Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Inhibits ovulation at high doses in rats via intrperitoneal injection.  This is not considered relevant for human health risk assessment.

Additional information

γ-Butyrolactone (GBL) is not expected to be a selective reproductive toxicant as indicated by available chronic, reproductive / developmental, and toxicokinetic/metabolism data. In an OECD 422 guideline study with 1,4-Butanediol (BDO; CAS# 110-63-4), a substance that follows the same pharmacokinetic/dynamic pathways as GBL (NTP, 1996), a NOAEL for reproductive toxicity was determined to be 800 mg/kg/day for parental and F1 animals (MHW, 1999). In this study, male and female rats were given daily oral doses of 200, 400 and 800 mg/kg and parental animals exhibited no alteration in reproductive parameters. In addition, in a 2-yr cancer assay on GBL conducted by the National Toxicology Program (NTP), no adverse pathological findings were noted in reproductive organs (NTP, 1992). Since there are no serious concerns about the potential for adverse effects on fertility, and in the interest of animal welfare, an Extended One Generation Reproductive Toxicity Study is not being proposed.

Short description of key information:

γ-butyrolactone (GBL) is not believed to be a selective reproductive toxicant.

Effects on developmental toxicity

Description of key information

γ-Butyrolactone (GBL) is not believed to be a selective developmental toxicant.

Additional information

γ-Butyrolactone (GBL) is not expected to be a selective developmental toxicant. No developmental effects were observed in an OECD 414 oral (gavage) study of GBL up to 500 mg/kg-bw with rats (Kronevi, 1988). 

A summary report (NTP, 1996) presents a toxicokinetic analysis which documents that γ-butyrolactone is partially metabolized to gamma-hydroxybutyric acid and pharmacologic and toxicologic response to this chemical is due to its metabolic conversion to this metabolite. GBL shares common segments of its metabolism and toxicokinetic pathway with 1,4 -Butanediol.

In an OECD 422 guideline study with 1,4 -butanediol (BDO), which like GBL rapidly metabolizes to γ-hydroxybutyric acid (GHB), a slight but significant decrease in body weights of pups at day 4 of lactation was observed at 800 mg/kg bw (Japan MHW, 1999). Male and female rats were exposed daily (males 42 days, females 14 days prior to gestation to 3 days after lactation) by oral gavage to 200, 400, and 800 mg/kg-bw. The decrease in body weights of pups is considered secondary to maternal toxicity seen at 400 mg/kg-bw.

In a developmental toxicity study of BDO reported by NTP, mice were given daily oral doses of 100, 300 or 600 mg/kg from g.d. day 6 - 15. No maternal or developmental effects were observed at the low dose. Dams at the mid and high doses exhibited symptoms of central nervous system intoxication during the first 4 hr following daily administration. Maternal effects at the mid and high doses also included reduced food intake, reduced body weight, and reduced weight gain. The only definitive expression of developmental toxicity was a reduction in average fetal body weight at the middle and high doses, which may be considered as secondary to the maternal toxicity.

 

Toxicity to reproduction: other studies

Additional information

γ-Butyrolactone (GBL) administrated via i.p. injection during the proestrus phase inhibits the ovulation in rats (Beattie, 1976). In this study, a clear dose-dependent inhibition of ovulation was observed. In contrast to the control group where ovulation was seen in all the rats (percentage of inhibition = 0), no ovulation was seen at the highest tested dose of 750 mg/kg (percentage of inhibition = 100%). The effect dose ED was ca. 250 mg/kg bw.

Justification for classification or non-classification

Gamma-butyrolactone (GBL) is not expected to be a selective reproductive toxicant as indicated by available chronic, reproductive / developmental, and toxicokinetic / metabolism data. In an OECD 422 guideline study with 1,4-Butanediol (BDO; CAS# 110-63-4), a substance that follows the same pharmacokinetic/dynamic pathways as GBL, a NOAEL for reproductive toxicity was determined to be 800 mg/kg/day for parental and F1 animals. Male and female rats were given daily oral doses of 200, 400 and 800 mg/kg. Parental animals exhibited no alteration in reproductive parameters. In addition, in a 2-yr cancer assay on GBL conducted by the National Toxicology Program (NTP), no adverse pathological findings were noted in reproductive organs. GBL is not expected to be a selective developmental toxicant as indicated by available reproductive / developmental and toxicokinetic/metabolism data. No developmental effects were observed in an OECD 414 oral (gavage) study of GBL up to 500 mg/kg-bw with rats. Additionally, no distinct developmental effects were found in the NTP's developmental toxicity study of BDO conducted in mice given doses of 100, 300, 600 mg/kg b.w. Based on this information, GBL should not be rated for reproductive or developmental hazard under the EU CLP classification system (EU Regulation 1272/2008).