Amoxicillin

Endpoint summary

Description of key information

RESPIRATORY SENSITISATION (OCCUPATIONAL EXPOSURE): According to the available evidence showing that amoxicillin can lead to specific respiratory hypersensitivity based on human experience and also based on the evidence from chemical structure related substances known to cause respiratory hypersensitivity (penicillins), the substance amoxicillin is proposed to be classified as respiratory sensitiser. 
SKIN SENSITISATION (OCCUPATIONAL EXPOSURE): According to the available evidence showing that amoxicillin can lead to skin sensitisation based on human experience and also based on the evidence from chemical structure related substances (penicillins), the substance amoxicillin is proposed to be classified as skin sensitiser.
TERATOGENICITY (EXPOSURE RELATED OBSERVATIONS):
Epidemiological studies that investigated the risk of teratogenicity of amoxicillin in humans have not identified any increased risk.

Additional information

RESPIRATORY SENSITISATION: Occupational exposure:

A number of reports indicate that workers who have been exposed to penicillins have developed asthma. The findings of bronchial challenge tests conducted in some subjects demonstrate that penicillins such as ampicillin can cause a delayed asthmatic reaction.

Anaphylactic reactions to penicillins were reported soon after their introduction, and asthma became recognised as part of the anaphylactic response to systemic administration. However, it was over 20 years before cases of occupational asthma related to penicillin exposure were clearly documented in the open literature (Montanaro, 1992).

Four workers employed in a factory producing penicillin and a number of semisynthetic antibiotics were studied by Davies et al (1974). Three developed asthma and rhinitis 2 years after starting work with these materials. The fourth subject developed shortness of breath and productive cough after 4 years. Bronchial challenge testing was carried out in a single-blinded manner using ampicillin and, in 3 subjects, with benzyl penicillin. Lactose was used as a vehicle and as a negative control substance. Late and generally marked asthmatic reactions were demonstrated in each asthmatic worker after challenge with the penicillins. The fourth individual showed no response and was subsequently diagnosed with chronic obstructive bronchitis.

Wuthrich and Hartmann (1982) have described the case of a factory worker who developed respiratory difficulties whilst employed in a production facility where tetracyclines, chloramphenicol and ampicillin were formulated. When the subject discontinued work, slow recovery occurred. Within 2 weeks of resuming duties, considerable worsening of respiratory problems was observed. A bronchial challenge test was conducted using lactose, tetracycline, ampicillin and chloramphenicol given in an order which was unknown to the patient. Four hours after inhalation of ampicillin, the forced expiratory volume in one second dropped by 42%. It was

claimed by the authors that the data indicated a delayed asthmatic response to ampicillin.

In a Danish study, 45 workers in a factory producing the semisynthetic penicillins pivmecillinam and pivampicillin developed dermatitis, of which 19 also showed allergic symptoms of the eyes, nose or lungs indicative of hayfever (17 cases) and/or asthma in 5 cases (Moller et al., 1986). The duration of exposure before these symptoms arose was short, often only weeks and in all cases within 5 months. The asthma attacks found in these cases were often of the delayed type, starting 5-6 hours after the exposure that provoked them. A follow-up study revealed further information regarding the progress of this outbreak, briefly reporting on the 56 cases of allergy recorded during 15 years of production of pivampicillin (Moller et al., 1990). Of these 56, 11 developed asthma, 31 hay fever and 50 allergic dermatitis on the face and arms.

The prevalence of allergic disease of the respiratory tract and skin among Russian workers engaged in the production of ampicillin trihydrate and ampicillin sodium salt has been investigated (Karpenko, 1986). The actual number of workers evaluated is not known. Antibiotic concentration in the air varied with stage of production. Overall, there was an apparent association between airborne levels and occurrence of respiratory disease, with 80% prevalence at the highest level of exposure and 12% where exposure was lowest.

A review indicates that during the 1960s there were sporadic cases of occupational asthma among health professionals (particularly doctors, midwives and nurses) that were related to their preparation of penicillin for injection, when the antibiotic was handled in powdered form, and their administration of aerosols of the drug (Rosenberg and Gervais, 1991). The use of greater precautions now apparently prevents this sort of occupational asthma.

Little further useful information is available. One of 17 confirmed cases of occupational asthma in Singapore was ascribed to ampicillin exposure at a pharmaceutical facility (Lee and Phoon, 1989). No further details are available as only a summary of the report could be obtained. A study of 331 workers in a Polish penicillin factory found one with bronchial asthma alongside 79 with

allergic dermatitis and 6 with urticaria (Rudzki et al., 1965). Similarly, a study of 169 workers involved in the manufacture of synthetic penicillins in an American factory found 2 that complained of wheezing, 27 with rhinorrhea and/or sneezing, 14 with itching eyes and 37 with localised rash (Shmunes et al., 1976).

According to the available evidence showing that amoxicillin can lead to specific respiratory hypersensitivity based on human experience and also based on the evidence from chemical structure related substances known to cause respiratory hypersensitivity (penicillins), the substance amoxicillin is proposed to be classified as respiratory sensitiser.

REFERENCES

Davies RJ, Hendrick DJ and Pepys J (1974) Asthma due to inhaled chemical agents: ampicillin, benzyl penicillin, 6 amino penicillanic acid and related substances Clin Allergy. 4; 227-247

Karpenko LZ (1986) The effect of production factors on the incidence of allergic diseases in ampicillin production operators Gigiena Truda Prof Zabol. No. 10; 37-40

Lee HS and Phoon WH (1989) Occupational asthma in Singapore. Database from the National Institute for Occupational Safety and Health. (Full reference: J Occup Med, Singapore. 1; 29-37)

Moller NE, Nielsen B and von Wurden K (1986) Contact dermatitis to semisynthetic penicillins in factory workers Cont Derm. 14; 307-311

Moller NE, Nielsen B and von Wurden K (1990) Changes in penicillin contamination and allergy in factory workers Cont Derm. 22; 106-107

Montanaro A (1992) Occupational asthma due to inhalation of antibiotics and other drugs. In “Occupational Asthma” (Bardana EJ, Montanaro A, O’Hallaren MT, eds.), Hanley and Belfus, Philadelphia, pp205-211

Rosenberg N and Gervais P (1991) Occupational rhinitis and asthma due to antibiotics Docs Med Trav. 45; 37-41

SKIN SENSITISATION: Occupational exposure:

Among the antibiotics, the natural and the semisynthetic penicillins are the most common drug allergens causing symptoms, particularly in pharmaceutical workers.

According to the available evidence showing that amoxicillin can lead to skin sensitisation based on human experience and also based on the evidence from chemical structure related substances (penicillins), the substance amoxicillin is proposed to be classified as skin sensitiser.

TERATOGENICITY: Exposure related observations:

Several epidemiological studies evaluated the developmental toxicity or teratogenic potential of amoxicillin or amoxicillin–clavulanic acid used in pregnant women. In general, penicillins, including amoxicillin, are considered to have minimal reproductive toxicity. The results, did not identify an increased risk of major congenital anomalies, malformations or teratogenic potential in children when their mothers were treated with amoxicillin during various stages of gestation. Based on these data, the increased risk of teratogenicity in humans is considered “unlikely”.