Registration Dossier

Administrative data

Description of key information

Several studies on the toxicity of triclosan in different species under repeated administration conditions are available for the oral, the dermal and the inhalation route.
For the repeated oral route of exposure, following studies were retained as key studies:
A 28-day study with mouse according to OECD TG 407 (Ciba-Geigy Ltd 864005).
A 13-week study with hamster according to OECD TG 408 (RCC 356490)
A 90-day study with dog with a conduct similar to OECD TG 409 (LPD 8/70)
A 90-week study with hamster according to OECD TG 451 (HLS Ltd CBG 756/972896)
A 2-year combined toxicity/carcinogenicity study with rat according to OECD TG 453 (Ciba-Geigy Corp 85152).
Following studies served as support:
A 90-day study with mouse according to EPA OPP 82-1 (Hazleton HWA 483-287)
A 90-day study with rat with a conduct similar to OECD TG 408 (Litton Bionetics Inc. 22188)
A 4- and 13-week study with baboon conducted prior to the implementation of TG (HRC 2736/69/162)
For the repeated dermal route of exposure, the following study was retained as key study:
A 90-day study with rat according to EPA OPP 82-3 (Exxon Biomedical Sciences Inc 139910B)
For the repeated inhalation route of exposure, the following study will be mentioned despite the fact that the study was discarded:
A 21-day study with rat with a conduct similar to OECD TG 412 (Ciba Geigy Ltd Siss. 3725)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
75 mg/kg bw/day
Study duration:
subchronic
Species:
hamster, Syrian

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
80 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Repeated dose studies ranging from 14 days to 2 year in duration have been conducted in mice, rats, hamsters, rabbits, dogs, and non-human primates via the oral route (see references above), with the only consistent changes being in the liver of rodents (oral and dermal). Hepatic effects were marked in mice, and included biochemical changes measured in blood or plasma, liver weight changes, and histopathologic changes. In contrast, liver changes were seen less frequently and with decreased severity in rats and hamsters. The results of pivotal, GLP-compliant subchronic studies for orally-administered triclosan in rodents show that there were few toxicological effects following up to 90 days or 104 weeks of dosing.

Because of the similarity of the metabolic profile between hamster and primates, it is assumed that the effects observed in the hamster are more relevant for human risk assessment than the liver effects that the other rodent species revealed. The most critical effects in the hamster were related to nephrotoxic events seen with higher doses of triclosan. These effects included polyuria, increased blood urea nitrogen and nephropathy. Both in the subchronic and the chronic hamster study, the NOAEL for this complex of effects is 75 mg/kg bw/day. It is proposed to adopt this value as a general NOAEL for triclosan.

No systemic effects were seen in the GLP-compliant 90-day toxicity study using the dermal route of administration in rats. The dermal NOAEL for triclosan is 80 mg/kg bw/day, which was the highest dose tested.

The results of the studies in this section are considered representative of triclosan having the composition as was defined above in this document. To our judgement the dioxin and furan impurities that can occur in triclosan synthesis when present at higher concentrations than used for these studies can be expected to have some level of effect on repeated dose endpoints and the resultant NOAELs determined for the respective study. Thus, in order to be represented by the animal testing included in this dossier the triclosan composition should have impurities equal to or below the values shown in the following Table 1.

Table 1.  Name of Substance

Composition

Triclosan: Phenol, 5-chloro-2-(2,4-dichlorophenoxy)-

>99.1% <100 % (w/w)

2,4-dichlorophenol

<10 mg/kg

3-Chlorophenol and 4-Chlorophenol, total

<10 mg/kg

2,8-Dichlorodibenzo-p-dioxin

<0.5 mg/kg

2,8-Dichlorodibenzofuran

<0.25 mg/kg

1,3,7-Trichlorodibenzo-p-dioxin

<0.25 mg/kg

2,4,8-Trichlorodibenzofuran

<0.5 mg/kg

2,3,7,8-Tetrachlorodibenzodioxin

ca. 0.0%(w/w)

2,3,7,8-Tetrachlorodibenzofuran

ca. 0.0%(w/w)

non-specified impurities

<0.8785%(w/w)

Triclosan as aerosol was administered to rats, nose-only, in a 21-day inhalation toxicity study; particle size distribution analysis of the chamber airborne particles showed that >90 % were smaller than 7 µm in diameter, indicating that all aerosol was respirable. The following mean concentrations (in mg/L air) were tested: 0.05 (group 2), 0.115 (group 3) and 0.301 (group 4). The control group (group 1) was subjected to the same experimental procedure as the treated groups but without test item. On the first day of the experiment groups 3 and 4 had been exposed to concentrations of 0.227 and 1.300 mg/L air respectively, but these were not tolerated and had to be reduced to 0.115 and 0.301 mg/L air, respectively. Each group consisted of nine male and nine female rats. After the conclusion of treatment, 8 rats each (4/sex) from the control group and from group 3 were kept under observation for a further period of 17 days for reversibility testing.

Based on mortality, clinical symptoms, decreased food consumption, reduced body weight gain, slight tendency to leucocytosis probably associated with inflammatory changes seen in the nasal cavity or in the trachea, increased alkaline phosphatase activity, the LOAEC for triclosan was 0.301 mg/L air; thus, the LOEC was 0.115 mg/ L air and the NOEC was 0.05 mg/L air. At the end of the recovery period, the mean body weight of both the males and the females of the 0.115 mg/ L air group was again comparable to that of the controls, and the laboratory findings (AP activity) were again within physiological limits and comparable to the controls.

Despite of the results reported above, the 21 day inhalation study was discarded since the study shows some main deficiencies and further is unsuitable for hazard assessment and classification, due to the use of ethanol for aerosolization. Referring to the deficiencies, it has to be noticed that the initially highest selected concentration level of 1.3 mg/L air had resulted in mortalities, and the test concentration was changed/lowered from the second day of treatment to 0.301 mg/L air until test ending. Because of the increased mortility rate observed from day 2 to 15 and since the animals exposed to 0.301 mg/L air were not replaced but were, first exposed to 1.3 mg/L air for 2 days, it is not clear whether the observed mortalities truly were due to the refined concentration or resulted from the initial applied concentration. This reduces the reliability of using the 0.301 mg/L air expsoure concentration as the LOAEC for the study, because this concentration may have also served as a NOAEC had higher exposures not occurred.

Similarly in the mid-dose group the exposures were reduced from 0.227 mg/L air on day 1 to 0.115 mg/l air thereafter. Thus, assigning effect levels with these 2 groups is not reliable because of the changed exposure concentrations and the resulting uncertainty of the what exposure effected the observed toxic signs. Moreover, the study showed some principle deviations from the requirement of OECD TG 412, including (1) the reduced daily exposure duration of 2 hours instead of the required 6 hours, and (2) the test duration was 21 days instead of 28 days. Accordingly, it is difficult to use the present study for assessment and classification of long-term triclosan toxicity via the inhalation route not only for the study execution issues, but because triclosan in an ethanol aerosol is a non-representative human exposure scenario. Since the effects seen at 0.115 mg/L air were rather slight and reversible when exposure ceased, this concentration level was defined as LOEC and as NOAEC; the higher concentration level having resulted in mortalities and more severe findings; 0.301 mg/L air was considered as LOAEC.

Justification for classification or non-classification

Triclosan in listed in Annex I and according to the EU Directive 67/548/EEC, the substance is not classified for repeated toxicity.

According to the Annex VI of the CLP regulation, there is no need for classification of triclosan for the oral, dermal and inhalation route of exposure.