Registration Dossier

Administrative data

Description of key information

The subacute oral toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA) was investigated according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents).

The aim of this study was to obtain information on the toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl) acetamide (MPA) in rats when given by oral administration via gavage daily for 28 days. The animals were treated with100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day. None of the animals died prematurely.

The body weight of the male animals and the relative food consumption of the male and female animals treated with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day were slightly reduced.

Oral treatment withN-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day caused an increase in the plasma level of cholesterol and in the plasma activity of ALAT in the animals treated with1000 mg/kg of both sexes.

Treatment with N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused increases in relative and absolute liver weights at 1000 mg/kg b.w./day for both sexes. Microscopic evaluation of the animals treated orally with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day revealed a test item-related change in the liver in both males and females (hepatocellular hypertrophy, centrilobular).

Additional histopathological evaluation of the liver (low and intermediate dose groups, both sexes) revealed no microscopic changes that could be related to the test item.

No test item-related changes were noted in behavior, external appearance or faeces, functional observation tests, the fore- and hind limb grip strength or spontaneous motility, in haematological parameters, in the eyes and the optic region, at macroscopic inspection at necropsy and for the myeloid: erythroid ratio.

At the end of the recovery period, the body weight of the previously high dosed male animals was still slightly decreased. Furthermore, the plasma level of cholesterol was still increased for the previously high dosed females. All other changes had subsided at the end of the recovery period. Based on the above results the No-Observed-Adverse-Effect-Level (NOAEL) was 300 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day, p.o.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Only one study available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013-04-03 - 2013-09-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: CD / Crl:CD (SD)
Sex:
male/female
Details on test animals and environmental conditions:
Breeder Charles River Laboratories
Research Models and Services Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany

Age (at 1st dosing) Males: 35 days, Females: 36 days

Body weight (at 1st dosing) Males: 130.6 - 160.3 g, Females: 127.1 - 153.4 g

Selection of species: Selected because of its proven suitability in toxicology studies and to comply with regulatory requirements for testing in a rodent animal species.

Identification of animals: Each rat received a continuous number: according to a differentiated number scheme, which allowed all figures from 1 to 60, points were set on paws and/or tail by tattoo; additionally, the animal cages were labelled with study number, animal number, sex and treatment group.

Number and sex of animals: 60 animals (30 male and 30 female rats)
Main study animals:
- 40 animals (20 male and 20 female rats)
- 5 animals/sex/group
Recovery animals:
- 20 animals (10 male and 10 female rats)
- 5 animals/sex for groups 1 and 4
Additionally, 6 spare animals (3 males and 3 females) of the same delivery were reserved for possible replacement during the adaptation period.

Adaptation period: 5 days

Housing: The animals were kept singly in MAKROLON cages (type III plus) with a basal surface of approx. 39 cm x 23 cm and a height of approx. 18 cm at a room temperature of 22°C ± 3°C (maximum range) and a relative humidity of 55% ± 15% (maximum range). The rooms were lit (about 150 lux at approx. 1.50 metres room height) and darkened for periods of 12 hours each.

Diet (e.g. ad libitum): Commercial ssniff R/M-H V1530 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany; see Appendix 2 'Composition of the Diet') served as food. This food was offered ad libitum. Food residue was removed and weighed.

Water (e.g. ad libitum): Drinking water was offered ad libitum. Drinking water is examined according to the 'Deutsche Trinkwasserverordnung, 2001' by the Hamburger Wasserwerke, 20539 Hamburg, Germany, at least four times a year (see Appendix 2 'Limitation for Contaminants in the Drinking Water').
Route of administration:
oral: gavage
Vehicle:
other: 0.5% Methocel
Details on oral exposure:
The test item was administered orally, by gavage, at a constant administration volume of 5 mL/kg b.w./day once daily for 28 days.
The amount of the test item was adjusted to each animal's current body weight daily.
The control animals received the vehicle at the same administration volume of 5 mL/kg b.w. once daily for 28 days in the same way.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the analysis of the test item formulations by HPLC, samples of approximately 10 mL were taken at the following times and stored at -20°C or colder until analysis.
The samples were labelled with the study number, species, type of sample, concentration, sampling time and date.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Once daily for 28 days
Remarks:
Doses / Concentrations:
100 mg/kg b.w./day, 300 mg/kg b.w./day, 1000 mg/kg b.w./day
Basis:
actual ingested
No. of animals per sex per dose:
5 males and 5 females per dose

Main study animals:
- 40 animals (20 male and 20 female rats)
- 5 animals/sex/group

Recovery animals:
- 20 animals (10 male and 10 female rats)
- 5 animals/sex for groups 1 and 4
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale:
The dose levels have been selected in agreement with the Sponsor based on available toxicity data and a 14-day dose-range-finding study.
In this dose-range-finding study, rats were treated orally with 100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day.
None of the animals died prematurely.
The relative food consumption of the female rats treated orally with 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day was decreased by 14% in test week 1 and by 10% in test week 2. No changes were noted for the high dosed male animals.
No changes in behaviour, external appearance or faeces were noted for the male and female animals treated orally with 100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day.
No test item-related influence was noted for the body weight, body weight gain and drinking water consumption at any of the tested dose levels.
No test item-related changes were noted at macroscopic inspection at necropsy.

Post-exposure recovery period in satellite groups: Recovery animals: 20 animals (10 male and 10 female rats), 5 animals/sex for groups 1 and 4, 14 recovery days
Positive control:
not required
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: before and after dosing at each time of dosing
- Cage side observations checked were included: yes.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the first exposure (to allow for within-subject comparisons) and once a week thereafter (1, 2, 4, 8 and 24 h after administration)

BODY WEIGHT: Yes
- Time schedule for examinations: at the time of group allocation, on the day of commencement of treatment and once a week thereafter always on the same day of the week throughout the experimental period

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


WATER CONSUMPTION: Yes
- Time schedule for examinations: Drinking water consumption was monitored daily by visual appraisal throughout the study.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Examinations were performed on all animals prior to the start of administration and at study termination (main study and recovery period).

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination (on the day of dissection): All main study animals, At the end of the recovery period (on the day of dissection): All recovery animals

- Anaesthetic used for blood collection: Yes (identity): isoflurane
- Animals fasted: Yes, animals fasted overnight
- How many animals: At study termination (on the day of dissection): All main study animals, At the end of the recovery period (on the day of dissection): All recovery animals
- Parameters checked: haemoglobin content, (HGB), erythrocytes, (RBC), leucocytes, (WBC), differential blood count (absolute and relative), reticulocytes (Reti), platelets (PCT), haematocrit value, (HCT), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), thromboplastin time, (TPT), activated partial thromboplastin time (aPTT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At study termination (on the day of dissection): All main study animals, At the end of the recovery period (on the day of dissection): All recovery animals
- Animals fasted: Yes, animals fasted overnight
- How many animals: At study termination (on the day of dissection): All main study animals, At the end of the recovery period (on the day of dissection): All recovery animals
- Parameters checked: albumin, globulin, albumin/globulin ratio, bile acids, bilirubin (total), cholesterol (total), creatinine, glucose, protein (total), urea (in blood), calcium chloride, potassium, sodium, alanine aminotransferase (ALAT), alkaline phosphatase (aP), aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH),

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: The screening test was conducted approximately one to two hours after dosing: In test week 4: All main study animals, In test week 6: All recovery animals

- Battery of functions tested: grip strength, motor activity
other: see table 1
Sacrifice and pathology:
Necropsy:
All superficial tissues were examined visually and by palpation and the cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral midline incision and skin reflection, all subcutaneous tissues were examined. The condition of the thoracic viscera was noted with due attention to the thymus, lymph nodes and heart.
The abdominal viscera were examined before and after removal, the urinary bladder was examined externally and by palpation. The gastro-intestinal tract was examined as a whole and the stomach and caecum were incised and examined. The lungs were removed and all pleural surfaces examined under suitable illumination. The liver and the kidneys were examined. Any abnormalities in the appearance and size of the gonads, adrenal glands, uterus, intra-abdominal lymph nodes and accessory reproductive organs were recorded.
The weights of the following organs of all animals were determined before fixation:
adrenal gland (2), kidney (2), ovary# (2), brain, heart, spleen epididymis# (2), liver, testicle# (2), thymus, as a whole: prostate, seminal vesicles with coagulating glands# (# animals of the relevant gender)

Histopathology:
The following organs or parts of organs of all animals were fixed in 7% buffered formalin. The eyes were preserved in Davidson’s solution and the testes in Bouin's solution for optimum fixation:
adrenal gland (2)
bone (os femoris with joint)
bone marrow (os femoris)
brain (cerebrum, cerebellum, medulla/pons)
caecum
epididymis# (2)
eye with optic nerve (2)
gross lesions
heart (left and right ventricle, septum)
intestine, small (duodenum, jejunum,
ileum, incl. Peyer's patches), Swiss roll
method
intestine, large (colon, rectum)
kidney and ureter (2)
liver
lungs (with mainstem bronchi and
bronchioles (preserved by inflation with
fixative and then immersion))
lymph node (cervical) (1)
lymph node (mesenteric) (1)
mammary gland
muscle (skeletal, leg)
nerve (sciatic)
ovary# (2)
pituitary
prostate and seminal vesicles with
coagulating glands#
spinal cord (3 sections: cervical,
midthoracic, lumbar)
spleen
stomach
testicle# (2)
thymus
thyroid (2) (incl. parathyroids)
tissue masses or tumours
(including regional lymph nodes)
trachea (incl. larynx)
urinary bladder
uterus# (incl. cervix and oviducts)
vagina#
( # animals of the relevant gender)

Bone marrow:
During dissection fresh bone marrow was obtained from the os femoris (3 air-dried smears/animal) of all animals and stained according to PAPPENHEIM. The myeloid : erythroid ratio was determined for groups 1 and 4 by cell differentiation (counting of 200 nuclei-containing cells).
Statistics:
For body weight, food consumption and organ weight data, homogeneity of variances was tested by using the BARTLETT chi-square test. If the variances were homogeneous, the DUNNETT test (p ≤ 0.01 and p ≤ 0.05) was used to compare the experimental groups with the control group.
In case of heterogeneity of variances, the STUDENT's t-test was carried out; limit of significance were p ≤ 0.01 and p ≤ 0.05.
Clinical signs:
no effects observed
Description (incidence and severity):
No changes in behaviour, external appearance or faeces were noted.
Mortality:
no mortality observed
Description (incidence):
None of the animals treated orally with 100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day died prematurely.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight of the male animals treated with 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day was
reduced by up to 10% compared to the control group in test weeks 1 to 4. Body weight gain changed accordingly. The body weight at
autopsy was slightly reduced by 8% for the high dosed male animals at terminal sacrifice. The female animals were not affected.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The relative food consumption of the male rats treated orally with 1000 mg N-((3(5)-Methyl-1Hpyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day
was slightly decreased by 6% in test week 1 and the relative food consumption of the high dosed female animals was decreased by up to 10% in test weeks 1 to 4. No test item-related influence was noted for the drinking water consumption at any of the tested dose levels.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test item-related influence was noted for the drinking water consumption at any of the tested dose levels.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No test changes were noted.
Haematological findings:
no effects observed
Description (incidence and severity):
No test item-related changes were noted.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Oral treatment with N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused an increase in the plasma level of cholesterol and
in the plasma ctivity of ALAT in the animals treated with 1000 mg/kg of both sexes.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No test item-related changes were noted.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Treatment with 1000 mg N-((3(5)-Methyl-1Hpyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused increases in relative and absolute liver weights:
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test item-related changes were noted.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Microscopic evaluation of the animals treated orally with 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day
revealed a test item-related change in the liver in both males and females (hepatocellular hypertrophy, centrilobular).
Additional histopathological evaluation of the liver (low and intermediate dose groups, both sexes) revealed no microscopic changes that could be
related to the test item.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
other: see 'Remark'
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
no
Conclusions:
Based on the above results the No-Observed-Adverse-Effect-Level (NOAEL) was 300 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day, p.o.
Executive summary:

The subacute oral toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA) was investigated according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents).

The aim of this study was to obtain information on the toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl) acetamide (MPA) in rats when given by oral administration via gavage daily for 28 days. The animals were treated with100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day.

None of the animals died prematurely.

The body weight of the male animals and the relative food consumption of the male and female animals treated with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day were slightly reduced.

Oral treatment withN-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day caused an increase in the plasma level of cholesterol and in the plasma activity of ALAT in the animals treated with1000 mg/kgof both sexes.

Treatment withN-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused increases in relative and absolute liver weights at1000 mg/kg b.w./day for both sexes. Microscopic evaluation of the animals treated orally with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day revealed a test item-related change in the liver in both males and females (hepatocellular hypertrophy, centrilobular).

Additional histopathological evaluation of the liver (low and intermediate dose groups, both sexes) revealed no microscopic changes that could be related to the test item.

No test item-related changes were noted in behaviour, external appearance or faeces,functional observation tests, the fore- and hind limb grip strength or spontaneous motility, in haematological parameters, inthe eyes and the optic region, at macroscopic inspection at necropsy and for the myeloid:erythroid ratio.

At the end of the recovery period, the body weight of the previously high dosed male animals was still slightly decreased. Furthermore, the plasma level of cholesterol was still increased for the previously high dosed females. All other changes had subsided at the end of the recovery period. Based on the above results the No-Observed-Adverse-Effect-Level (NOAEL) was 300 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day, p.o.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The key study is GLP-compliant and has Klimisch score 1.
System:
hepatobiliary
Organ:
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

The subacute oral toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA) was investigated according to OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents).

The aim of this study was to obtain information on the toxicity of N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl) acetamide (MPA) in rats when given by oral administration via gavage daily for 28 days. The animals were treated with100, 300 or 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day. None of the animals died prematurely.

The body weight of the male animals and the relative food consumption of the male and female animals treated with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day were slightly reduced.

Oral treatment withN-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/ kg b.w./day caused an increase in the plasma level of cholesterol and in the plasma activity of ALAT in the animals treated with1000 mg/kg of both sexes.

Treatment withN-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused increases in relative and absolute liver weights at 1000 mg/kg b.w./day for both sexes. Microscopic evaluation of the animals treated orally with1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day revealed a test item-related change in the liver in both males and females (hepatocellular hypertrophy, centrilobular).

Additional histopathological evaluation of the liver (low and intermediate dose groups, both sexes) revealed no microscopic changes that could be related to the test item.

No test item-related changes were noted in behavior, external appearance or faeces, functional observation tests, the fore- and hind limb grip strength or spontaneous motility, in haematological parameters, in the eyes and the optic region, at macroscopic inspection at necropsy and for the myeloid:erythroid ratio.

At the end of the recovery period, the body weight of the previously high dosed male animals was still slightly decreased. Furthermore, the plasma level of cholesterol was still increased for the previously high dosed females. All other changes had subsided at the end of the recovery period. Based on the above results the No-Observed-Adverse-Effect-Level (NOAEL) was 300 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day, p.o.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Only one study available.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

According to the CLP Regulation (EU GHS Regulation (EC) No 1272/2008) classification and labelling is not required for Specific Target Organ Toxicity-Repeated Exposure (STOT-RE) of N-(3(5)-Methyl-1 H-pyrazol-1 -yl-methyl)-acetamid.

Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges of 10 < effect level < 100 mg/kg bw/d. For a 28-day study the guidance values are increased by a factor of three: 30 <effect level < 300 mg/kg bw/d.

Treatment with N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day caused increases in relative and absolute liver weights at 1000 mg/kg b.w./day for both sexes. This effect level is well below the above defined guidance value of 300.

Microscopic evaluation of the animals treated orally with 1000 mg N-((3(5)-Methyl-1H-pyrazol-1-yl)methyl)acetamide (MPA)/kg b.w./day revealed a test item-related change in the liver in both males and females (hepatocellular hypertrophy, centrilobular).

Additional histopathological evaluation of the liver (low and intermediate dose groups, both sexes) revealed no microscopic changes that could be related to the test item.

According to the ECHA Guidance document: Guidance on the Application of the CLP Criteria, 11/2013, p-481, STOT-RE is assigned on the basis of findings of ‘significant’ or ‘severe’ toxicity. In this context ‘significant’ means changes which clearly indicate functional disturbance or morphological changes which are toxicologically relevant.

Although for N-(3(5)-Methyl-1 H-pyrazol-1 -yl-methyl)-acetamid some incidences of liver toxicity were observed in this study with laboratory animals, these cannot be regarded as significant health effects for humans, because hepatocellular hypertrophy following enzyme induction is normally considered an adaptive response to chemical stress.