Triclosan

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Dose descriptor:

NOAEL

238 mg/kg bw/day

Additional information

One GLP-compliant two-generation study was conducted in rats, providing both fertility and reproduction, and post-natal data (Hazleton Lab 2386-100). Fertility and reproduction parameters of mating, pregnancy, duration of gestation, and parturition were assessed and based on the absence of effects in F0 and F1 parental generation rats, the NOAEL for fertility and reproduction was determined to be 3000 ppm (238/285 mg/kg bw/day, males/females), the highest dose tested.

In the examination of post-natal development in rats, the primary findings were a slight decrease in mean fetal body weights and a slight decrease from day 0 to day 4 survival in the F1 generation at the high dose of 3000 ppm (152/76 mg/kg/day, males/females). A similar albeit not significant trend was observed for F2 offspring. Thus, the fetal and post-natal NOEL for this study was determined to be 1000 ppm (152/76 mg/kg/ day, males/females) for triclosan administered in the diet.

Short description of key information:
For reproduction toxicity, the following valid guideline study was as key study:
Two-generation study with rat conducted according to FIFRA § 83-4, which is similar to the OECD TG 416 (Hazleton Lab 2386-100)

Effects on developmental toxicity

Description of key information

For developmental toxicity and teratogenicity, several valid studies are available, which were retained either as key studies or for support.
The following studies were retained as key studies:
A segment II teratology study with rabbit, without guideline statement but conducted in compliance with OECD TG 414 requirements as in its original version dated 1981 (Bio/dynamics Inc 91-3666), with corresponding range-finder (Bio/dynamics Inc 91-3655)
A segment II teratology study with rat, without guideline statement but conducted in compliance with OECD TG 414 requirements as in its original version dated 1981 (Bio/dynamics Inc 91-3665), with corresponding range-finder (Bio/dynamics Inc 91-3654)
The following study was retained for support:
A developmental toxicity study with mouse, without guideline statement but conducted in compliance with OECD TG 414 requirements as in its original version dated 1981 (Argus Research Lab Inc  92-001), with corresponding range-finder (Argus Research Lab Inc  91-016)

Effect on developmental toxicity: via oral route

Dose descriptor:

NOAEL

50 mg/kg bw/day

Additional information

In rabbits, triclosan has been investigated in one range-finding and one definitive teratology study (Bio/dynamics Inc 91-3655 and Bio/dynamics Inc 91-3666). Triclosan was orally administered by gavage from day 6 to 18 of gestation.

Doses of 0, 15, 50, or 150 mg/kg bw/day were administered in the definitive oral gavage study in rabbits (Bio/dynamics Inc 91-3666). The does showed evidence of significant maternal toxicity in the form of decreased body weights, body weight gains, and food consumption at the high dose. There was no evidence of embryo or fetal toxicity or of teratogenic effect of triclosan. Based on the lack of fetal effects in this study, the fetal NOEL was determined to be 150 mg/kg bw/day administered by gavage, with the maternal NOEL being 50 mg/kg bw/day.

In summary, triclosan showed no teratogenic and no embryotoxic effects at any of the doses in the definitive GLP study conducted in rabbits. Findings of maternal toxicity (decreases in maternal body weight gains) at the high dose indicated that dose levels were adequately high in the study. Hepatotoxic effects were not observed in any of the dams. The fetal NOEL is considered to be 150 mg/kg bw/day in rabbits given triclosan via oral gavage, with the maternal NOEL being 50 mg/kg bw/day.

In rats, triclosan has been investigated in one range-finding and a definitive teratology study (Bio/dynamics Inc 91-3654 and Bio/dynamics Inc 91-3665). Doses of 0, 15, 50, or 150 mg/kg bw/day were administered in the definitive oral gavage study using triclosan in 1% carboxymethylcellulose (Bio/dynamics Inc 91-3665). The dams showed evidence of maternal toxicity in the form of slight, but significant, decreases in food consumption from day 6 to 11 of gestation in high-dose animals. There was no evidence of any teratogenic effect of triclosan.

Fetal effects (fetal variations) were manifest as delayed ossification at the high dose of 150 mg/kg bw/day, and with maternal toxicity occurring at the same dose. Based on observations of delayed ossification at the high dose, the foetal NOEL in this study was determined to be 50 mg/kg bw/day (the maternal NOEL was also 50 mg/kg bw/day).

The finding of maternal toxicity at the high dose in each of the studies indicated that dose levels were adequately high in each case. (It should be noted that the observed decreases in food consumption followed the administration of triclosan by oral gavage, and therefore would not likely have been due to any decreased palatability of the diet.) Hepatotoxic effects were not noted in the dams. There was no evidence of any teratogenic effects of triclosan.

The fetal NOEL is considered to be 50 mg/kg bw/day in rats given triclosan via oral gavage, with the maternal NOEL being also 50 mg/kg bw/day.

The potential for triclosan to induce developmental toxicity effects has been investigated in one range-finding and one definitive teratology study in mice (Argus Research Lab Inc 91-016 and Argus Research Lab Inc 92-001). Doses in the definitive mouse study were 0, 10, 25, 75, or 350 mg/kg bw/day administered in the diet on days 6 to 15 of gestation. Maternal toxicity was observed at doses greater than 25 mg/kg bw/day, including liver effects (i.e., increased liver weights and tan-coloured livers). Triclosan was not teratogenic in either the dose range finding or the definitive study. Foetal effects (classified as foetal variations) included slightly decreased body weights at the two higher doses that also caused maternal toxicity, as well as reversible delays in ossification at the same doses. A fetal NOEL of 25 mg/kg bw/day was determined based upon decreases in foetal body weights and delayed ossification at higher dose levels in the definitive study.

It is important to note that liver effects of tan-coloured livers and increased absolute and relative liver weights were observed in maternal animals administered doses of 75 or 350 mg/kg bw/day in the definitive mouse study. No liver effects were observed in any of the studies conducted in rats or rabbits (doses up to 300 mg/kg bw/day).

Consistent with the findings from the rat studies, there were clear indications that the fetal variations of significantly decreased body weight and delayed ossification observed at the two higher doses in the mouse study were likely to be secondary to maternal toxicity (there were no foetal effects at doses that were not maternally toxic). Nevertheless, it should be noted that the mouse is not considered to be a relevant model for the evaluation of human safety based on its known unusual sensitivity to triclosan’s effects in liver, where peroxisome-proliferator-like effects have been observed. As such, results (e.g., NOEL or NOAEL values) from the mouse developmental toxicity studies represent findings in an overtly-sensitive species not considered to be relevant for the assessment of human risk, and, thus, were not considered in the process of selecting an overall NOAEL for reproductive effects during pregnancy. In summary, the NOAEL retained for fertility and reproduction was 238 mg/kg bw/day, the highest dose tested in the two-generation rat study with triclosan administered in the diet. The overall NOAEL (NOEL) for fetal effects of triclosan was 50 mg/kg bw/day, based on fetal variation effects of delayed ossification observed at the high dose that also produced maternal toxicity in the rat oral gavage study. The NOAEL for post-natal effects of triclosan was 76 mg/kg bw/day as tested in rats in the two-generation study with triclosan in the diet. It is important to note that the selection of the fetal NOAEL was based on fetal variation effects that were most likely secondary to general maternal toxicity, and no direct effects of triclosan per se.

Justification for classification or non-classification

Owing to the results obtained from the studies and discussed above, there is no need for classification of triclosan for reproduction toxicity according to the EU Directive 67/548/EEC, and there is no need for classification according to the Annex VI of the CLP regulation.