4-chlorobutyryl chloride

Endpoint summary

Description of key information

Rats exposed to 0.002, 0.012, and 0.059 mg/l 4-chlorobutyryl chloride for 4 weeks (6hrs/day, 5days/week) by inhalation showed clinical symptoms linked to respiratory tract inflammation/ irritation (TNO, 1996). Growth retardation, changes in blood parameters clinical chemistry, and organ weights (liver, kidney, spleen, and lung, adrenals) are predominantly noted at the high dose level and can be explained to be secondary due to severe effects on the respiratory tract. They were noted in a dose-related manner, regarding both severity and localization. The entire respiratory tract was severely affected in all high-dose animals, whereas only very slight effects on the transitional and respiratory epithelium were in animals exposed to the lowest dose of 0.002 mg/l, which may be regarded as a lowest observed adverse effect level (LOAEL).  Based on histology findings, there was no other target organ than the respiratory tract in concentrations up to 0.059 mg/L. 

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

LOAEC

2 mg/m³

Study duration:

subacute

Species:

rat

Additional information

In an OECD TG 412 study with supporting substance CCl2, groups of 5 Wistar rats/sex were exposed by inhalation to 0, 2.1, 11.8, and 59.1 mg/m³ (0, 0.002, 0.012, and 0.059 mg/L) as a vapor for 6 h/d, 5 d/week for 4 weeks (20 exposures days for males and 21 for females) (TNO, 1996).

There were no deaths and clinical signs were limited to sniffing in all high-dose rats during the last week of exposure and in a few rats of the mid-dose group. Statistically significant decreased body weights were observed in both high-dose and mid-dose (males only) groups.

Statistically significant increases in red blood cells, hemoglobin and packed cell volume were observed in high dose males; similar but less pronounced effects were noted in females (only packed cell volume and red blood cells reached a level of significance). The differential white blood cell count revealed statistically significantly increased absolute and relative numbers of neutrophils and decreased absolute and relative numbers of lymphocytes in the high-dose groups. There were no test substance related clinical chemistry changes.

Statistically significant relative organ weight increases were noted for adrenals, kidneys, and lungs in both high-dose groups; only the relative kidney weight was increased in the mid-dose group. Absolute weight increases were noted for adrenals (females only) and lungs (increase), and liver and spleen (decrease) in the high dose group.decrease) in the high dose group. Small testes, either unilateral or bilateral, were noted in 4 males, one from each group including the control group. Since this finding was seen in all groups, this finding was not considered to be treatment-related. Swollen lungs were observed in all high-dose animals and in 5 mid-dose animals.

Microscopic changes were noted in the nasal cavity for low dose rats; in the nasal cavity, larynx and trachea for mid-dose rats; and in the entire respiratory tract for high-dose rats. The effects (severity, localization, extension) in the nasal cavity depended on the dose level. In low-dose animals, it was described as very slight to slight squamous metaplasia and hyperplasia of the transitional epithelium, and very slight focal hyperplasia of the respiratory epithelium. In mid-dose animals, the localization of effects on the transitional epithelium was comparable to that seen in low-dose rats; the severity ranged from slight to moderate. The transitional epithelium was almost entirely hyperplasic and included mucous cell hyperplasia. Very slight to slight suppurative rhinitis was seen. In high-dose rats, almost the entire transitional and ciliate respiratory lining of the nasal cavity was affected by squamous metaplasia, hyperplasia, and suppurative rhinitis, which included focal intraepithelial microabcesses and focal epithelial erosion. Epithelial hyperplasia was seen in the larynx of 9 high-dose and 3 mid-dose rats. Occasionally, very slight inflammatory cell infiltrates, epithelial erosion and intraluminal cell debris with mucous were observed. Focal hyperplasia predominated in mid-dose animals; a more diffuse, disorganized atypical hyperplasia was mainly noted in high-dose rats. Epithelial hyperplasia of the trachea and extrapulmonary bronchi was found in animals of the mid- and high-dose groups. The lesion progressed from focal, organized hyperplasia with mucous cell hyperplasia mainly in mid-dose rats to diffuse, more disorganized, atypical hyperplasia mainly in high-dose animals. Microscopic changes in lungs were seen in high-dose rats only. The lesions consisted of epithelial hyperplasia lining the bronchi/bronchioli, an increased number of polymorphonuclear cells around blood vessels and bronchi/bronchioli, perivascular edema and an increase in size and activation of peribronchial/peribronchiolar lymphoid tissue. The epithelial hyperplasia ranged from an atypical hyperplasia in the upper bronchi to mucous cell hyperplasia in the lower bronchi/bronchioli. No lesions were observed in the epithelium of the terminal bronchioli.

The entire respiratory tract was severely affected in all high-dose animals, whereas only very slight effects on the transitional and respiratory epithelium were observed in animals exposed to the lowest dose of 0.002 mg/L, which may be regarded as a lowest observed adverse effect level (LOAEL). 

Based on histology findings, there was no other target organ than the respiratory tract in concentrations up to 0.059 mg/L.  

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: larynx; respiratory: lung; respiratory: nose; respiratory: trachea

Justification for classification or non-classification

No classification concerning repeated dose toxicity is warranted according to EU Regulation 67/548 and EU Regulation 1272/2008 as classification criteria are not met.