicutaneous, no other information mentioned
Vehicle:
other: saline:2-methoxyethanol:Tween 80 (45:45:10)
Concentration / amount:
not mentioned
Day(s)/duration:
not mentioned
Adequacy of induction:
not specified
No.:
#1
Route:
other: epicutaneous, not specified
Vehicle:
other: saline:2-methoxyethanol:Tween 80 (45:45:10)
Concentration / amount:
Not specified
Day(s)/duration:
Not specified
Adequacy of challenge:
not specified
No. of animals per dose:
5
Positive control substance(s):
yes
Remarks:
Benzyl penicillin
Positive control results:
At 24 hours, only 2/9 animals treated with Benzyl Penicillin gave positive results. This increased to 5/9 animals at 48 hours. This is a low result for the positive control substance, as sensitisation usually occurs in >80% of the animals.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test group
Dose level:
Not available
No. with + reactions:
1
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test group
Dose level:
Not available
No. with + reactions:
2
Total no. in group:
10
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
Not available
No. with + reactions:
2
Total no. in group:
9
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
Not available
No. with + reactions:
5
Total no. in group:
9
Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Conclusions:
Skin sensitising potential of 1132/4 DMF (CQ Intermediate) is low, but cannot be ignored.
Over 20% of the animals showed positive responses to the challenge after 48 hours, which is sufficient to classify the substance as a Skin Sensitiser Category 1, according to the criteria set for animal studies in section 3.4.2.2.4.1 of Annex I of the CLP Regulation.
Executive summary:

The skin sensitisation potential of 0/4 dihydrochloride dihydrate, 1132/4 DMF and 1132/4 bis hydrochloride was assessed in the guinea pig topical sensitisation test. The results indicate that repeated contact of the human skin with 0/4 dihydrochloride dihydrate might produce contact dermatitis. The contact allergenic potential of 1132/4 DMF although low, cannot be ignored, and that of 1132/4 bis hydrochloride, if any, is very low.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)

Respiratory sensitisation

Link to relevant study records
Reference
Endpoint:
respiratory sensitisation: in chemico
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Justification for type of information:
All non-penicillin beta-lactams have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions in some patients. Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam classes can be lower than the risk within a class, the hazard posed is present and potentially lifethreatening. The potential health hazard of non-penicillin beta-lactams therefore is similar to that of penicillins. Further similarities between non-penicillin beta-lactams and penicillins are as follows:
• It is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans.
• There is a lack of suitable animal or receptor testing models that are predictive of human
sensitivity.
• The threshold dose at which allergenic response could occur is extremely low and
difficult to detect with current analytical methods.

Non-Penicillin Beta-Lactam Drugs:
A CGMP Framework for Preventing Cross Contamination: US Food and Drug Administration, April 2013
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)

Justification for classification or non-classification

Based upon the human experience of individual sensitivity to penicillin and non-penicillin beta-lactam drugs, it is appropriate to classify the substance for both respiratory and skin sensitisation in accordance with 1272/2008/EC. A supporting study conducted in guinea pigs resulted in a positive response rate of 20% to the challenge after 48 hours, which is sufficient to classify the substance as a Skin Sensitiser Category 1. The substance has been classified as a Respiratory Sensitiser Category 1 on the basis of human experience.