Benzaldehyde, 5-dodecyl-2-hydroxy-, oxime, branched

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study according to OECD guideline uner GLP. Assessment supported with ToxRTool (Schneider, K. et al. "ToxRTool", a new tool to assess the reliability of toxicological data. Toxicol Lett. 2009 Sep 10:189(2):138-44)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-[(1Z)-(hydroxyimino)methyl]-4-(2-methylundecyl)phenol

EC Number:

627-071-6

Cas Number:

1233873-37-4

Molecular formula:

C19H31NO2

IUPAC Name:

2-[(1Z)-(hydroxyimino)methyl]-4-(2-methylundecyl)phenol

Details on test material:

- Name of test material (as cited in study report): C-SAT 070058
- Physical state: amber viscous liquid
- Analytical purity: 91.9 %
- Impurities (identity and concentrations): 2.8 % dodecylphenol, 4.97 % mixed by-products, 0.28 % di-oxime, 0.05 % hexane
- Lot/batch No.: LAB 310807
- Expiration date of the lot/batch: 31.12.2008
- Storage condition of test material: room temperature

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Procured from Charles River Laboratories (USA) and bred at IIBAT animal house facility.
- Age at study initiation: 6-8 weeks
- Weight at study initiation: males: 203.98 ± 11.30 g; females: 154.38 ± 9.98 g
- Housing: Group caging (5 animals/cage). On 43rd day, animals of both sexes belonging to all the groups were separated into two cages containing three and two animals. The body weight range of the animals at the time of separation was 319-3 74 g for males and 217- 236 g for females.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2°C- 23.1 °C
- Humidity (%): 52%-61%
- Air changes (per hr): 12-15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
A given amount of the test substance is mixed with an appropriate volume of vehicle (corn oil) to
achieve three different concentrations (15. 50 and 150 mg/kg b.w.) on each day prior to the
administration of the test substance.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil was a suitable vehicle
- Amount of vehicle (if gavage): Administration volume was maintained as 10 mL/kg b.w.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical method describes the determination of active content in C-SAT 070058 in corn oil.
The test sample was dissolved in 25 ml petroleum ether and partitioned with 25 ml acetonitrile
thrice. To the acetonitrile layer approximately 350 ml of 3% sodium chloride solution was added
and partitioned with 25 ml hexane thrice. Concentrated to near dryness and suitably diluted with
mobile phase, so as to fit with dynamic calibration curve. The samples were quantified by linear
regression method.
The linearity of the test procedure, its ability within a gtven range to obtain test results
proportional to the concentration of the analyte in the sample, is confinned by the correlation
co-efficient (CC) of 0.999927.

Duration of treatment / exposure:

90 d

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
15 mg/kg bw
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
50 mg/kg bw
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
150 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The range finding study was conducted as a non-GLP test at IIBAT. In the range finding study, 5
males and 5 females per group each, received the test substance once daily for a period of 14 days
at 15, 50 and 150 mg/kg b.w. All animals were observed twice daily for mortality and clinical
signs of toxicity for the entire treatment period. The range finding study doses were suggested by
the sponsor.
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: random
- Post-exposure recovery period in satellite groups: 4 weeks
- Section schedule rationale (if not random): random

Positive control:

not required

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS/DETAILED CLINICAL OBSERVATIONS: Yes
All animals were observed twice daily for morbidity/mortality during the entire treatment and post
treatment period.

General clinical observations for signs of behavioural changes, reaction to treatment or illness
were made for each individual animal once daily throughout the observation period. The general
health condition and any clinically relevant signs were recorded daily for each individual animal of
all groups.

BODY WEIGHT: Yes
Body weight of individual animals was recorded prior to administration of the test substance/vehicle or on day 1 for G7 and G8 and weekly during the treatment and post treatment period (G5 and G6 only)

FOOD CONSUMPTION:
Food consumption was recorded cage-wise (5 and 3+2 animals of the same sex/cage) on a daily basis through out the treatment and post treatment period.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:

OPHTHALMOSCOPIC EXAMINATION: Yes
Ophthalmologic examination was done prior to the start ofthe experiment (day 0), at the end of the treatment for all groups (G1 to G8), and at the end of the withdrawal period (day 118) for G5 and G6.

HAEMATOLOGY: Yes
Animals were fasted overnight prior to blood collection. Blood was collected from the orbital
sinus of all animals before start of dosing (day 1 ), end of the treatment period (on 91st day) and at the end of the post treatment period (on 119th day) in EDT A buffer (for hematology) and in heparinised vials for the separation of plasma (for biochemistry).

Erythrocyte count (RBC), hemoglobin, HCT (Hematocrit), MCV(Mean Corpuscular Volume), MCH(Mean Corpuscular Hemoglobin), MCHC(Mean Corpuscular Hemoglobin Concentration), platelet count, total leucocyte count (WBC) and differential count (5 parameters namely neutrophils, eosinophils, basophils, lymphocytes and monocytes) were determined by using Bayer ADVIA 120, fully automated hematology analyzer (Bayer, Germany). Clotting time was determined by capillary tube method.

CLINICAL CHEMISTRY: Yes
Animals were fasted overnight prior to blood collection. Blood was collected from the orbital
sinus of all animals before start of dosing (day 1 ), end of the treatment period (on 91st day) and at the end of the post treatment period (on 119th day) in EDT A buffer (for hematology) and in heparinised vials for the separation of plasma (for biochemistry).

Heparinised blood was centrifuged at 1000-1200 g for 15 minutes. Plasma was investigated for:
Glucose, urea, BUN (blood urea nitrogen), creatinine, total cholesterol, triglycerides, ALT (alanine aminotransferase), AST (aspartate aminotransferase). ALP (alkaline phosphatase), total protein. albumin and calcium were estimated using Humastar 300 fully automated biochemistry
analyzer (Human GmbH., Germany).
For all determinations. Human (Human GmbH .. Germany) and Erba (Transasia Bio medicals Ltd, India) reagent kits were used.
Sodium and potassium were analyzed by means of a humalyte electrolyte analyzer (Human GmbH., Germany).

URINALYSIS: Yes
Qualitative
Urine samples from individual animals were collected in pre-labeled, clean and sterile vials before start of dosing and at the end of experiment and at the end of the post treatment period.
Samples were collected in the morning hours and were subjected to qualitative analysis (Sood, 1990). The analysis (qualitative) performed together with the methods used is as follows:
Physical
Parameter
a. Color
b. Appearance
c. Reaction (pH)
d. Specific Gravity (S.G)
e. Volume (mL)

Chemical
a. Total Protein
b. Glucose
c. Hemoglobin

Multistrip (Multistix I 0 SG) procured from SIEMENS medical solutions diagnostics Itd., are semi quantitative. The reporting conventions were either based on individual values or a grading system. The other parameters were reported as specific values (glucose, protein, and pH).

Microscopic
Sediments obtained after centrifuging the samples at 1600 rpm for I 0 minutes, were microscopically investigated for the following parameters:
Polymorph nuclear leucocytes, mononuclear leucocytes and erythrocytes were counted by frequency (no. of cells per field 40X).

NEUROBEHAVIOURAL EXAMINATION: Yes
The following parameters were carried out as visual/manual methods:
Righting reflex, body temperature, salivation, respiration, mouth breathing, urination, convulsions, pilo-erection, diarrhea, pupil size, lacrimation, impaired gait, tremors, toe pinch, tail pinch, wire maneuver, hind leg splay, positional passivity, positive geotropism, limb rotation, locomotor activity and grip strength were measured for all groups (G1 to G7) on day 0, day 90 and for satellite groups (G5 and G6) on day 118.
Auditory function was performed during acclimatisation. during week 13 for all the groups ( G1 to G7) and during week 17 for satellite groups (G5 and G6).

OTHER:
Home cage observations:
These observations were performed with as little movement or noise as possible. Animals were observed in their cage before the cage was removed from the rack.
Respiration
The data classification for this parameter is descriptive.
Whether normal
Abnormal (labored. increased rate, etc)

Handling Observations
These observations were made while removing the animal from the cage and holding on the hand.
Salivation
The data classification for this parameter is based on rank order.
None (1)
Slight (2)
Severe (3)
Lacrimation
The data classification for this parameter is based on rank order.
None (1)
Slight (2)
Severe (3)
Piloerection
The hair coat was stroken against the grain and it was observed whether or not it returned to the normal state. The data classification for this is quantal I yes or no data.
Y - indicates presence of piloerection (i.e. coat does not lie down after stroking)
N- indicates no piloerection.
Pupil size
Pupil size was examined with a pen light. The data classification is based on rank order.
Normal (1)
Constricted (2)
Dilated (3).

Open- field measurements
Each animal was placed for 3 minutes in the center of a flat surface with a perimeter barrier and covered with clean absorbent paper. During this time. the observations were made.

Urination
The classification is based on count data. During the 3 minutes of open field measurements the no
of urine pools which were separate and distinct on the paper were counted. Tracking spots w·ere
not counted. ''X'' is recorded if polyuria or overlapping pools were present.

Gait
The data classification is based on rank order.
Normal i.e .. no abnormal gait (1)
Slightly abnormal (2)
Moderately abnormal (3)
Severely abnormal (4)

Tremors
The data classification is descriptive.
None (1)
Slight -localized to fingers or paws (2)
Mild -limbs (fore limb, hind limb or both) (3)
Severe multiple locations ( 4).

Convulsions
The data classification is descriptive.
None (1)
Slight (2)
Mild (3)
Severe (4)

Reflexes
Reflex measurements are performed while the animal was sitting on the open field box surface after completion of the open field measurements.
The data classification is based on rank order.

Righting reflex
Animal was held supine, and then dropped from approximately 30 cm. The nature of landing is indicated with ranks.
Rat lands on feet, normal ( 1)
Slightly in coordinated (2)
Lands on side (3)
Lands on back (4)
Toe pinch response

Forceps was used to pinch the paw of the hind limb.
No response ( 1)
Normal (2)
Exaggerated response (3)
TaiJ pinch response
Forceps was used to pinch the tail approximately 2-3 cm from the tail. No reaction (1), animal may turn or walk forward. or vocalize with little or no movement (2 ). animal freezes, with actual muscle contractions (3). more energetic response including vocalizations (4), exaggerated
reaction-jumps. bites. or attacks (5).

Limb rotation
The animal was allowed to walk on a single leg by holding off all the three legs from the ground.
This procedure was repeated for all the legs.
Rotate freely (1)
Struggle to rotate (2)
Unable to rotate (3)

Physiological

Body temperature
Rectal temperature was taken using a Microprobe thermometer (AD Instruments, Clifton, USA).

Mouth breathing
The animal was observed for its mouth breathing behaviour,
Breathing through the mouth - yes (Y)
Breathing through the nose - no (N)

Wire maneuver
The data classification is based on rank order.
Each animal was placed on the metal rod suspended parallel to the card 2 feet above it. Its ability
to move along the rod is evaluated.
Able to move fi·eely over the rod (1)
Slightly impaired (2)
Unable to stay on the rod (3)

Hind leg splay
Hind paws of each animal were dotted with ink and animal was dropped from prone position about
30cm above onto the foot splay from (FRM!fOX/048). The center of the hind paw footprints left
on the white paper serves as marking medium. Right and left foot prints are connected with a line
and distance is measured. Measurements were made in triplicate.

Positional passivity
The data classification is based on rank order.
When an animal is placed in an awkward position (such as on the edge of the top of the wire
bottom cage) on the cm1 surface, does the animal immediately move into a more normal; position.
Normal ( 1)
Slight impaired (2)
Cataleptic (3)

Positive geotropism
The data classification is quantal.
The animal is placed in an inclined position (at an angle of -30°) on the top surface of the wire cage
with its head facing downward.
Animal turns 180° to face uphilL yes (Y)
Animal does not turn. no (N)

Grip strength
A pair of digital force gauges was used to measure the grip strength of fore and hind limbs (Grip
strength meter, UGO BASILE, Biological research apparatus, Comerio, Italy). The animal was
placed to the grip bar of the meter which permitted the animal to grasp it with its feet. The force
necessary to pull the animal off was measured .

Locomotor activity
Locomotor activity was performed in the activity cages (Activity cage, UGO BASILE, Biological
research apparatus, Comerio, Italy). Each animal was placed in a single cage connected to the
electronic unit. The animal was kept undisturbed in the cage for ten minutes and the activity (both
horizontal and vertical) was recorded automatically.

Auditory function
Auditory function was measured by means of a Responder-X startle meter, (Columbus
instruments, Columbus, Ohio, USA). The animal is placed in the load cell and acclimatised for 5
minutes. During acclimation, the noise amplitude was 65 decibels. During the experiment the
animal was treated with pulses of 90,105 and 120 decibels (10 repetitions). In response to the
startle the force exerted by the animal was measured by the load cell.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Animals were sacrificed by using C02. A detailed gross examination was conducted on all animals of the main and satellite groups on day 91 and 119, respectively. After external examination, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs
were recorded. All gross pathological changes were recorded individually for each animal.

HISTOPATHOLOGY: Yes
The following organs were preserved in 10% buffered formalin:
Spinal cord, brain, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small intestine, large intestine, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, ovary, uterus, accessory sex organs, female mammary gland, prostate, urinary bladder,
lymph nodes (one lymph node covering the route of administration and one distant from the administration route), peripheral nerve, bone marrow (histopathology) , skin, uterine cervix, vagina and male mammary gland.
Eyes and testes were preserved in Davidson fixative and modified Davidson fixative respectively.
The tissues were subjected to dehydration procedures and processed in a tissue processor. Tissues were embedded in paraffin, sectioned at 5 microns and stained with haematoxylin - eosin.

ORGAN WEIGHTS: Yes
Wet weights of various organs namely: liver, kidneys, adrenals, testes, epididymides, uterus, ovaries, thymus, spleen, brain, heart, prostate lobes (ventral and dorsal), coagulating glands with seminal vesicles and thyroid were recorded for all the animals.

Other examinations:

N/A

Statistics:

A detailed statistical analysis was conducted

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No morbidity/mortality was observed in any of the animals from the control or treatment groups.
None of the animals from any group showed any clinical signs of toxicity during the treatment or the post treatment period.

BODY WEIGHT AND WEIGHT GAIN
All animals were weighed on a weekly basis during treatment ( 13 weeks) and/or the post treatment (13-17weeks) period.
All males of the main dose groups (G2, G3 and G4) did not show statistically significant changes when compared to the vehicle control (G1).
The male satellite high dose group (G6) showed a statistically significant decrease from week 9 onwards up to week 13 when compared to the satellite vehicle control (G5). This effect was not observed in the main dose groups hence it was considered not to be treatment related.
Females of the intermediate dose group (G3) showed a statistically significant decrease in the last week (week 13) and females of the high dose group (G4) showed a statistically significant decrease during the last three weeks (1 0, 12 and 13) when compared to the vehicle control (G1 ). Since the body weight of intermediate group (G3) on week 13 was comparable with the untreated control groups (G7 and G8) on week 13, the effect was not considered to be adverse. Further, the effect observed in the high dose group (G4), was not noted in the satellite high dose group (G6). Hence this effect was not considered to be dose related.

FOOD CONSUMPTION
Food consumption was recorded cage wise daily and reported on a weekly basis. There were no statistically significant changes observed in any of the groups

OPHTHALMOSCOPIC EXAMINATION
None of the animals revealed ocular lesions in any of the groups.

HAEMATOLOGY
Day 1 (Pre-treatment)
In male. a statistically significant decrease was observed in eosinophil in groups G2 and G3 and an increase in basophils in group G3 when compared with the vehicle control (G1). The satellite high dose group (G6) showed a statistically significant increase in MCHC and a decrease in leucocytes when compared with the satellite vehicle control (G5). In females, a statistically significant decrease was observed in WBC of groups G2 and G4 and an increase in neutrophils in G4 when compared to the vehicle control (G1). Although the mean values were statistically significant, the values were well with in the normal range.

Day 91 (Termination of treatment)
In males, no statistical significant changes were observed in the main dose groups (G2, G3 and G4) when compared with the vehicle control (G1). A statistically significant decrease was observed in Hb, HCT, neutrophils and an increase in MCHC and lymphocytes of the satellite high dose group
(G6) when compared with the satellite vehicle control (G5).
Since this effect was not observed in the main dose groups it was considered not to be treatment related.
In females of the high dose group (G4), a statistically significant increase was observed in neutrophils and an increase was observed in lymphocytes when compared with the vehicle control (G1).
Since this effect was not observed in the satellite dose groups it was considered not to be treatment related.
Day 119 (Termination of post treatment) (G5 and G6 only)
There were no statistically significant changes observed in both satellite groups (G5 and G6).

CLINICAL CHEMISTRY
Day 1 (Pre-treatment)
In males, no statistical significant changes were observed in all dose groups.
In females, a statistically significant decrease was observed for triglycerides of groups, G2, G3 and G4 and an increase in ALT of groups G2 and G3 when compared with the vehicle control (G1). Although group mean values differed statistically, they were in the normal range for the species.
Similarly, a statistically significant decrease was observed in ALP and calcium in satellite high dose group G6 when compared with the satellite vehicle control (G5).
Although the mean values were statistically significant they are comparable with the control values (G7 & G8).

Day 91 (Termination of treatment)
In males, no statistically significant changes were observed in the main dose groups G2, G3 and G4 when compared to the vehicle control (G1). However, a statistically significant decrease was observed in total protein and sodium levels of the satellite high dose group (G6) when compared to
the satellite vehicle control (G5). A recovery was observed in the values of sodium. Although the mean values were statistically significant they were comparable with the untreated control group values (G7 & G8) and hence were not considered to the treatment related.
In females. a statistically significant increase was observed in urea. BUN in the main dose groups G2, G3 and G4 and a decrease in ALP in the high dose group (G4) when compared to the vehicle control (G1). Similarly, a statistically significant decrease was observed tor calcium in the satellite high dose group (G6) when compared to the satellite vehicle control (G5). Although the mean values were statistically significant they were comparable with the control values (G7 & G8) and hence was not considered to the treatment related.

Day 119 (Termination of post treatment) (G5 and G6 only)
In males, a statistically significant decrease was observed for urea, BUN, triglycerides, ALP, total protein and calcium of the satellite high dose group (06) when compared to the satellite vehicle control (G5).
Although group mean values differed statistically for parameters mentioned above, they were in the normal range for the species and were not dose related. Hence, these changes were considered to be not test substance related and have no toxicological importance.
In females, no statistical significant changes were observed in any of the parameters.

URINALYSIS
Urinalysis data did not show any changes in the composition ofurine in any of the treated groups except in females of the intermediate dose group (G3) on day 1. Since this effect was not observed in any of the treatment groups, it was not considered to be biologically adverse.

NEUROBEHAVIOUR
Day 0 (Pre-treatment)
In males, a statistically significant increase in the activity level (LAH and LAV) was observed in the satellite high dose group (G6) when compared to the vehicle satellite control (G5). A statistically significant increase in the auditory response for amplitude I (90db) was recorded in both intermediate
(G3) and high dose (G4) groups when compared to the vehicle control group (G1). Similarly, a statistically significant increase was observed for the auditory response at amplitude III (120 db) in the high dose satellite groups (G6) when compared to the satellite vehicle control (G5)
In females, statistically significant increase in foot splay, LAH and LAV was recorded for the satellite high dose group (G6) when compared to the satellite vehicle control (G5). A statistically significant increase in body temperature was recorded in the intermediate dose (G3) group when
compared to the vehicle control (G1).
Day 90 (Termination of treatment)
A statistically significant increase in the activity level (LAV) of high dose group males (G4) was recorded, and similarly in the intermediate and low dose group females G2 and G3) when compared to the vehicle control (G1). A statistically significant decrease in auditory response was recorded for
the satellite high dose group males (G6) at amplitude I (90decibels) and amplitude II (105 decibels) when compared to the satellite vehicle control (G5).
Although group mean values differed statistically for parameters mentioned above, the values were comparable to the control animals (G7 & G8). Hence, these changes were considered to be not test substance related and have no toxicological importance.
Day liS (Termination of post treatment, G5 and G6 only)
There were no statistically significant changes observed in any of the FOB parameters.

ORGAN WEIGHTS
In males, there were no statistically significant changes in both relative and absolute organ weights in any of the groups.
In females, a statistically significant increase was observed for relative organ weights of brain and adrenals in the high dose group (G4), and a statistically significant increase in absolute organ weights of adrenals and spleen in the high dose group (G4) when compared to the vehicle control (G1).
Since these effects were not observed in satellite groups and not correlated with microscopic findings, they were not considered to be treatment related.

GROSS PATHOLOGY
Recurrent lesions were observed in thymus (multifocal red spots), mandibular and cervical lymphnodes (enlarged and reddish) in all the groups including vehicle control and untreated control animals. There were no statistically significant differences between the groups.
All other macroscopic findings were either spontaneous or incidental and of the type routinely observed in Wistar rats of this age.
No test substance related gross pathological findings were observed.

HISTOPATHOLOGY
A statistically significant recurrence of pancreatic hemorrhage was observed in high dose group (G4) females. All microscopic findings were spontaneous, incidental and are usually observed in Wistar rats of this age.

Effect levels

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day (actual dose received)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

As no treatment related adverse effects were observed in a GLP study according to OECD test guideline 408, the NOAEL for repeated dose 90-days oral toxicity of the test substance, which is a close homologue of the registered substance, was determined to be 150 mg/kg bodyweight.

Executive summary:

The registered substance has been tested using the OECD 408 protocol. The study was performed under GLP.Ten male/female Wistar rats received either 15, 50 or 150 mg/kg bw or a control by gavage for 90 days. Clinical signs, food consumption, body weight, gross necropsy, opthalmoscopy, clinical chemistry, haematology, urinalysis and histopathology were recorded as required by OECD 408. Furthermore, a functional observation battery was included in the study. No treatment related adverse effects were observed up the highest applied dose. NOAEL of the test substance for repeated dose 90 -days oral toxicity was 150 mg/kg bodyweight.No treatment related adverse effects were observed up to the highest dose tested. The NOAEL of the test substance for repeated dose 90-days oral toxicity was 150 mg/kg bodyweight. The result for this close homologue substance was taken as a read across result for the registered substance.

Consequently, the registered substance has not to be labelled with regard to its subchronic toxicity.