Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study according to EU/OECD guideline

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Analytical verification of doses or concentrations:
yes

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2.5 mg/kg bw/day (actual dose received)
Sex:
male/female
Dose descriptor:
NOEL
Effect level:
2.5 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

2-Chlor-5-chlormethylpyridine was administered daily via gavage in Polyethylene glycol 400 (PEG 400) to 5 male and 5 female Wistar rats per dose group, in doses of 0, 0.5, 2.5 and 12.5 mg/kg body weight for a period of 4 weeks.

Survival rate as well as behavior and appearance of the rats

were not influenced by the treatment. There were no signs of neurotoxicity or oculotoxicity up to 12.5 mg/kg.

Body weights were not affected up to 12.5 mg/kg.

No toxicologically relevant change in food intake was seen up to 12.5 mg/kg.

Hematology, clinical chemistry and urine parameters were not altered up to 12.5 mg/kg.

Histopathology revealed treatment-induced minimal to slight hyperplasia of the forestomach basal cells, which occurred in all males and 4 of 5 females at 12.5 mg/kg.

Additionally, in the liver of females Kupffer cell activation was present at 12.5 mg/kg (incidence: 0-0-0-4) attributed to a minimal severity level.

Gross findings as well as organ weight measurements and histopathology in the other organs gave no indication of test substance-related effects up to 12.5 mg/kg.

Under the conditions described the NOAEL (=NOEL) for 2-Chlor-5-chlormethylpyridine is established at 2.5 mg/kg body weight per day in male and female rats.

In a previous dose finding toxicity study for the main

study groups of rats (3/sex/group) were given doses of

0, 10, 50, 250 and 500 mg/kg bw/d via gavage for a period

of 14 consecutive days. Mortality occurred at 250 and

500 mg/kg bw/d. In rats receiving 50 mg/kg bw/d a slight body weight depression was noted. Necropsy revealed

severe changes at the stomach in the died animals given

250 and 500 mg/kg bw/d. Microscopy of animals receiving

0, 10, or 50 mg/kg bw/d demonstrated changes in the

stomach from 10 mg/kg bw/d onwards. There was a squamous hyperplasia in 2/3 males at 10 mg/kg bw/d and in all

males and females at 50 mg/kg bw/d.

Prominent basal cells were noted in 3/3 males at 10 and

50 mg/kg bw/d as well as in 2/3 females at 10 mg/kg bw/d

and all three females at 50 mg/kg bw/d. Additionally at

50 mg/kg bw/d stoma edema was evident in 2/3 males and

3/3 females.

No test substance-related mortality occurred during the main study used dose levels up to 12.5 mg/kg bw/d. Relevant toxic effects were also noted in the forestomach in male and female rats. Microscopically, minimal to slight hyperplasia of the forestomach basal cells seen in the four week study at 12.5 mg/kg bw/d correlated with the observations in males and females given 10 and 50 mg/kg bw/d in the dose finding study.

With regard to the observed alterations in forestomach and liver in the subacute study, a no-observed-adverse-effect-level (NOAEL) and a no-observed-effect-level (NOEL) was established at 2.5 mg/kg bw/d in animals of both sexes.

In consideration of the results of the previous dose finding study and the main study it was shown that the effects in the forestomach were largely dose-related in frequency and intensity. Oral administration of 250 and 500 mg/kg bw/d for two weeks produced mortality due to severe changes at the stomach.

According to the classification criteria outlined in Directive 2001/59/EC, Annex 6, the substance has to be classified as harmful and labelled with R48/22 based on the results of the pilot and main study."