Reaction mass of dodecyltrimethylammonium bromide and tetradonium bromide

Endpoint summary

Description of key information

Data on relevant read-across substances:
An oral 28D study in rats has been conducted on a 24-26% cetrimonium chloride solution with dose-levels

of 0; 30; 100; and 300 mg/kg bw/d (corresponding to 0; 7.5; 25, and 75 mg/kg bw/d). The dose was given as gavage in 10 ml of water/ kg bw. The NOAEL was 25 mg/kg bw/d. At 75 mg/kg bw/d severe local effects in the stomach was noted (thickening of forestomach mucosa, sporatic ilceration. Slight increase in adrenal weight and slight decrease in spleen weight were also noted at this dose level but this was only considered as possible and not clear systemic effects.

In an oral 1-year study rats were dosed via drinking water with cetrimonium bromide at 0; 10; 20 and 45 mg/kg bw/d. No histopathological findings were observed in the stomach (only organ subject to histopathological examination). At 45 mg/kg bw/d significant and persistent decrease in body weight was observed in male which was suggested to be due to lower observed efficiency of food conversion. The authors concluded that cetrimonium bromide may potentially prevent proper nutrition by increasing the rate of gastric emptying and intestinal transit and/or interfering with absorption of nutritional substances.
In an evaluation of the study by the SCCS, a NOAEL of 10 mg/kg bw/d from this study was concluded.

In a 28D dermal study with rabbits dosed on 25% of their body surface with 10 mg/kg bw/d (2 ml/kg bw/d) cetrimonium chloride no systemic effects were noted.
However, the exposed skin at this exposure level ( corresponding to a to a dermal load of 0.05 mg/cm2 when assuming 25% of a body surface of 2500 cm2 (625 cm2) and a body weight of 3 kg) showed mild to marked acanthosis with active mitosis, hyperkeratosis, and partial to extensive necrosis of the epidermis and hair follicles, partly with encrustation and exudate.

See read-across justification to C12 -14 TMAB attached in section 13

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Klimisch score 2. The systemic effects observed (reduced growth) is considered secondary to local effects in the gastrointestinal tract leading to decrease in feed efficiency of the animals.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Klimisch score 2

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

0.05 mg/cm²

Study duration:

subacute

Species:

rabbit

Additional information

No clear systemic effects have been observed in the repeated dose toxicity studies with cetrimonium chloride and cetrimonium bromide.

The local effects are considered the most critical effects in connection with repeated exposure.

The lack of systemic effects in the repeated dose toxicity studies may be explained by a low dermal and oral absorption rates as indicated by the toxicokinetic studies where absorption rates for dermal and oral exposure have been estimated to 3% and 6%, respectively (see 7.1 toxicokinetics)

As seen from the repeated dose toxicity studies, the potent local effect of the comparable read-acros substances very much limit the exposure levels to be used in repeated dose toxicity studies for further examining systemic effects. Thus, there seems to be no rationale for further RDT testing of C12 -14 TMAB at ANNEX IX level as a valid NOAEL for the read across substance cetrimonium bromide has been establisehd in a 1 - year drinking water study.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
long-term RDT study on cetrimonium bromide (1 year study) for read-across to C12 -14 TMAB.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
28D repeated dermal toxicity study on cetrimonium chloride for read-across to C12 -14 TMAB

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
28D repeated dermal toxicity study on cetrimonium chloride for read-across to C12 -14 TMAB

See read-across justification to C12 -14 TMAB attached in section 13

Justification for classification or non-classification

Using read-across to the 28D oral study on cetrimonium chloride where severe effects were noted in the gastrointestinal tract at a dose level of 75 mg/kg bw/d the substance should according to the CLP regulation be classified as STOT RE 2; H373 (oral route; gastrointestinal tract). This classification is also considered relevant to apply for C12 -14 TMAB.