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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No impairment of fertility was observed at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats. No impairment of fertility was observed at oral dose levels up to 50 mg/kg in male rats.

Source: TOMES® System: Klasco RK: TOMES® System. Truven Health Analytics, Greenwood Village, Colorado.

Effects on developmental toxicity

Description of key information

Teratogenicity studies in mice and rats at up to 120 mg/kg and 60 mg/kg, respectively (subcutaneously to the dams) did not show an increase in visceral or skeletal abnormalities in the offspring; there were also no effects on litter size or fetal weight. There was no significant maternal toxicity at these doses.

Based on experimental animal studies, use of tramadol during pregnancy is not expected to increase the risk of congenital anomalies. There are case reports of withdrawal in a newborn after habitual tramadol use by the mother during pregnancy.

Source: REPROTOX ® Database: Klasco RK: REPROTOX® Database. Truven Health Analytics, Greenwood Village, Colorado.

One study suggests a moderately increased risk of a teratogenic effect of tramadol. When tramadol is used during pregnancy, there is a serious risk for neonatal abstinence syndrome. Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses, but was not teratogenic at these dose levels.

Source: Hazardous Substances Data Bank [Internet]. Bethesda (MD): National Library of Medicine (US). Available from:

http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB

Toxicity to reproduction: other studies

Description of key information

Tramadol and its active metabolite, O-desmethyltramadol, are excreted in human milk in small amounts. Seventy-five mothers who were 2 to 4 days postpartum provided 3 milk samples from both breasts during the 6 h following a dose of 100 mg of oral tramadol after taking at least 4 doses. The average milk concentration of tramadol was 748 mcg/L (range 681 to 815 mcg/L) and the average milk concentration of its active metabolite, O-desmethyltramadol, was 203 mcg/L (range 188 to 217 mcg/L). These values translate to an average infant dosage of 112 and 30 mcg/kg daily of the drug and metabolite, respectively. An exclusively breastfed infant would receive maternal weight-adjusted dosages of 2.24% of tramadol and 0.64% of its metabolite. This dose would represent roughly 3% of a typical intravenous newborn dosage.

Source: REPROTOX ® Database: Klasco RK: REPROTOX® Database. Truven Health Analytics, Greenwood Village, Colorado.

Justification for classification or non-classification

Additional information