Chlorothalonil

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

5 Mar 1982 to 3 Sep 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Groups of Sprague-Dawley rats (25 per sex per dose) were exposed by admixture with the diet for 13 weeks of treatment followed by a 13-week withdrawal period for rats not killed at week 6 or 13 (no guideline, non-GLP). Exposure levels were 1.5, 3.0, 10.0 and 40.0 mg/kg bw/day. Controls received powdered diet only.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chlorothalonil

EC Number:

217-588-1

EC Name:

Chlorothalonil

Cas Number:

1897-45-6

Molecular formula:

C8Cl4N2

IUPAC Name:

tetrachlorobenzene-1,3-dicarbonitrile

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15 mg/kg bw/day (nominal)

Remarks:

Group 2: Dietary equivalent to 1.54 and 1.50 mg/kg bw/day for males and females, respectively

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

Group 3: Dietary equivalent to 3.04 and 3.10 mg/kg bw/day for males and females, respectively

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Group 4: Dietary equivalent to 10.27 and 10.17 mg/kg bw/day for males and females, respectively

Doses / concentrations 4

Dose / conc.:

400 mg/kg bw/day (nominal)

Remarks:

Group 5: Dietary equivalent to 40.71 and 40.74 mg/kg bw/day for males and females, respectively

Control animals:

yes, plain diet

Results and discussion

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

Dietary equivalent to 10.3 and 10.2 mg/kg bw/day for males and females, respectively.

Target system / organ toxicity

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

30 mg/kg bw/day (nominal)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Any other information on results incl. tables

No treatment-related clinical signs were recorded. Six rats died during the study. None of these deaths was considered directly attributable to treatment. No apparent treatment-related effect was seen. Marginally lower alkaline phosphatase (AP) and glutamic-pyruvic transaminase (GPT) levels were recorded in week 6 among males and females treated at 40 mg/kg bw/day. Lower AP levels were recorded among females treated at 40 mg/kg bw/day and all treated male groups in week 13. Lower GPT levels were recorded among treated male and female groups at week 13. At weeks 19 and 26 during the withdrawal period these changes were not seen among the treated male groups but lower AP values were recorded among the treated female groups. Haematology, urinalysis, urine concentrating and diluting tests and microbiological assay did not reveal any treatment-related effects. No changes considered to be related to treatment were seen at either the week 6 , week 13 or week 26 kills. Higher kidney weights were recorded among males
treated at 40 or 10 mg/kg/day at the week 6 kill. Higher kidney weights were recorded for males and females from all treated groups at the week 13 kill, although there was only a slight increase in weights among rats treated at 1.5 mg/kg bw/day. Similar kidney weights were recorded for males and females from all treated groups compared to the controls at the termination of the withdrawal period. Slightly higher liver weights were recorded at the 13-week kill for males treated at 40 mg/kg bw/day. Liver weights recorded at the end of the withdrawal period for this group were similar to control values. Treatment-related changes were confined to the non-glandular epithelium of the stomach. There was an increase in incidence of epithelial hyperplasia and hyperkeratosis among rats treated with 10 or 40 mg/kg bw/day compared to the Controls. This effect was seen at interim kill at 6 weeks after the start of dosing and at termination at 13 weeks after the start of dosing. This increase in incidence was not apparent in rats kept for the withdrawal period.

No NOAEL was derived in this study.

Applicant's summary and conclusion

Conclusions:

Based on effects on the liver and kidney the NOAEL is set on 10 ppm (dietary equivalent to 10.3 and 10.2 mg/kg bw/day for males and females, respectively).

Executive summary:

Groups of Sprague-Dawley rats (25 per sex per dose) were exposed by admixture with the diet for 13 weeks of treatment followed by a 13-week withdrawal period for rats not killed at week 6 or 13 (no guideline, non-GLP). Exposure levels were 1.5, 3.0, 10.0 and 40.0 mg/kg bw/day. Controls received powdered diet only.

No treatment-related clinical signs were recorded. Six rats died during the study. None of these deaths was considered directly attributable to treatment. No apparent treatment-related effect was seen. Marginally lower alkaline phosphatase (AP) and glutamic-pyruvic transaminase (GPT) levels were recorded in week 6 among males and females treated at 40 mg/kg bw/day. Lower AP levels were recorded among females treated at 40 mg/kg bw/day and all treated male groups in week 13. Lower GPT levels were recorded among treated male and female groups at week 13. At weeks 19 and 26 during the withdrawal period these changes were not seen among the treated male groups but lower AP values were recorded among the treated female groups. Haematology, urinalysis, urine concentrating and diluting tests and microbiological assay did not reveal any treatment-related effects. No changes considered to be related to treatment were seen at either the week 6 , week 13 or week 26 kills. Higher kidney weights were recorded among males treated at 40 or 10 mg/kg/day at the week 6 kill. Higher kidney weights were recorded for males and females from all treated groups at the week 13 kill, although there was only a slight increase in weights among rats treated at 1.5 mg/kg bw/day. Similar kidney weights were recorded for males and females from all treated groups compared to the controls at the termination of the withdrawal period. Slightly higher liver weights were recorded at the 13-week kill for males treated at 40 mg/kg bw/day. Liver weights recorded at the end of the withdrawal period for this group were similar to control values. Treatment-related changes were confined to the non-glandular epithelium of the stomach. There was an increase in incidence of epithelial hyperplasia and hyperkeratosis among rats treated with 10 or 40 mg/kg bw/day compared to the Controls. This effect was seen at interim kill at 6 weeks after the start of dosing and at termination at 13 weeks after the start of dosing. This increase in incidence was not apparent in rats kept for the withdrawal period.

In conclusion, based on effects on the liver and kidney the NOAEL is set on 10 ppm (dietary equivalent to 10.3 and 10.2 mg/kg bw/day for males and females, respectively).