6-aminopenicillanic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Additional information

No effects were noted in a one litter prenatal toxicity study in rats dosed with either 200 or 400 mg/kg bw/day of ampicillin anhydrous.

Toxicity to Reproduction, Developmental toxicity and Teratogenicity:

The following substances are considered to be similar in order to facilitate read-across for systemic toxicity endpoints: Ampicillin and Penicillin. The read-across justification is based on the very high water solubility of the substances; they all contain the β- lactam ring and have low acute toxicity.

A literature review of available human and animal data on reproductive toxicity to 6-Aminopenicillanic Acid (6-APA) and its read-across substances showed no unequivocal evidence of reproductive/ developmental toxicity. Penicillin G, V and Ampicillin have been used at all stages during pregnancy. As a general principle, pregnant women should not take any drugs, but if an antibiotic must be prescribed, the doctor can choose from Penicillin G, V and Ampicillin, as they have never been shown to cause harmful adverse effects. It has therefore been concluded that beta-lactams are the preferred antibiotic for use against bacterial infection in pregnancy.

The pharmacokinetics of Ampicillin during human pregnancy has been studied in detail and the placental transfer of Ampicillin has been well characterized. Ampicillin and other Penicillins accumulate in amniotic fluid in large amounts after maternal ingestion. This accumulation is caused by fetal urinary excretion of the antibiotic into the amniotic fluid, which continues until the mother stops ingesting the drug. Thereafter, the fetus gradually reabsorbs the antibiotic (probably by swallowing the amniotic fluid) and clears the drug by passage across the placenta to the mother. No adverse fetal effects have been associated with this process.

Primary studies have been conducted in rats with anhydrous Ampicillin (oral dosing by incorporation into diet, 200 or 400 mg/kg/day for 60 days before mating, through pregnancy and nursing for a minimum of either 15 weeks (1 litter study) or 21 weeks (2 litter study) and in rats with Ampicillin sodium (subcutaneous dosing, 200 mg/kg/day for the first 14 days of gestation and then through end of lactation). In both the 1 and 2 litter oral dose studies (20 maternal animals per Ampicillin treatment group) the authors reported no difference between control and Ampicillin-treated groups with respect to fertility (Ampicillin-treated male rats were used along with females), gestation period, litter size or ratio of sex of offspring, length or weight of pups at birth, weaning, or 3 weeks after weaning; pup morphology (by gross observation and alizarin red-stained skeletal examination) was also unaffected by treatment. In addition, dams from the 2 litter study were euthanised and reproductive organs examined; no Ampicillin-related effects of toxicological significance were observed. With subcutaneous administration, the authors reported no effect of Ampicillin treatment of reproductive success or outcomes.

Overall 6-APA is off low toxicological activity (no evidence of toxicity seen in any of the test available) and the very low log Pow suggests that there is unlikely to be any accumulation of test material in body fat.

Therefore, taking into account the low toxicity and animal welfare, this test is not considered scientifically necessary in accordance with Annex XI, section 1.1.

References:

Bray R et al: Transfer of ampicillin into fetus and amniotic fluid from maternal plasma in late pregnancy. Am J Obstet Gynecol 96:9328-42, 1966.

Greselin E, Herr F, Charest MP, Sadeek M, Vlielander L & Hajdu A. Toxicology studies of R-12, 101-5 (Penbritin oral, 6 (D(-)- α-Aminophenylacetamido) penicillanic acid –Type W.2/B (anhydrous).Beecham Research Laboratories Ltd. 1964

 Jordhein O, Hagen AG: Study of ampicillin levels in maternal serum, umbilical cord serum and amniotic fluid following administration of ampicillin. Acta Obstet Gynecol Scand 59:315-7, 1980.

Knothe N & G.A Dette .Antibiotics in Pregnancy: Toxicity and Teratogenicity.. Infection (1985) 13.Nr.2

 

Kraybill EN et al: Transplacental ampicillin: inhibitory concentrations in neonatal serum.Am J Obstet Gynecol 138:793-6, 1980.

MacAulay M et al: Placental transfer of ampicillin. Am J Obstet Gynecol 96:943-50, 1966.

 

 Philipson A: Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 136:370-6, 1977.

Short description of key information:

Toxicity to reproduction was determined by two studies conducted to a good scientific standard.