2-Chloro-5-chloromethylpyridine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: summary

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Based on GLP studies

Data source

Reference

Reference Type:

other: Position paper

Title:

Unnamed

Year:

2006

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

454-800-3

EC Name:

-

Cas Number:

70258-18-3

Molecular formula:

C6H5Cl2N

IUPAC Name:

2-chloro-5-(chloromethyl)pyridine

Test material form:

solid

Applicant's summary and conclusion

Executive summary:

The toxicity of the substance has been assessed in a standard base set package, including acute oral and dermal toxicity, skin and eye irritation potential, skin sensitization in the guinea pig, mutagenicity in the Ames bacterial mutagenicity assay, chromosomal aberrations study, mammalian mutagenicity assay in vitro, and 28-day dosing study.

In the rat acute oral toxicity study with the substance, males were dosed with 100, 250, 500, 750, or 2000 mg/kg bw by oral gavage. Female rats were dosed with 100, 250, or 500 mg/kg bw by oral gavage. Both males and females showed no mortalities or clinical signs at 100 mg/kg bw, and no male rats died at 250 mg/kg bw. From 250 mg/kg bw in females and 500 mg/kg bw in males, the majority or totality of the animals in each group died. Clinical signs observed included apathy, difficult breathing, stumbling gait, decreased motility, lying on sides or abdomen, decreased reflexes, tearing, closed eyelids, salivation, piloerection, and reddening of hairless areas. Animals which died showed necropsy findings which included dark liver, pale spleen, stomach with clear or red fluid, reddened mucous membranes, and clear fluid throughout the gastrointestinal tract. The acute oral toxicity of the substance is moderate to high, with the LD50 concluded to be between 250 and 500 mg/kg bw for males and 100 and 250 mg/kg bw for males.

In the rat acute dermal toxicity study with the substance, male rats were administered 100, 250, 750, or 2000 mg/kg bw substance and female rats were administered 100 or 500 mg/kg bw under aluminum foil and a semi-occlusive bandage for a 24-hour application period. In males and females, 100 mg/kg bw produced no clinical signs and no mortalities. Doses of 250 mg/kg and above in males, and the dose of 500 mg/kg bw in females, produced clinical signs and mortalities in both sexes. Necropsy findings of animals which died included darkened livers, pale spleen, reddened forestomach with ulcer-like lesions, enlarged stomachs filled with mixture of feed and water, and expanded lungs. The dermal LD50 for the substance was determined to be between 250 and 750 mg/kg bw in males, and between 100 and 500 mg/kg bw in females.

Groups of 5 male and 5 female Wistar rats were exposed by nose only to an aerosol atmosphere of the substance at concentrations of 0, 131.8, 896.3, and 1404 mg/m3 of air for four hours. There were no mortalities at any dose. In both males and females, the clinical sign of a reddened nose were observed in all dose groups. This clinical observation reversed rapidly. There was no effect on reflexes, body weight, or body weight gain. No treatmentrelated findings were noted at necropsy. The inhalation LD50 for the substance was determined to be greater than 1404 mg/m3 of air in both males and females.

Application of the substance in water to the skin of three rabbits, or in paraffin oil to the skin of three other rabbits, for four hours produced dermal corrosion after 4 hours exposure to the test substance. Erythema and edema were observed in all six animals at 1 hour after removal of substance. In the animals treated with the substance in water, one animal showed necrosis after 7 days while a second animal showed induration of the test site. The animals were euthanized at 7 days after treatment. The animals administered the substance in paraffin oil all showed necrosis by day 14 after treatment. Based on these findings, the test compound is concluded to be corrosive to the skin.

Instillation of 40 mg substance into the conjunctival sac of one eye each in three rabbits produced slight corneal changes in one animal which were also visible by fluorescein application through three days after application. This rabbit also had redness and swelling of the conjunctivae and increased tear secretion, all through 48 hours after treatment. In the other animals, the only changes observed were reddening and swelling of the conjunctivae, and increased tear secretion. These effects were completely resolved within 48 hours after treatment. The substance is evaluated as slightly irritating to the eye.

In the LLNA study with the substance, application of 25 μl of 1%, 3%, or 10% solutions of CCMP in DMSO to the ear of mice produced increases in both the weight index of a tissue sample and the cell count index in the auricular lymph nodes. Thus the substance is considered to have a moderate sensitizing potential in the mouse local lymph node assay.

The substance was administered to groups of 5 male and 5 female Wistar rats by oral gavage at doses of 0, 0.5, 2.5, and 12.5 mg/kg bw/day for 4 weeks. Body weight and food consumption were measured weekly, and detailed clinical observations were also conducted on a weekly basis. Hematology, clinical chemistry, urinalysis, Functional Observation Battery, and Motor Activity tests were conducted at the end of the study. There were no mortalities and no clinical signs observed, and the FOB and motor and locomotor activity studies revealed no effects of treatment. Body weight, body weight gain, and food consumption were no different among treated and control groups. Ophthalmology, hematology, clinical chemistry, and urinalysis showed no effect of treatment. There were no effects visible at gross necropsy, and organ weights were unchanged. At 12.5 mg/kg bw/day, the forestomach basal cells showed minimal to slight hyperplasia in both males and females, and Kupffer cell activation was seen in the liver of females at this dose. Based on the histopathological findings in the forestomach and liver, the NOAEL is established at 2.5 mg/kg bw/day.

Based on these data, the substance is evaluated as being rapidly absorbed in the gastrointestinal tract and via the skin. Distribution appears to be fairly wide after dermal administration based on the findings observed in the spleen, liver, lungs, and forestomach.