Registration Dossier

Administrative data

Description of key information

ORAL:
Male and female F344 rats and male and female B6C3F1 mice received orally by gavage 0, 30, 60, 125, 250, 500 or 750 mg/kg bw/day diluted in corn oil over once daily, 5 days per week over period of 13 weeks. The study was conducted according to OECD guideline 408 with deviations. On the basis of the observations, the NOAEL(systemic) was estimated to be 125 mg/kg bw/day. Prolongation of oral treatment up to 2 years (details in section 7.7 Carcinogenicity; male and female F344 rats and female B6C3F1 females: 60 or 120 mg/kg bw/day; male B6C3F1 mice 30 or 60 mg/kg bw/day) the overall NOAEL(systemic) was considered to be 60 mg/kg bw/day (NTP1985 , SCOEL 2001)
INHALATION
There is no standard repeated dose toxicity study availble using the inhalation exposure route. However, there is a reliable 2 -generation reproduction toxicity study availble using the inhalation exposure route.(0, 50,150 or 450 ppm) This study can be considered as surrogate for a subchronic study due the overall period of exposure to monochlorobenzene. The LOAEC (systemic toxicity) is considered to be 50 ppm (corresponding to 234 mg/m³, Nair 1987, SCOEL 2001).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
chronic

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
234 mg/m³
Study duration:
subchronic

Additional information

ORAL:

A 13-week study of orally administered (gavage, in corn oil) monochlorobenzene was conducted in male and female Fischer-344 rats. 0, 60, 125, 250, 500 or 570 mg/kg bw/day monochlorobenzene was administered once daily, 5 days per week. The study was conducted according to OECD guideline 408 with deviations (Ophthalamoscopic and sensory examinations were not performed. Two Hematological parameters not measured. Five parameters of clinical chemistry not tested; Kluwe 1985, NTP 1985)

Survival was reduced at 500 and 750 mg/kg bw/day (mortality: 500 mg/kg: 4/10 males, 3/10 females; 750 mg/kg: 9/10 males, 8/10 females). Body weight gains appeared to be reduced in male rats at doses >= 250 mg/kg and female rats at doses  >= 500 mg/kg. Slight increases in serum alkaline phosphatase and slight to moderate increases in serum gamma glutamyl transpeptidase activities, as well as slight increases in total liver porphyrins were observed in surviving female rats at 500 and 750 mg/kg; porphyrinuria was detected in male and female rats at 500 and 750 mg/kg. Slight increases in liver and kidney weights and slight decreases in spleen weights were observed in male and female rats, predominately at higher doses. Histologic examinations revealed chemically related changes in the liver (primarily centrilobular hepatocellular necrosis), kidney (proximal tubular degeneration and necrosis), bone marrow (myeloid depletion), spleen (lymphoid depletion) and thymus (lymphoid depletion). These changes were most apparent in the 500 and 750 mg/kg groups;

On the basis of these results, the NOAEL(systemic) was estimated to be 125 mg/kg bw/day.

A second 13-week study of orally administered (0, 60, 125, 250, 500 or 750 mg/kg bw/day, gavage, in corn oil) chlorobenzene was conducted in male and female B6C3F1 mice. Survival was reduced at >= 250 mg/kg bw/day as well as body weight gains appeared to be reduced in males at >= 250 mg/kg bw/day and females at >= 500 mg/kg bw/day. Porphyrinuria as detected in at doses >= 250 mg/kg bs/day. Liver weights were increased in males at >= 250 mg/kg and females at >= 500 mg/kg bw/day whereas heart weights wer slightly decreased in all treated male mice. Histological examinations revealed dose-dependent chemical-induced injuries in liver kidney, bone marrow, spleen and thymus at doses >=250 mg/kg bw/day. On the basis of these results a NOAEL of 125 mg/kg can be deduced.

Prolongation of oral treatment up to 2 years (details in section 7.7 Carcinogenicity; male and female F344 rats and female B6C3F1 females: 60 or 120 mg/kg bw/day; male B6C3F1 mice 30 or 60 mg/kg bw/day) caused only an increase in male rat mortality at 120 mg/kg bw/day. No other adverse systemic effects were noted. The failure of chlorobenzene to elicit toxic responses in the kidney, liver or haematopoetic system in the chronic study indicates at the most a slight potential for progressive toxicity with continued chlorobenzene administration beyond 13 weeks. Based on the increased male rat mortality at 120 mg/kg bw/day, the overall NOAEL(systemic) was considered to be 60 mg/kg bw/day (NTP1985 , SCOEL 2001)

INHALATION

There is no reliable standard repeated dose toxicity study availble using the inhalation exposure route. However, there is a reliable 2 -generation reproduction toxicity study availble using the inhalation exposure route. This study can be considered as surrogate for a subchronic study due the overall period of exposure to monochlorobenzene.

Groups of 30 males and 30 females CD rats, designed as P generation, were exposed to vapor of monochlorobenzene (MCB) at target concentrations of 0 , 50 , 150, or 450 ppm (0, 234, 702 or 2106 mg/m³) for 10 weeks prior to mating and during mating, gestation, and lactation. The progeny of the P generation was designed as the F1 generation and groups of 30 male and 30 female F1 animals were exposed to the same concentration of MCB as the F0 parents. Exposure of F1 animals was initiated 1 week postweaning and lasted 11 weeks prior to the mating and through mating, gestation, and lactation. All F2 pups were observed through weaning at which time they were killed. Observations made during the study included body weights, food consumption, mating and fertility indices, pup and litter survival indices, and histopathology of selected tissues.

No mortality was observed during the course of this study. No adverse effect of treatment was evident on body weight, food consumption, and physical observation. Overall, reproductive performance, fertility and development of pups were not affected by treatment with monochlorobenzene yielding a NOAEC of 450 ppm (corresponding to 2106 mg/m³) for reproduction and development.

However, post mortem examinations revealed significantly elevated absolute and relative liver weights in F0 and F1 male and female rats at 150 and 450 ppm and at 50 ppm in F1 males accompanied by hepatocellular hypertrophy in F0 and F1 males exposed to 150 and 450 ppm. In addition, renal changes (tubular dilation with eosinophilic material, interstitial nephritis, and foci of regenerative epithelium) were observed mainly in F0 and F1 male rats exposed to 150 and 450 ppm. The significance of reported degeneration of the testicular germinal epithelium in male rats at 450 ppm is unclear because no histopathological correlate is reported. Thus, the LOAEC (systemic toxicity) is considered to be 50 ppm (corresponding to 234 mg/m³ Nair 1985, SCOEL 2001).

Justification for classification or non-classification

Up to now monochlorobenzene is not classified . Based on the available data no classification/labelling is required