Chlorothalonil

Endpoint summary

Description of key information

- Oral: NOAEL = 10.3 and 10.2 mg/kg bw/day for males and females, respectively, rat, sub-chronic, 90 days, feed, no guideline, Colley 1983

- Oral: LOAEL = 15 mg/kg bw/day, dogs, sub-chronic, 90 days, capsule, EPA OPP 82 -1, Fillmore 1993

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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

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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

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

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

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

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

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.

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

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.

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).

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

05 Jun 1992 to 11 Sep 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

EPA OPP 82-1 (90-Day Oral Toxicity)

GLP compliance:

yes

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 6 months old
- Weight at study initiation: females: 6.6 - 9.0 kg; males: 7.3 - 10
- Housing: Individually in elevated metal grid cages
- Diet: 200 g of standard laboratory diet twice a day, for a total of 4.5 h
- Water: ad libitum
- Acclimation period: 1 month

DETAILS OF FOOD AND WATER QUALITY: Analysis of each feed lot used during
this study was performed by the feed provider

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15 - 24.4
- Humidity (%): 40 - 74
- Air changes (per hr): at least 12
- Photoperiod: 12 hours light/dark cycle

IN-LIFE DATES: From: 5 Jun 1992 To: 10 September 1992

Route of administration:

oral: capsule

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Appropriate amounts of the test substance were weighed and placed into gelatin capsules. Individual doses were adjusted by most recent weekly body weight. Control animals received empty gelatin capsules, equal in number to the high-dose. Capsules were prepared weekly, placed in individually labeled containers and stored under the same conditions as the remaining test substance.

Capsules containing the appropriate amount of test substance were administered each animal once daily as follows:
a. Each morning, each dog received half of its daily dietary ration (200 grams).
b. Approximately one-half hour later, the dog received the appropriate capsule(s).
c. The dogs were observed frequently for a period of at least one-half hour after administration of the test substance with emphasis on emesis. Emesis of capsule(s) was documented.
d. The remaining half (200 grams) of the normal daily dietary ration was presented to each dog following the observation period.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

95 to 98 days, depending on the day of sacrifice

Frequency of treatment:

Daily (7 days per week) through the day prior to necropsy

Dose / conc.:

15 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

Dose / conc.:

500 mg/kg bw/day (nominal)

Remarks:

750 mg/kg/day on Days 1 through 4

No. of animals per sex per dose:

4 animals per sex per dose

Control animals:

yes, sham-exposed

Details on study design:

- Rationale for animal assignment: Dogs were ranked by body weight and distributed into 4 blocks of 4 animals per sex so that body weight means for each group were comparable. Groups were assigned to control and dose levels
randomly.
- Fasting period before blood sampling for clinical biochemistry: Dogs were fasted overnight prior to blood collections and were not dosed or fed until after samples were collected. Animals were water-deprived for approximately 2 hours for the collection of freshly voided samples for urinalysis and food- and water-deprived for the 16-hour urine volume collections.

Observations and examinations performed and frequency:

MORTALITY AND GROSS SIGNS OF TOXICOLOGIC EFFECTS:
At least twice daily (once in the morning and once in the afternoon). In addition, daily post-dose observations were performed, with emphasis on emesis, for a period of at least one half hour after capsule administration.

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: pre-test and weekly thereafter.

BODY WEIGHT:
- Time schedule for examinations: Pretest, weekly during treatment and terminally (after fasting)

FOOD CONSUMPTION AND COMPOUND INTAKE
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

OPHTHALMOSCOPIC EXAMINATION:
- Time schedule for examinations: pretest and approximately 1 week before termination

HAEMATOLOGY:
- Time schedule for collection of blood: pretest and Months 1.5 and 3
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: Performed on all animals pretest and on all survivors at Months 1.5 and 3
- Parameters checked: haemoglobin concentration, haematocrit, erythrocyte count, reticulocyte count, platelet count, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, prothrombin time, activated partial thromboplastin time, total and differential leukocyte counts, erythrocyte morphology

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: pretest and Months 1.5 and 3
- Animals fasted: Yes
- How many animals: Performed on all animals pretest and on all survivors at Months 1.5 and 3
- Parameters checked: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, creatinine, fasting glucose, cholesterol, total protein, albumin, globulin (calculated), A/6 ratio (calculated ), total bilirubin, sodium, potassium, chloride, calcium, inorganic phosphorous.

URINALYSIS:
- Time schedule for collection of urine: two pretests, month 1.5, termination
- Metabolism cages used for collection of urine: Not specified
- Parameters checked: gross appearance, refractive index, specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen, 16-hour volume, microscopic analysis

Sacrifice and pathology:

GROSS PATHOLOGY:
Animals Found Dead or Killed at Terminal Sacrifice: Complete gross postmortem examinations were performed on all animals. External surface, all orifices, the cranial cavity, carcass, the external and sectioned surfaces of the brain and spinal cord, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs were examined for all animals. Animals were fasted prior to scheduled sacrifice.

The following organs were weighed for all animals at the scheduled sacrifice intervals. Paired organs were weighed together with the exception of the
kidneys which were weighed individually , designated left and right: brain, kidneys, liver, ovaries, testes with epididymides, thyroid/parathyroids

HISTOPATHOLOGY:
Slides were prepared, stained and examined by a third party laboratory. All tissues listed below were examined for all animals (number of organs examined in brackets): adrenals (2), aorta, bone with marrow (sternal ), brain (medulla/pons, cerebellar cortex and cerebral cortex), epididymides (2), esophagus, eyes with optic nerve, lens and lacrimal apparatus (2), gallbladder, heart, intestine, kidneys (2), liver (sections from 2 lobes), lungs (with mainstem bronchi - 2),
lymph nodes (mesenteric and cervical ), mammary gland (females - left inguinal ), ovaries (2), pancreas, peripheral nerve (sciatic), pituitary, prostate,
salivary gland (submandibular), skeletal muscle ( biceps femoris), skin ( left inguinal region), spinal cord (cervical, midthoracic and lumbar), spleen, stomach ( including portions of cardiac, pyloric and fundic regions), testes, thymus, thyroid/parathyroids (2), tongue (base), trachea, urinary bladder, uterus (corpus and cervix uteri ), gross lesions ( including a section of normal -appearing portion of same tissue), tissue masses

Statistics:

Body weight, body weight gain, haematology and clinical chemistry parameters, terminal organ and body weights and organ/body weight and
organ/brain ratios were analyzed. Mean values of all dose groups were compared to control values at each time interval

Clinical signs:

no effects observed

Description (incidence and severity):

Weekly physical examinations revealed no significant abnormalities. Daily observations revealed an increased incidence of emesis in dogs receiving
750 mg/ kg/day during the first four days of study. No clear pattern of differences between the control and high-dose groups was evident after the dose
was decreased to 500 mg/ kg/day, although the incidence of emesis in high-dose females, primarily in one animal was slightly higher than the incidence in control females through Week 7. The incidence of emesis in high-dose males and low- and mid-dose males and females was comparable to that in control dogs throughout the study.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One high-dose male was found dead on Test Day 3, after receiving 750 mg/ kg/day for two days. Signs on Day 2 consisted of excessive emesis and no apparent food consumption. Microscopic postmortem examinations revealed pulmonary changes indicating that death resulted from bronchitis and pneumonia subsequent to aspiration of foreign material. Because of this death, the high dose was lowered to 500 mg/kg/day beginning on Day 5. All other animals survived to study termination.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights and weight gains for mid- and high-dose males and high-dose females were slightly lower than concurrent control values throughout the study. Weights and weight gains for mid-dose females were slightly lower than concurrent control values through Week 6 but were comparable to control values thereafter. Differences in weight gain were statistically significant at most intervals for mid- and high-dose males and on some occasions for mid- and high-dose females. Body weight patterns for low-dose animals were generally comparable to those of control animals.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption values were generally comparable for control and treated animals or exhibited normal variability. No clear effect of the test substance administration was evident.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Description (incidence and severity):

Terminal ophthalmoscopic examinations revealed no evidence of any ocular abnormalities attributed to the test substance administration.

Haematological findings:

no effects observed

Description (incidence and severity):

No effect of test substance administration was evident in haematology values obtained after one and one-half or three months of treatment.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Clinical chemistry studies performed after 1.5 and 3 months of treatment revealed marked decreases, relative to control and pretest values, in serum alanine aminotransferase (SGPT) levels for all treated groups of both sexes. Statistically significant elevations, relative to control values, were also evident for serum cholesterol values of high-dose males and mid- and high-dose females.
Other alterations suggestive of an effect of test substance administration included slight, non-statistically significant, elevations in serum alkaline phosphatase values for high-dose males and mid- and high-dose females and slight depressions in serum albumin levels for mid- and high-dose animals which were statistically significant for mid- and high-dose males at both intervals and for high-dose females at Month 3. A slight , statistically significant , difference between serum aspartate aminotransferase values for control and high-dose females (high-dose value lower than control value) at study termination was not considered to be toxicologically significant.

Urinalysis findings:

no effects observed

Description (incidence and severity):

No effect of test substance administration was evident in urinalysis data obtained after one and one-half or three months of treatment. Values were comparable for control and treated groups or exhibited normal variability.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Slight, statistically significant, elevations, relative to control values, were evident in liver/body weight ratios for high-dose males and females. This is consistent with the fact that mean terminal body weights for these groups were slightly lower than control body weights while absolute liver weights were comparable to or slightly higher than control liver weights.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic postmortem observations of animals killed at study termination were generally unremarkable. No effect of test substance administration was evident.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related microscopic alterations were seen in any of the tissues examined from the treated dogs. A few sporadic incidental microscopic alterations were seen in some of the tissues from both the treated and control dogs. The incidence and severity of these microscopic alterations were generally comparable among the control and treated dogs.
Microscopic examination of the lungs from one high-dose male which died on Test Day 3 indicated aspiration of foreign material which resulted in severe pulmonary oedema, moderately severe diffuse haemorrhage, moderately severe necrotizing bronchitis and a moderately severe diffuse pneumonia. A slight epithelial desquamation was also seen in the trachea.
One mid-dose female dog also possessed lesions of the lung suggestive of foreign material aspiration. In this female dog there was a moderate increase in alveolar macrophages and squamous metaplasia of the bronchial epithelium, along with a slight focal fibrosis and focal pneumonitis. In the trachea from this dog there was a slight focal epithelial erosion and slight focal squamous metaplasia of the tracheal epithelium. These microscopic alterations are suggestive of a non-fatal foreign body aspiration. A few scattered incidental microscopic alterations were seen in the remaining tissues from both the control and treated dogs. The incidence and severity of these incidental microscopic alterations was comparable among the treated and control dogs.

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

LOAEL

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

Critical effects observed:

yes

Lowest effective dose / conc.:

15 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Table 1. Summary of results from a sub-chronic oral toxicity study in dogs exosed to the test substance

Dose (mg/kg bw/day)	0		15		150		500		dose related
	m	f	m	f	m	f	m	f
Mortality	0/4	0/4	0/4	0/4	0/4	0/4	1/4	0/4
Clinical signs (vomiting)							+	++
Body weight (gain)					dc		dc	d
Food consumption
Ophtalmoscopy
Haematology
Clinical chemistry:
ASAT								dc*
ALAT			dc	dc	dc	dc	dc	dc	m, f
alkaline phosphatase							i	i
cholesterol						ic	ic	ic	m, f
albumin					dc		dc	dc*	m, f
Urinanalysis
Organ weights (liver)							ic r	ic r
Pathology (macroscopy)
Pathology (microscopy)

dr – dose related

dc/ic - statistically significant decrease (dc)/increase (ic) compared to the controls

d/i – decrease (d)/increase (i), but not statistically significant compared to the controls

r – relative organ weight

+ - present in one/a few animals

++ - present in most/all animals

* - observed only at termination

Conclusions:

Based on the presence of reduced serum alanine aminotransferase levels at all dose levels, a no effect level (NOEL) for oral administration of the test substance to dogs for 3 months, under conditions of this study was not attained. The lowest dose level (15 mg/kg bw/day) is considered a LOAEL based on decreased plasma alanine aminotransferase activity.

Executive summary:

This study, conducted in compliance with GLP and following a FIFRA 82-1 guideline was designed to assess the subchronic toxicity of the test substance when administered orally, via gelatin capsules to Beagle dogs. The test substance was administered to 24 dogs (4/sex/group) at dose levels of 15, 150 and 750 mg/kg/day for a period of at least 90 days. Because of mortality seen in the high-dose group, this dose level was lowered from 750 to 500 mg/kg/day on Day 5. Control animals (4/sex) received empty gelatin capsules. Physical observations, ophthalmoscopic examinations and body weight and food consumption measurements were performed and haematology, clinical chemistry, and urinalyses parameters were evaluated for all animals pretest and at selected intervals during the treatment period. After at least 90 days of treatment, all survivors were sacrificed, selected organs were weighed and organ/body and organ/brain weight ratios calculated. Complete gross postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals.

One high-dose male was found dead on Test Day 3 , after receiving 750 mg/kg/day for two days. Signs on Day 2 consisted of excessive emesis and no apparent food consumption. Microscopic postmortem examinations revealed pulmonary changes indicating that death resulted from bronchitis and pneumonia subsequent to aspiration of foreign material. (Because of this death, the high dose was lowered to 500 mg/kg/day beginning on Day 5.) All other animals survived to study termination. An increased incidence of emesis, relative to control and pretest levels, was evident in dogs receiving 750 mg/kg/day during the first four days of study. No clear pattern of differences between the control and high-dose groups was evident after the dose was decreased to 500 mg/kg/day. Mean body weights and weight gains for mid- and high-dose males and highdose females were slightly lower than concurrent control values throughout the study. Weights and weight gains for mid-dose females were slightly lower than concurrent control values through Week 6 but were comparable to control values thereafter. Food consumption values were generally comparable for control and treated animals or exhibited normal variability. No clear effect of the test substance administration was evident. Clinical chemistry studies performed after 1.5 and 3 months of treatment revealed marked decreases, relative to control and pretest values, in serum alanine aminotransferase (SGPT) levels for all treated groups of both sexes. Elevations, relative to control values, were also evident for serum cholesterol values of high-dose males and mid- and high-dose females. Other alterations suggestive of an effect of test substance administration included slight elevations in serum alkaline phosphatase values for high-dose males and mid- and high-dose females and slight depressions in serum albumin levels for mid- and high-dose males and females. Slight elevations, relative to control values, were evident in liver/body weight ratios for high-dose males and females. This is consistent with the fact that mean terminal body weights for these groups were slightly lower than control body weights while absolute liver weights were comparable to or slightly higher than control liver weights. Weights of other organs were comparable for control and treated groups or exhibited normal variability. Ophthalmoscopic examinations revealed no effects of test substance administration. No treatment-related effects were seen in haematology or urinalysis studies and no treatment-related lesions were observed macroscopically or microscopically. Based on the presence of reduced serum alanine aminotransferase levels at all dose levels, a no effect level (NOEL) for oral administration of the test substance to dogs for 3 months, under conditions of this study was not attained. The lowest dose level (15 mg/kg bw/day) is considered a LOAEL based on decreased plasma alanine aminotransferase activity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10.2 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Sub-chronic toxicity study in rats, non-GLP

System:

urinary

Organ:

kidney

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

All available data was assessed and the study representing the worst-case effects was included as key study. Other studies are included as supporting information. The key study is considered to be worst-case and was selected for the CSA.

Key: Sub-chronic toxicity study in rats

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).

Supporting: Sub-chronic toxicity in dogs

This study, conducted in compliance with GLP and following a FIFRA 82-1 guideline was designed to assess the sub-chronic toxicity of the test substance when administered orally, via gelatin capsules to Beagle dogs. The test substance was administered to 24 dogs (4/sex/group) at dose levels of 15, 150 and 750 mg/kg/day for a period of at least 90 days. Because of mortality seen in the high-dose group, this dose level was lowered from 750 to 500 mg/kg/day on Day 5. Control animals (4/sex) received empty gelatin capsules. Physical observations, ophthalmoscopic examinations and body weight and food consumption measurements were performed and haematology, clinical chemistry, and urinalyses parameters were evaluated for all animals pretest and at selected intervals during the treatment period. After at least 90 days of treatment, all survivors were sacrificed, selected organs were weighed and organ/body and organ/brain weight ratios calculated. Complete gross postmortem examinations and histopathological evaluation of selected tissues were conducted on all animals. One high-dose male was found dead on Test Day 3 , after receiving 750 mg/kg/day for two days. Signs on Day 2 consisted of excessive emesis and no apparent food consumption. Microscopic postmortem examinations revealed pulmonary changes indicating that death resulted from bronchitis and pneumonia subsequent to aspiration of foreign material. (Because of this death, the high dose was lowered to 500 mg/kg/day beginning on Day 5.) All other animals survived to study termination. An increased incidence of emesis, relative to control and pretest levels, was evident in dogs receiving 750 mg/kg/day during the first four days of study. No clear pattern of differences between the control and high-dose groups was evident after the dose was decreased to 500 mg/kg/day. Mean body weights and weight gains for mid- and high-dose males and highdose females were slightly lower than concurrent control values throughout the study. Weights and weight gains for mid-dose females were slightly lower than concurrent control values through Week 6 but were comparable to control values thereafter. Food consumption values were generally comparable for control and treated animals or exhibited normal variability. No clear effect of the test substance administration was evident. Clinical chemistry studies performed after 1.5 and 3 months of treatment revealed marked decreases, relative to control and pretest values, in serum alanine aminotransferase (SGPT) levels for all treated groups of both sexes. Elevations, relative to control values, were also evident for serum cholesterol values of high-dose males and mid- and high-dose females. Other alterations suggestive of an effect of test substance administration included slight elevations in serum alkaline phosphatase values for high-dose males and mid- and high-dose females and slight depressions in serum albumin levels for mid- and high-dose males and females. Slight elevations, relative to control values, were evident in liver/body weight ratios for high-dose males and females. This is consistent with the fact that mean terminal body weights for these groups were slightly lower than control body weights while absolute liver weights were comparable to or slightly higher than control liver weights. Weights of other organs were comparable for control and treated groups or exhibited normal variability. Ophthalmoscopic examinations revealed no effects of test substance administration. No treatment-related effects were seen in haematology or urinalysis studies and no treatment-related lesions were observed macroscopically or microscopically. Based on the presence of reduced serum alanine aminotransferase levels at all dose levels, a no effect level (NOEL) for oral administration of the test substance to dogs for 3 months, under conditions of this study was not attained. The lowest dose level (15 mg/kg bw/day) is considered a LOAEL based on decreased plasma alanine aminotransferase activity.

Justification for classification or non-classification

Kidney weights were consistently increased following administration of the test substance and these increases were often associated with microscopic pathology findings. However, the proposed mode of action of renal effects is not relevant for human hazard/risk assessment purposes due to quantitative differences in the balance of hepatic GGT activity and renal ß-lyase activity between rodents and man, which is reported to be one of the main factors in different susceptibility to glutathione related nephrotoxicity between rats and humans. In summary, the data support the conclusion that Chlorothalonil does not pose a renal carcinogenic hazard in humans

Based on the available information classification upon repeated exposure is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.