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Description of key information

4 repeated dose toxicty (oral) studies are available and 9 repeated dose toxicity (inhalation) studies are available.  The species used for conduction of these studies included rat, mouse, guinea pig, rabbit and dog.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
75 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
150 mg/m³

Additional information

Repeated dose toxicity

Oral studies

The investigations have been conducted within the US NTP program. After oral dosing (gavage) for 14 days, the NOAELs were found to be 313 and 625 mg/kg bw/d in rats and mice, respectively. After 13 weeks these values were <75 and 150 mg/kg bw/d, respectively.

Inhalation studies

Following inhalation, a preliminary subchronic NOAEC(13 wk) of 0.15 mg/L (51 ppm) can be established from a study in rats. Additional studies in rats and dogs that were carried out at higher exposure levels resulted in LOAELs of 0.34 mg/L (125 ppm), based on nasal irritation. No systemic adverse effects were reported at any concentration.

Species

Exp. protocol

Critical Effects

Reference

Evaluation

Rat

14 d, 12x  0, 156, 313, 625, 1250, and 2500 mg/(kg*d)

Mortality 10/10 at the top dose, 3/10 at 1250 mg/(kg*d) and 1/10 at 156 mg/(kg*d). Nasal [APW1] lesions and stomach lesions at 625 mg/(kg*d) and above. The NOAEL and LOAEL in rats were 313 and 625 mg/(kg*d), respectively.

French et al. 1986 (see also NTP Testing Status 2007)

Rel 4
(secondary source)

Mouse

14 d,  12x  0, 156, 313, 625, 1250, and 2500 mg/(kg*d)

Mortality 2/10 at the top dose. Nasal [APW2] lesions at the top dose, dose-related stomach lesions. The NOAEL and LOAEL in rats were 625 and 1250 mg/(kg*d), respectively.

French et al. 1986 (see also NTP Testing Status 2007)

Rel 4
(secondary source)

Rat

13 wk  0, 75, 150, 300, 600, and 1200 mg/(kg*d)

Mortality was dose‑related. Nasal lesions at all doses, stomach lesions at 600 mg/(kg*d), decreased bw gain at 1200 mg/(kg*d). The LOAEL in rats was 75 mg/(kg*d), no NOAEL established

Wolfe et al. 1987 (see also NTP Testing Status 2007)

Rel 4
(secondary source)

Mouse

13 wk  0, 75, 150, 300, 600, and 1200 mg/(kg*d)

Nasal lesions at 300 mg/(kg*d), stomach lesions, decreased bw gain and mortality at 1200 mg/(kg*d). The NOAEL and LOAEL in mice were 150 and 300 g/(kg*d), respectively.

Wolfe et al. 1987 (see also NTP Testing Status 2007)

Rel 4
(secondary source)

Rat

6 h/d; 5 d/wk for 4 wks;
0.3; 0.6; 0.9 mg/l

No mortalities, local irritation. No NOAEC provided

Monsanto 1979

Rel 4
(secondary source)

SD Rat

6 h/d; 5 d/wk for 13 wks; 0.34, 1.36, 5.44 mg/L (125, 500, 2000 ppm)

Treatment-related changes in the nasal cavity, including squamous metaplasia of the mucosal epithelium, hyperplasia of the mucosa cell, inflammation. No other effects observed. LOAEC = 125 ppm (0.34 mg/L).

Union Carbide 1979

Rel 4
(secondary source)

F344 Rat

6 h/d; 5 d/wk for 12 wks; 0.0032, 0.03, 0.151 mg/L (1.1, 10.3, 51.3 ppm)

No treatment-related specific effects. NOAEC = 51 ppm (0.151 mg/L).

Union Carbide 1980

Rel 4
(secondary source)

Dog

0.34, 1.36, 5.44 mg/L (125, 500, 2000 ppm) for 14 wks

Treatment-related changes in the nasal cavity, including squamous metaplasia of the mucosal epithelium, hyperplasia of mucosal cells, inflammation. Significant levels of goblet cell hyperplasia in the nasal mucosa at 125 and 500 ppm.  No other effects observed. LOAEC = 125 ppm (0.34 mg/L).

Union Carbide 1979

Rel 4
(secondary source)

Rat,

mouse,

guinea pig,

rabbit,

dog

9 exposures;
6 h/d;
5.9, 9.1, 18.9 mg/L (2000, 3100, and
  6400 ppm)

Eye and respiratory irritation, and decreases in body weight gain in most species at concentrations of 3100 and 6400 ppm. Other signs in most animals at 6400 ppm included coordination loss, anesthesia and death, at 3100 ppm observed only in the dog.
In some animals exposed to 2000 ppm decreased weight gain.  Scattered organ weight differences in rats exposed to 2000 and 3100 ppm. No pathologically significant treatment related gross lesions were found among animals exposed to 3100 or 2000 ppm.

LOAEC = 5.9 mg/L (lowest dose tested)

Union Carbide 1978

Rel 3
(limited test performance)

Rat

12 exposures,

6 h/d to 3 mg/L (1000 ppm)

Evidence of slight nasal irritation, but no evidence of systemic toxicity

Gage 1970

Rel 3
(limited test performance)

Justification for classification or non-classification

The effects of repeated oral administration and repeated inhalation exposure of the substance are primarily local and reflect the irritant nature of the substance. No evidence of systemic toxicity was seen, therefore no classification for repeated dose toxicity according to Directive 67/548/EEC or Regulation 1272/2008/EC is required