cis-4-[3-(p-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine

Carcinogenicity

Description of key information

In a a rat carcinogenicity study, where fenpropimorph was given via food, test substance related effects were reduced body weights, increased liver weights with associated histopathological changes and a decrease in brain and and plasma cholinesterase

activity at 50 and 250 ppm. The NOAEL in this study was 10 ppm, equivalent to 0.3 mg/kg bw/d in males and 0.4 mg/kg bw/d in females. Fenpropimorph was not carcinogenic in rats.

In an oral feeding carcinogenicity study in mice, main test substance related effects were reduced body weight and increased liver weight.

The NOAEL in this study was 150 ppm, equivalent to 16 mg/kg bw/d in males and 17 mg/kg bw/d in females. Fenpropimorph was not carcinogenic in mice.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Nov. 1978 - Oct. 1981

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

national guideline test performed according to GLP

Qualifier:

according to guideline

Guideline:

other: US EPA guideline, Federal register, Vol. 43, No. 163

Version / remarks:

August 22, 1978

GLP compliance:

yes

Remarks:

GLP was implemented during the course of the study. Quality assurance unit certificate available (Oct. 1981)

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River laboratories, Wilmington USA
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age: 28 days at arrival
- Housing: 5 per cage
- Diet (e.g. ad libitum): ad libitum, Spratt's Laboratory Animal diet No. 2 (admixed with the test substance except for the control treatment); food was removed overnight from animals sampled for urinanalysis, haematology and blood-chemistry (except cholinesterase analysis)
- Water (e.g. ad libitum): ad libitum, tap water, water was removed overnight from animals sampled for urinanalysis
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Spratt's Laboratory Animal diet No. 2
- Storage temperature of food: Room temperature

Analytical verification of doses or concentrations:

yes

Remarks:

Samples of the diet were send to the sponsor for analysis to confirm homogeneity and accuracy of mixing. The test substance concentrations in the diet were within tolerable agreement with the desired test substance levels.

Details on analytical verification of doses or concentrations:

Not specified

Duration of treatment / exposure:

Main group: 52 wk for 10 males/females, 107/115 wk for all surviving female/male animals
Satellite group: 104 wk for all surviving animals

Frequency of treatment:

daily

Post exposure period:

No

Dose / conc.:

5 ppm (nominal)

Remarks:

corresponding daily intake: males: 0.2 mg/kg bw/d, females: 0.2 mg/kg bw/d

Dose / conc.:

10 ppm (nominal)

Remarks:

corresponding daily intake: males: 0.3 mg/kg bw/d, females: 0.4 mg/kg bw/d

Dose / conc.:

50 ppm (nominal)

Remarks:

corresponding daily intake: males: 1.7 mg/kg bw/d, females: 2.1 mg/kg bw/d

Dose / conc.:

250 ppm (nominal)

Remarks:

corresponding daily intake: males: 8.8 mg/kg bw/d, , females: 11.2 mg/kg bw/d

No. of animals per sex per dose:

Main groups: 60/sex/dose
Satellite group: 15/sex/dose

Control animals:

yes, plain diet

Details on study design:

- Rationale for selecting satellite groups: Satellite animals were intended for blood sampling and not included in tumorigenic evaluation.
- Post-exposure recovery period in satellite groups: No recovery period; animals were killed 104 weeks after treatment

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily (except weekends), after 4 weeks in weekly intervals
- Cage side observations checked: all signs of ill health and behavioral changes
- mortality was checked twice daily (in the morning and afternoon, at weekends and holidays the second check was at mid-day)

DETAILED CLINICAL OBSERVATIONS: Not specified

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: One week before commencement of treatment and weekly intervals thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for animals of a cage determined and mean weekly diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Group mean food conversion ratios were calculated for successive four-wekly periods during the first 24 weeks of treatment as weight of food consumed per unit gains in bodyweight

WATER CONSUMPTION: Yes (for the main group)
- Time schedule for examinations: Daily examination by visual examination
- Consumption for each main group cage in the control and 250 ppm group was measured daily for a 5-day period during week 5, 12, 23. Since there was no evidence of an effect, no further measuring was performed.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Before commencement of the treatment, during week 6, 13, 26, 52, 78, 104, and 114 (for males only) all animals of the control and 250 ppm group were examined by indirect ophthalmoscopy.
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior treatment, and during weeks 25, 51, 77, 103
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: Yes
- How many animals: 10/sex/dose group, blood samples of week 104 were taken from 10 males only/dose group
- Parameters checked: Packed cell volume, hemoglobin, red cell count, reticulocyte count, mean corpuscular hemoglobin concentration, mean cell volume, total white cell count, differential count of neutrophils, lymphocytes, eosinophils, basophils, monocytes, thrombotest (at week 25 and subsequent occasions)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 25, 51, 77, and 103
- Animals fasted: Yes
- How many animals: 10/sex/dose, blood samples of week 104 were taken from 10 males only/dose group
- Parameters checked: Serum urea, plasma glucose, serum total protein, serum albumin, serum alkaline phosphatase, serum glutamic-pyruvic transaminase, serum glutamic axaloacetic transaminase, serum total lactic dehydrogenase, serum total billirubin, serum creatinine, serum cholesterol, serum triglycerides, serum sodium, serum potassium, serum chloride, serum calcium, serum inorganic phosphorus,
- (brain)cholinesterase; analysed from the blood of 10 unfasted rats/dose (male/female) during weeks 25, 51, 77, 103; during week 114 (males only)

URINALYSIS: Yes
- Time schedule for collection of urine: week 24, 50, 76, and 102
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
- Parameters checked in table: pH, specific gravity, protein, reducing substances, glucose, ketones, bile pigments, urobilinogen, hemoglobin, microscopy of spun deposits (epithelial cells, polymorphonuclear leucocytes, mononuclear leucocates, erythrocytes, organisms, casts, abnormal constituents

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Palpable masses were recorded at the time of clinical observation. Thereafter, the dimensions were recorded every 2 weeks

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- All superficial tissues including all urogenital orifices and tail, each pinna, eye and external auditory meatus, mammary tracts, and subcutaneous structures were examined visually and by palpation for distortion, swelling or other evidence of tumor formation
- external nares, buccal cavity, and tongue, brain, pituitary gland and cranial nerves, all subcutaneous tissues including regional lymph nodes, mammary and thyroid/parathyroid glands, thoracic viscera with due attention to the thymus, lymph nodes and heart, lung
- abdominal viscera, urinary bladder, gastroinstestinal tract (stomach, portions of duodenum, jejunum, ileum, colon, caecum), liver and kidney
- gonads, adrenals, uterus, intra-abdominal lymph nodes, and acessory reproductive organs
- organ weights of all animals killed after 52 and 104 weeks of treatment: brain, heart, kidneys, liver, testes

HISTOPATHOLOGY: Yes
adrenals, bone, brain, caecum, duodenum, eyes, harderian gland, head, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes, mammary gland, mid-colon, oesophagus, ovaries, pancreas, pituitary, prostate, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, sternum, stomach, testes, thymus, thyroids, trachea, urinary bladder, uterus plus cervix and any other tissue showing macroscopic abnormalities

Statistics:

Analysis of variance followed Student's t-test: food consumption, bodyweight, clinical laboratory data. Analysis of food consumption data was performed using the means of all the cage total food intakes (sum of the weekly cage mean food intake) in each group over specified time periods. Analysis of body weight data was performed using the individual weight gains of rats surviving throughout the specified time periods. Organ weight analysis was performed using analysis of covariance. Organ weights were adjusted for final body weight as covariate where this was the more efficient method of analysis. Where appropriate log transformation was performed to stabilize variance. Group means were compared using Student's t-test and Williams' test. The incidence of eosinophilic foci in the liver was analyzed using a chi-squared test for trend amongst proportions using stratified contingency tables

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Isolated areas of hair loss, ulceration and scab formation, and discoloration and matting of the fur were observed. The incidence and time of onset of palpable masses was unrelated to the treatment.
During the pre-treatment week and week 1, rats of all groups had a mild outbreak of a viral disease occasionally seen in rats of this age and strain. Recovery was already seen before the start of exposure. No treatment related disturbance of the disease was observed and residual effects were confined to ophthalmic lesions observed in a small number of rats. A second, milder outbreak of the disease occurred (only a few rats of each dose group were affected). Recovery appeared soon, without major residual effects.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Main group:
34, 31, 37, 34, 31 dead female rats of 60 (0, 5, 10, 50, 250 ppm, respectively);
33, 36, 29, 33, 30 dead male rats of 60 (0, 5, 10, 50, 250 ppm, respectively)
Satellite group:
7, 9, 4, 6, 8 dead male rats of 15 (0, 5, 10, 50, 250 ppm, respectively);
4, 10, 6, 7, 9 dead female rats of 15 (0, 5, 10, 50, 250 ppm, respectively)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

During the first 92 weeks of exposure, body weight gain of male and females dosed with 250 ppm was decreased. Males treated with 50 ppm showed a marginally lower body weight gain (not statistically significant).
From week 92 until termination, intergroup differences reflected increasing senility and variation in mortality incidence.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption was decreased for females exposed to 250 ppm test substance. Males of the same dosage group were unaffected.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

High-dosed rats (250 ppm) showed a decreased food utilization (associated in part with the lower body weight gains)

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Group mean values of red and white blood cell parameters of treated rats did deviate from that of controls (statistically significant on occasion), however, without any consistency of this effect.
An increased thrombotest time was observed for male rats of all treatment groups including the control.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Plasma cholinesterase: The enzyme was inhibited from week 6 onwards among females receiving 250 ppm; among males receiving 250 ppm from week 26 onwards. A marginal bur biologically relevant reduction in activity was recorded in the 50 ppm dose group prior termination in males and females in comparison to the control values after 114 and 104 weeks, respectively.
Brain cholinesterase: The enzyme was inhibited at termination (week 115) in males receiving 50 and 250 ppm.

Endocrine findings:

not examined

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Interim kill after 52 weeks: increased liver weights among males treated with 50 and 250 ppm and females treated with 250 ppm
Interim kill after 104 weeks: increased liver weights for males treated with 250 ppm
Terminal kill: Increased liver weights among males exposed to 50 and 250 ppm

The increased liver weights were associated with hepatocytes enlargement.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- enlargement of centrilobular hepatocytes in 16/50 males treated with 250 ppm and enlargement of periportal hepatocytes in 16/50 females treated with 250 ppm and 15/50 females treated with 50 ppm
- multinucleate hepatocytes in 5/50 males and 4/50 females treated with 250
ppm
- cellular pleomorphism was prominent in 4/50 males treated with 250 ppm
- no dosage-related effect could be revealed for the observation of foci or areas of altered hepatocytes. The increase of eosinophilic lesions for high-dosed animals was unlikely to be of toxicological relevance

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

There was no treatment-related effect on the incidence of any tumor type, nor any effect on the distribution of the total number tumour-bearing rats, or the number of rats with with multiple tumours and malignant tumours.
Most common tumours observed for male rats: pituitary tumours, subcutaneous tumours, panceratic islet cell tumours; female rats: pituitary tumours and mammary tumours.

Relevance of carcinogenic effects / potential:

The incidence and distribution of neoplasms were consistent with normal spontaneous tumour profile for this rat strain maintained in the laboratory.

Key result

Dose descriptor:

NOEL

Effect level:

0.4 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

clinical biochemistry

histopathology: non-neoplastic

Key result

Dose descriptor:

NOEL

Remarks:

systemic effect

Effect level:

0.3 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical biochemistry

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

> 11.2 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: no carcinogenicity observed up to and including the highest tested dose

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

> 8.8 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: no carcinogenicity observed up to and including the highest tested dose

Critical effects observed:

yes

Lowest effective dose / conc.:

50 ppm

System:

hepatobiliary

Organ:

liver

Reference 2

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Jul. 1979 - Jul. 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

national guideline test performed according to GLP; limitations in the examined parameters (reduced blood biochemistry analysis , lack of urinanalysis, ophthalmoscopic examination, and water consumption)

Qualifier:

according to guideline

Guideline:

other: US EPA guideline, Federal register, Vol. 43, No. 163

Version / remarks:

August 22, 1987

GLP compliance:

yes

Remarks:

Quality assurance audit statement available

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Age at arrival: 24 days
- Fasting period before study:
- Housing: 4 per cage
- Diet (e.g. ad libitum): ad libitum, Spratt's Laboratory Animal diet No. 2 (admixed with the test substance except for the control treatment); food was removed overnight from animals sampled for urinanalysis, haematology and blood-chemistry (except cholinesterase analysis)
- Water (e.g. ad libitum): ad libitum, tap water, water was removed overnight from animals sampled for urinanalysis
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of the diet were send to the sponsor for analysis to confirm homogeneity and accuracy of mixing. The test substance concentrations in the diet were within tolerable agreement with the desired test substance levels.

Duration of treatment / exposure:

95 weeks; 10 animals /sex/dose were already killed after 52 days of treatment

Frequency of treatment:

daily

Post exposure period:

Yes; after 95 weeks of treatment

Dose / conc.:

5 ppm (nominal)

Remarks:

corresponding to a daily intake for males: 0.5 mg/kg bw/d, females: 0.5 mg/kg bw/d

Dose / conc.:

30 ppm (nominal)

Remarks:

corresponding to a daily intake for males: 3.0 mg/kg bw/d, females: 3.5 mg/kg bw/d

Dose / conc.:

150 ppm (nominal)

Remarks:

corresponding to a daily intake for males: 16 mg/kg bw/d, females: 17 mg/kg bw/d

Dose / conc.:

1 000 ppm (nominal)

Remarks:

corresponding daily intake for males: 106 mg/kg bw/d, females: 118 mg/kg bw/d

No. of animals per sex per dose:

60

Control animals:

yes, plain diet

Details on study design:

Post-exposure recovery period: 7 weeks (males) 8 weeks (females)

Positive control:

No

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily (except weekends), after 4 weeks in weekly intervals
- Cage side observations checked: all signs of ill health and behavioral changes
- mortality was checked twice daily (in the morning and afternoon, at weekends and holidays the second check was at mid-day)

DETAILED CLINICAL OBSERVATIONS: Not specified

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: One week before commencement of treatment and at weekly intervals thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for animals of a cage determined and mean weekly diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Group mean food conversion ratios were calculated for successive four-wekly periods during the first 24 weeks of treatment (group mean food consumption (g)/Group mean body weight gain (g)

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: During weeks 51, 95, and 101
- Anaesthetic used for blood collection: Yes, ether
- Animals fasted: No
- How many animals: 10/sex/dose group
- Parameters checked: Packed cell volume, hemoglobin, red cell count, reticulocyte count, mean corpuscular hemoglobin (concentration), mean cell volume, total white cell count, differential count of neutrophils, lymphocytes, eosinophils, basophils, monocytes, platelet count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 51, 91, and 101
- Animals fasted: No
- How many animals: 10/sex/dose
- cholinesterase determination (RBC and plasma cholinesterase), brain cholinesterase levels were measured in 10 animals/sex/dose after 52 and 95 days of treatment

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: Palpable masses were recorded at the time of clinical observation. Thereafter, the dimensions were recorded every 2 weeks

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
- All superficial tissues including all urogenital orifices and tail, each pinna, eye and external auditory meatus, mammary tracts, and subcutaneous structures were examined visually and by palpation for distortion, swelling or other evidence of tumor formation
- external nares, buccal cavity, and tongue, brain, pituitary gland and cranial nerves, all subcutaneous tissues including regional lymph nodes, mammary and thyroid/parathyroid glands, thoracic viscera with due attention to the thymus, lymph nodes and heart, lung
- abdominal viscera, urinary bladder, oesophagus, stomach and intestines inclusing caecum, liver and kidney
- gonads, adrenals, uterus, intra-abdominal lymph nodes, and accessory reproductive organs
- organ weights of all animals killed after 52 and 95 weeks of treatment: brain, heart, kidneys, liver, testes

HISTOPATHOLOGY: Yes
adrenals, bone, brain, caecum, duodenum, eyes, harderian gland, head, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes, mammary gland, mid-colon, oesophagus, ovaries, pancreas, pituitary, prostate, salivary gland, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, sternum, stomach, testes, thymus, thyroids, trachea, urinary bladder, uterus plus cervix

Statistics:

Analysis of variance on raw or log transformed data followed by Student's t-test was used to assess the significance of intergroup differences in clinical pathology data. Williams' test was used in addition to the t-test when appropriate. If raw transformed data were unsatisfactory, the Kruskal-Wallis analysis of mean ranks was used, followed by the non-parametric equivalents of Student's t-test and if appropriate Williams' test.
Analysis of the food consumption data was performed using the means of all the cage total food intakes in each group over specified time periods. The cage totals were a sum of the weekly cage mean food intakes. The weekly cage means were calculated using the amounts of food given to and left by each cage in each week and the number of animals surviving in the cage for the maiority of days in the week. The cage mean food consumption figures were
rounded to the nearest whole number, but the cage totals were calculated using the exact mean weekly figures.
Analysis of the body weight data was performed using the individual weight gains of mice surviving throughout the specified time period.
Analysis of organ weights was performed using analysis of covariance. Organ weights were adjusted for final body weight as covariate where this was a more efficient method of analysis. Where appropriate, organ weights were log transformed to stabilize variance. Group means were compared using both Student's 't' test and Williams' test.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

isolated areas of hair loss, ulceration, scab formation and discolouration and matting of the fur were those commonly seen in the strain of mouse employed. In particular, the incidence and time of onset of swellings and palpable masses
appeared to show no treatment-related deviation.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Dead mice at termination of exposure (95 wk): 28, 24, 16, 22, 21 male mice of 50; 17, 17, 18, 19, 20 female mice of 50 (0, 5, 30, 150, 1000 ppm, respectively)
These mortalities accounted for 44 %, 52 %, 68 %, 56 %, 58 % (males), 66 %, 66 %, 64 %, 62 %, 60 % (females) for 0, 5, 30, 150, 1000 ppm, respectively

Post-exposure period: 0/12, 1/16, 8/24, 3/18, 3/19 male mice: 3/23, 5/23, 4/22, 4/21, 3/20 female mice (0, 5, 30, 150, 1000 ppm, respectively)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain by mice receiving 1000 ppm test substance was
lower than that of the controIs, although only the difference between values for controls and males receiving 1000 ppm attained a level of statistical significance.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

During the period of rapid body weight gain (weeks 1 to 13) marginally inferior efficiency of food utilisation which was associated in part with the lower body weight gain, was recorded for males receiving 1000 ppm test substance. From week 14 to 26 this effect was no longer apparent due to the smaller changes in body weight gain.

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

At week 51, several group mean values for red blood cell parameters, for both treated males and females attained a level of statistical significance in their differences from the control values. However, there was no consistency, between sexes, in the deviations from the control values. There was also no indication of any dosage-related disturbance for any of the parameters. Therefore, in the absence of any similar effects at week 95 these differences were considered
to have arisen fortuitously and to be of no toxicological importance.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

A reduction in red blood cell cholinesterase activity occurred at week 95 among females receiving 150 ppm or 1000 ppm ( about 74 % of the control).
After 6 weeks on untreated diet (week 101), investigations of enzyme activity did not reveal any significant effect.

At week 95 an increase in plasma cholinesterase activity was recorded among males receiving 1000 ppm. A similar high plasma cholinesterase level was found after 6 weeks of withdrawal from the test compound in males receiving 150 ppm, which implies that the result at week 95 is not due to treatment.

No biologically relevant disturbance of brain cholinesterase activity was recorded in this study.

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Interim kill after 52 wk: Analysis of organ weights revealed increased liver weights in males treated with 1000 ppm when compared with controls. However in the absence of any changes at the cellular level and as liver weights in males killed at the end of the study were similar to those of the controls, this finding was considered to be of doubtful toxicological significance. Males treated with 5, 30 or 150 ppm were not thus affected and liver weights of treatment females were essentially similar to that of the controls. There were no other significant differences in organ weights between control and treated mice.

Terminal studies: There were no marked intergroup differences in organ weights in mice killed at the end of the treatment period or withdrawal period. Although at the week 96 kill, |iver and kidney weights for females treated with 1000 ppm were maginally higher than those of the controls, no changes at the cellular level to account for these differences were seen, and these findings were therefore considered to be of doubtful toxicological significance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Animals killed after 95 wk: The number of males with liver masses was higher in treated groups when compared with controls. However, this finding was considered to be a result of a very low control incidence compared to historical data.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

The general incidence and distribution of the changes were considered to be within the spontaneous pathological prole of the strain of mice employed in this study. The most common morphological changes included: chronic pneumonitis in the lungs; hepatocyte enlargement, vacuolation and fat deposition in hepatocytes, chronic inflammatory cell aggregations in the liver; glomerulonephritis in the kidneys; amyloid deposits in many tissues particularly the kidneys; gastro-intestinal tract, thyroids, adrenals and ovaries; lymphoid hyperplasia and/or extramedullary haemopoiesis in the spleen; adenomatous hyperplasia in the stomach; seminal vesicles distended with colloid; dilatation of ducts and acini in preputial glands of male mice; ovarian cysts or dilatation of the ovarian bursae; cystic endometrial hyperplasia in the uterus; and areas of necrosis with inflammation in Harderian gland.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

No treatment-related effect was detected in the incidence or distribution of the neoplasia encountered in this study including mice allowed a withdrawal period.
The most frequent tumour types observed included pulmonary adenomas and odeneeatcinomas of lung; lymphoreticular tumours predominantly lymphosarcomas and reticulum cell sarcomas; and liver cell tumours, both benign and malignant.
The incidence of liver cell tumours in all male treatment groups was considered to be unrelated to treatment, as it was similar to that of concurrent control data and also showed no dose relationship.
Tumours of low incidence were observed in the spleen, kidney, gonads and reproductive tract, thyroids, adrenals, pancreas, pituitary, Harderian gland, skin, subcutis, skeletal muscle, bone, brain and stomach.

Details on results:

Possible lower red blood cell cholinesterase levels, in females receiving 150 or 1000 ppm were recorded after 95 weeks of treatment only. However the lack of any congruity between the measured red blood cell cholinesterase values and treatment, duration, sex and methods of malysis emphasises that a depressive
eect of the test compound on red blood cell cholinesterase activities cannot be clearly deduced from the compiled data.

Relevance of carcinogenic effects / potential:

The treatment had no effect on the spontaneous tumor profile of the mice.

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

17 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

16 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

> 118 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: no carcinogenicity up to and inclusing the highest tested dose

Key result

Dose descriptor:

NOAEL

Remarks:

carcinogenicity

Effect level:

> 106 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

histopathology: neoplastic

Remarks on result:

other: No carcinogenicity up to and including the highest tested dose

Critical effects observed:

no

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Justification for classification or non-classification

Due to the absence of any carcinogenic effect in both carcinogenicity studies in rats and mice, fenpropimorph does not need to be classified for carcinogenicity according to Regulation (EC) No. 1272/2008.