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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

Study Type  Species Findings  Guideline Reliability 
104-Week Feeding Study    Mice   Not Carcinogenic   

no guideline followed 

 2
2-Year Feeding Study   Rats Not Carcinogenic  

no guideline followed

 2
22-Month Feeding Study   Rats  Not Carcinogenic  

no guideline followed

 2

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
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:
The objective of the study was to evaluate the chronic toxicity and carcinogenic potential of the test substance in mice. The test substance was administered in the diet to mice at the levels of 0, 50, 75, and 200 ppm for 104 weeks. The animals were then observed for mortality, clinical signs, body weight, food consumption, hematology, gross pathology, organ weight and histopathology.
GLP compliance:
no
Specific details on test material used for the study:
- Substance name: Methomyl
- Substance ID: H-11,135
- Purity: >99%
Species:
mouse
Strain:
other: CD®-1, albino
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: diet
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
daily
Dose / conc.:
50 ppm
Dose / conc.:
75 ppm
Remarks:
At Week 39, dose level of the mid-dose group was decreased from 100 ppm to 75 ppm
Dose / conc.:
200 ppm
Remarks:
Because of unexpected high mortality, the high-dose level group was reduced to from 800 to 400 ppm beginning Week 28; the dose level was further reduced to 200 ppm as of Week 39.
No. of animals per sex per dose:
80
Control animals:
yes, plain diet
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Clinical observations noted during this study included: hunched appearance; head tilt; circling behaviour; localized sores (legs, ears, base of tail, and back) sometimes accompanied by alopecia; swelling in the lower midline region; pale, red, small, or lacrimating eyes; and fur stains. The frequency of these findings increased in all groups as the study progressed; however, no treatment-related trends were noted.
Mortality:
mortality observed, treatment-related
Description (incidence):
Statistical analysis revealed that by Week 26, suvival in the mid-dose females and both high-dose groups was significantly lower than that in control. Because of this unexpected high mortality beginning Week 28, the high-dose level group was reduced from 800 to 400 ppm. This was further reduced to 200 ppm as of Week 39. The mid-dose level was also reduced from 100 to 75 ppm at Week 39. Mortality noted in the high-dsoe females by Weeks 52, 80, and 104 continued to be significantly higher while the mid-dose females remained markedly higher at the same intervals. Mortality in the male groups was significantly higher in the high-dose males at Week 52, the mid- and high-dose males at Week 80, and all treated groups by Week 104. These differences in survival were considered related to the toxicity of the test substance.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Statistical analysis of weight gains through the first 26 weeks revealed that growth achieved by the treated groups of both sexes was equivalent to that of the control. Growth by the treated males was also equivalent to control through Week 46. Gains made by the high-dose females were significantly higher by Week 50. This finding was not considered biologically meaningful since the range of weights between control and high-dsoe females were one to two grams during the first 50 weeks. A comparison of the mean weights obtained at Weeks 60, 72, 84, 96, and 104 did not reveal any significant differences, except that the low-dose female weight was significantly increased at Week 72.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Statistical analysis of the male data revealed significantly higher consumption levels in all treated groups during Weeks 20 through 26 and Weeks 20 through 80; significantly higher levels were noted from Week 20 through 52 in the low- and mid-dose groups. These changes were not considered biologically meaningful since concurrent body weight changes were not noted. Total food consumption by the treated males was statistically equivalent to control during Weeks 20 through 104.
Statistical analysis of female data revealed a significantly higher intake in the low-dose group during Weeks 20 through 26. No other significant differences were noted.

The average daily theoretical compound consumption throughout the study was:
low dose: 8.720 mg/kg/day for males, 10.643 mg/kg/day for females
mid dose: 15.369 mg/kg/day for males, 19.082 mg/kg/day for females
high dose: 93.397 mg/kg/day for males, 118.542 mg/kg/day for females
Food efficiency:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Statistical analysis of the male data revealed the following differences: at Week 13, lower hematocrit in the mid- and high-dose group; at Week 26 lower hematocrit in the low-dose males, and lower hemoglobin and red blood cell count in the high-dose group. These changes are suggestive of compound-induced decrease in red cell mass. This trend was not apparent after Week 26; however, it should be noted that by Week 52, the high-dose level had been reduced from 800 to 200 ppm and the mid-dose level from 100 to 75 ppm.

In the females, decreases in hemoglobin levels occurred in the mid- and high-dose mice at Weeks 13 and 26 (a significantly lower level was noted in the mid-dose group at Week 13), and in the red cell count in mid- and high-dose animals at Week 26. These changes are suggestive of compound effect.

Mean white blood cell count values were frequently influenced by moderate to marked elevation in a few animals in a group. No distinct treatment-related trends were detected in the white cell counts.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Organ weight data were unremarkable except for a significantly higher absolute and slightly elevated relative adrenal weight in the high-dose males. The biological significance of this finding is unknown.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Necropsy findings noted in the animals found dead/sacrificed moribund were generally considered incidental in nature.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Test substance-related histomorphologic alterations were not observed in the tissues examined. Neoplastic and non-neoplastic spontaneous disease lesions were of the usual type and number observed in mice of this age and strain and were essentially comparable in incidence and severity between control and treated groups.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Test substance-related histomorphologic alterations were not observed in the tissues examined. Neoplastic and non-neoplastic spontaneous disease lesions were of the usual type and number observed in mice of this age and strain and were essentially comparable in incidence and severity between control and treated groups.
Key result
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: No histomorphologic alterations in tissues; no increase in neoplastic and non-neoplastic disease lesions
Conclusions:
104 Week study in mice: No histomorphologic alterations in tissues; no increase in neoplastic and non-neoplastic disease lesions
Executive summary:

This study was designed to evaluate and characterize the chronic toxicity and carcinogenic potential of the test substance when administered in the diet to albino mice for 104 weeks. Three groups of animals (80/sex/group) received the test compound initially at levels of 50, 100, and 800 ppm. A fourth group of animals received the basal diet only.

After 104 weeks of treatment, all surviving animals were sacrificed and necropsied. Criteria evaluated for compound-related effects were: mortality; body weights; food consumption; hematology profiles; tissue cultures; absolute and relative organ weights; and gross and microscopic pathology.

The survival in the high-dose males and females was significantly lower at Week 26. Survival in the mid-dose groups was also moderately lower. Due to these unexpected high mortality rates in the mid- and high-dose groups, the dose Level of the high-dose group was decreased to 400 ppm at Week 28. For the same reason, the dose level was further reduced to 200 ppm beginning Week 39; at the same week, the mid-dose level was reduced from 100 to 75 ppm. Survival of the high-dose females was statistically significantly lower after 52, 80, and 104 weeks, while the mid-dose females remained markedly lower at the same intervals. Survival was statistically significantly lower after 52 weeks in the high-dose males, the mid- and high-dose males Week 80, and all treated males after 104 weeks. Lower survival rates were considered related to the toxicity of the test substance.

Statistical analysis of the hemogram data revealed a significantly lower hematocrit in the mid- and high-dose males at Week 13. Significantly lower hemoglobin level, and red cell count were noted in the high-dsoe males at Week 26. Decreases in hemoglobin levels were noted in the mid- and high-dose females at Weeks 13 and 26 (a significantly lower level in the mid-dose females at Week 13). Decreases in red cell counts were also noted at Week 26 in the mid- and high-dsoe females. These changes are suggestive of a compound-related effect upon red cell mass. This trend was not noted after Week 26.

No other treatment-related findings were seen with respect to body weight gains, food consumption and utilization, or clinical observations.

Test substance-related histomorphologic alterations were not observed in the tissues examined. Neoplastic and non-neoplastic spontaneous disease lesions were of the usual type and number observed in mice of this age and strain and were essentially comparable in incidence and severity between control and treated groups.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
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:
The study was conducted to evaluate the chronic toxicity of test substance when administered orally in diet to rats for 24 months. The dietary levels were 50, 100, 200, and 400 ppm.
GLP compliance:
no
Specific details on test material used for the study:
Test substance Name: Lannate methomyl insecticide; S-Methyl N-[(methylcarbamoyl)oxy]thioace
timidate
Purity: S-Methyl N-[(methylcarbamoyl)oxy]thioacetimidate: 90% and Lannate methomyl insecticide:
100% active ingredient
Species:
rat
Strain:
other: Albino (Caesarean-derived)
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: feed
Duration of treatment / exposure:
22 Months
Frequency of treatment:
Daily
Dose / conc.:
50 ppm
Dose / conc.:
100 ppm
Dose / conc.:
200 ppm
Dose / conc.:
400 ppm
No. of animals per sex per dose:
35
Control animals:
yes, plain diet
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related effects were observed with regard to physical appearance and behavior was noted in rats received test substance at any dietary level tested.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Group observation of the deaths in each group indicated that the poor survival was due to spontaneous respiratory disease.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Growth for the high dose level (400 ppm) males (Weeks 0-52) was significantly lower compared with both male control groups. Growth during the first year for the 200 ppm males and the 400 ppm females was lower than, but not significantly different from, that for the corresponding control groups. Growth for the remaining male and female test groups was generally comparable with corresponding controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption for the 400 and 200 ppm males (Weeks 1-26) were significantly lower compared with both male control groups. Food consumption for all female test groups was comparable with that for female controls.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
At 18 and 22 months, a dose-related trend toward decreased hemoglobin values was evident in the female test groups. Abnormal individual hematological values determined at 18 and 22 months were associated with incidental disease and were not considered meaningful.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
The clinical biochemistry findings were comparable among control and test substance treated rats.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
The urine analysis results were comparable among control and test substance treated rats.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At terminal sacrifice, the testis/body weight ratio for 400 ppm group males was significantly higher than that of controls. This was probably due to weight suppression in the high level dose males.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No consistent gross pathological changes were observed in the organs and viscera of rats due to test susbtance at indicated levels.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic evaluation of tissue sections from rats fed 400 ppm of test substance for one year did not reveal any test substance effect. After 22 months of dietary administration, microscopic examination revealed test substance related histopathologic alterations (cystic follicles, fibrosis, salpingitis and atrophy of ovary) in the kidneys of males and females at 400 ppm level and in the spleens of the females at 200 and 400 ppm levels of the test substance.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The incidence of neoplastic lesions in the high-level test rats was generally comparable with that in the control animals.
Key result
Dose descriptor:
NOAEL
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
histopathology: non-neoplastic
Remarks on result:
other: for systemic toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
400 ppm
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Remarks:
for carcinogenicity
Conclusions:
After 22 months of dietary administration, microscopic examination revealed test substance related histopathologic alterations in the kidneys of males and females at 400 ppm level and in the spleens of the females at 200 and 400 ppm levels of the test substance.
Executive summary:

The study was conducted to evaluate the chronic toxicity of test substance when administered orally in diet to rats for 24 months. The dietary levels were 50, 100, 200, and 400 ppm.

No test substance related effects were observed with regard to physical appearance and behavior was noted in rats received test substance at any dietary level tested. Growth for the high level (400 ppm) males (Weeks 0-52) was significantly lower compared with both male control groups. Growth during the first year for the 200 ppm males and the 400 ppm females was lower than, but not significantly different from, that for the corresponding control groups. Growth for the remaining male and female test groups was generally comparable with corresponding controls. Food consumption for the 400 and 200 ppm males (Weeks 1-26) were significantly lower compared with both male control groups. Food consumption for all female test groups was comparable with that for female controls. Survival in the test rats was not adversely affected. Survival at 22 months for the 100 ppm males and the 50 and 400 ppm females was significantly higher compared with the controls. At 18 and 22 months, a dose-related trend toward decreased hemoglobin values was evident in the female test groups. Abnormal individual hematological values determined at 18 and 22 months were associated with incidental disease and were not considered meaningful. The biochemical values and the results of urine analysis were comparable among control and treated animals. At 12 months, all organ weights and ratios, brain weights and organ/brain weight ratio values for the high level test groups were comparable with control values. At terminal sacrifice, the testis/body weight ratio for 400 ppm group males was significantly higher than that of controls. This was probably due to weight suppression in the high-level dose males. Histopathologic evaluation of tissue sections from rats fed 400 ppm of test substance for one year did not reveal any test substance effect. After 22 months of dietary administration, microscopic examination revealed test substance related histopathologic alterations in the kidneys of males and females at 400 ppm level and in the spleens of the females at 200 and 400 ppm levels of the test substance. The NOEL for carcinogenicity was 400 ppm for males and females.

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
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:
The study was conducted to evaluate the chronic toxicity of test substance when administered orally in diet for 2 years. Test substance was fed to male and female rats, for two years at levels of 0, 50, 100, or 400 ppm in diet. During the period of administration the animals were observed for signs of toxicity. Animals that die or are euthanised during the test are necropsied and at the conclusion of the test surviving animals are euthanised and necropsied.
GLP compliance:
no
Specific details on test material used for the study:
Test substance Name: Technical methomyl (INX-1179-255)
Purity: >99 - <100%
Species:
rat
Strain:
other: ChR-CD
Sex:
male/female
Route of administration:
oral: feed
Vehicle:
other: feed
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Dose / conc.:
50 ppm
Dose / conc.:
100 ppm
Dose / conc.:
400 ppm
No. of animals per sex per dose:
80; 20 animals were added to all groups specifically for erythrocyte and brain cholinesterase determinations.
Control animals:
yes, plain diet
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no clinical signs of toxicity that could be attributed to the feeding of test substance for control and treated rats.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No dose-mortality realtionship was demonstrated among various feeding levels of test substance.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Although slight decreases in body weight were observed periodically throughout the study, after two years of continuous feeding, the average final body weights and average body weight gains of male and female rats fed various dietary levels of test substance were not significantly different from those of the corresponding controls.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There were no meaniningful differences among the control and treated groups with respect to food consumption data.
Food efficiency:
effects observed, non-treatment-related
Description (incidence and severity):
There were no meaningful differences among the control and treated groups with respect to food efficiency data.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Female rats fed 400 ppm test substance tended to have statistically significant lower erythrocyte counts, hemoglobin values and hematocrits than those of the corresponding controls. A similar trend occurred In the erythrocyte counts and hemoglobin values of male rats fed 400 ppm test substance but these changes were not statistically significant.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
All clinical chemistry measurements were essentially within the normal range, as established by the controls.
Urinalysis findings:
no effects observed
Description (incidence and severity):
The results of all urine analysis were essentially within the normal range, as established by the controls.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were no significant differences in absolute organ weights for either male or female rats and in relative organ weights for male rats fed various dietary levels of test substance, compared to those of controls. Female rats fed 100 or 400 ppm of test substance had significantly increased relative liver weights compared to those of controls. However, these differences did not appear to be related to any histopathological changes. Female rats fed 400 ppm test substance had increased relative spleen
weights which may be correlated with rear footpad dermatitis, a common naturally occurring lesion in wire cage-reared aging rats.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related findings were observed in either male or female rats that could be attributed to the dietary administration of the test substance.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related lesions were observed in either male or female rats that could be attributed to the dietary administration of the test substance.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related neoplastic lesions were observed in either male or female rats that could be attributed to the dietary administration of the test substance.
Key result
Dose descriptor:
NOAEL
Effect level:
800 ppm
Based on:
test mat.
Remarks on result:
not determinable due to adverse toxic effects at highest dose / concentration tested
Remarks:
with regards to carcinogenicity
Key result
Dose descriptor:
NOAEL
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
organ weights and organ / body weight ratios
Conclusions:
2 year Rat NOEL (Male/Female): 100 ppm (for systemic toxicity)
2 year Rat NOEL (Male/Female): 800 ppm (for carcinogenicity)
Executive summary:

The study was conducted to evaluate the chronic toxicity of test substance when administered orally in diet for 2 years. Test substance was fed to male and female rats for two years at levels of 0, 50, 100, or 400 ppm in diet. Although slight decreases in body weight were observed periodically throughout the study, after two years of continuous feeding, the average final body weights and average body weight gains of male and female rats fed various dietary levels of test substance were not significantly different from those of the corresponding controls. There were no clinical signs of toxicity that could be attributed to the feeding of test substance for control

and treated rats and no meaningful differences among mortality rates for control and treated rats. Female rats fed 400 ppm test substance tended to have statistically significant lower erythrocyte counts, hemoglobin values and hematocrits than those of the corresponding controls. All other hematological measurements and all clinical measurements and urine analysis were essentially within the normal range, as established by the controls. There were no significant differences in absolute organ weights for either male or female rats and in relative organ weights for male rats fed various dietary levels of test substance, compared to those of

controls. Female rats fed 100 or 400 ppm of test substance had significantly increased relative liver weights compared to those of controls. However, these differences did not appear to be related to any histopathological changes. Female rats fed 400 ppm test substance had increased relative spleen weights which may be correlated with rear footpad dermatitis, a common naturally occurring lesion in wire cage-reared aging rats. No test substance related non-neoplastic or neoplastic lesions were observed in either male or female rats that could be attributed to the dietary administration of the test substance. The No Observed Effect Level (NOEL) following dietary administration of test substance to male and female rats for two years was 100 ppm for systemic toxicity and 800 ppm for carcinogenicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Rat (dietary) 24-months: Under the conditions of the study, methomyl was not a carcinogen.

Mouse (dietary) 104-week: Under the conditions of the study, methomyl was not a carcinogen.

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on the results of chronic feeding studies in rats and mice, it can be concluded that the test substance does not pose a carcinogenic concern for humans. Therefore, the test substance is not classified for carcinogenicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.

Additional information

The chronic toxicity and carcinogenic potential of the test substance when administered in the diet to albino mice for 104 weeks was evaluated. Three groups of animals (80/sex/group) received the test compound initially at levels of 50, 100, and 800 ppm. A fourth group of animals received the basal diet only. After 104 weeks of treatment, all surviving animals were sacrificed and necropsied. Criteria evaluated for compound-related effects were: mortality; body weights; food consumption; hematology profiles; tissue cultures; absolute and relative organ weights; and gross and microscopic pathology. The survival in the high-dose males and females was significantly lower at Week 26. Survival in the mid-dose groups was also moderately lower. Due to these unexpected high mortality rates in the mid- and high-dose groups, the dose level of the high-dose group was decreased to 400 ppm at Week 28. For the same reason, the dose level was further reduced to 200 ppm beginning Week 39; at the same week, the mid-dose level was reduced from 100 to 75 ppm. Survival of the high-dose females was statistically significantly lower after 52, 80, and 104 weeks, while the mid-dose females remained markedly lower at the same intervals. Survival was statistically significantly lower after 52 weeks in the high-dose males, the mid- and high-dose males Week 80, and all treated males after 104 weeks. Lower survival rates were considered related to the toxicity of the test substance. Test substance-related histomorphologic alterations were not observed in the tissues examined. Neoplastic and non-neoplastic spontaneous disease lesions were of the usual type and number observed in mice of this age and strain and were essentially comparable in incidence and severity between control and treated groups.

The chronic toxicity of test substance when administered orally in diet for 2 years to rats at levels of 0, 50, 100, or 400 ppm in diet. No test substance related non-neoplastic or neoplastic lesions were observed in either male or female rats that could be attributed to the dietary administration of the test substance. The No Observed Effect Level (NOEL) following dietary administration of test substance to male and female rats for two years was 100 ppm for systemic toxicity and 800 ppm for carcinogenicity.

The chronic toxicity of test substance when administered orally in diet to rats for 24 months was evaluated. The dietary levels were 50, 100, 200, and 400 ppm. Histopathologic evaluation of tissue sections from rats fed 400 ppm of test substance for one year did not reveal any test substance effect. After 22 months of dietary administration, microscopic examination revealed test substance related histopathologic alterations in the kidneys of males and females at 400 ppm level and in the spleens of the females at 200 and 400 ppm levels of the test substance. The NOEL for carcinogenicity was 400 ppm for males and females.