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Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Feb 2017 - Mar 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018
Report Date:
2018

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Version / remarks:
adopted 21 Sep 1998
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Details on test material:
Batch identification: 0016134116
Content: 94.8% (study code 16L00508)
Stable until 10 Oct 2018 at ambient (room temperature)
Specific details on test material used for the study:
further information available within analytical report 16L00508

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
Crl:WI(Han)
Supplier: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany

The rat is a frequently used laboratory animal, and there is comprehensive experience with this animal species. Moreover, the rat has been proposed as a suitable animal species by the OECD and the EPA for this type of study.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age when supplied: 36 ± 1 days
- Age at the beginning of the administration period: 42 ± 1 days
- Fasting period before study: no
- Housing: The animals were housed together (5 animals per cage) in polysulfonate cages supplied by TECNIPLAST, Hohenpeißenberg, Germany (floor area about 2065 cm2). Dust-free wooden bedding was used in this study (the present supplier is documented in the raw data). Wooden gnawing blocks (Typ NGM E-022) supplied by Abedd® Lab. and Vet. Service GmbH, Vienna, Austria, and large play tunnels (Art. 14153) supplied by PLEXX B.V., Elst, The Netherlands, were added for environmental enrichment.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6d

DETAILS OF FOOD AND WATER QUALITY: The food used was ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland. The drinking water is regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and by the Environmental Analytics Water/Steam Monitoring Department of BASF SE as well as for the presence of microorganisms by a contract laboratory.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was applied as a solution. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, Corn oil was filled up to the desired volume and subsequently homogenized with a magnetic stirrer. The administration volume was 4 mL/kg body weight.

VEHICLE
- Justification for use and choice of vehicle (if other than water): commonly used vehicle
- Concentration in vehicle: up to 25%
- Amount of vehicle (if gavage): in total 4ml/kg bw were given (up to 25% TI content)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses of the test-substance preparations were carried out at the Competence Center Analytics of BASF SE, Ludwigshafen, Germany, as a part of this study. BASF project No. 17L00024
The 1H- and 13C-NMR-spectra show the expected signals for the givenchemical identity.
Purity: The purity of the test item is 94.8 corrected area % as a mixture of isononanoic acid C16-alkyl ester (46.6 corr. area %) and isononanoic acid C18-alkyl ester (48.2 corr. area %). The result is mean value of two injections of the
neat lest item, determined by gas chromatography and corrected with water content. Several isomers and side components were detected.
Structure identification: GC/MS confirmed the identity of the given chemical identity as mixture of
isononanoic acid C16-alkyl ester and isononanoic acid C18-alkyl ester. Furthermore, structures of several isomers and side components were clarified (see report BASF project No. 17L00024 for details)

Concentration control analyses
The concentration control analyses of all concentrations revealed that the values were in the expected range of the target concentrations, i.e. were always in a range of about 88-99% of the nominal concentrations. Taken together, the results demonstrate the correctness of the concentrations of Isononanoic acid, C16-18-alkyl esters
Duration of treatment / exposure:
90d
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
Testitem treated as such!
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
Testitem treated as such!
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Testitem treated as such!
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale based on 28d study RT 920239
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CLINICAL EXAMINATIONS
Mortality
A check for moribund and dead animals was made twice daily on working days and once daily on Saturdays, Sundays and public holidays. If animals were in a moribund state, they were sacrificed and necropsied.


Clinical observations
All animals were checked daily for any abnormal clinically signs before the administration as well as within 2 hours and within 5 hours after the administration. Abnormalities and changes were documented for each animal.


Detailed clinical observations
Detailed clinical observations (DCO) were performed in all animals prior to the administration period and thereafter at weekly intervals. The findings were ranked according to the degree of severity, if applicable. The animals were transferred to a standard arena (50 × 37.5 cm with sides of 25 cm high). The following parameters were examined:

1. Abnormal behavior when handled
2. Fur
3. Skin
4. Posture
5. Salivation
6. Respiration
7. Activity/arousal level
8. Tremors
9. Convulsions
10. Abnormal movements
11. Impairment of gait
12. Lacrimation
13. Palpebral closure
14. Exophthalmus
15. Feces (appearance/ consistency)
16. Urine
17. Pupil size


Food consumption
Food consumption was determined weekly and calculated as mean food consumption in grams per animal and day.


Water consumption
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume until study day 32. Since an increased water consumption was monitored, water consumption was determined once a week from study day 33 onwards.


Body weight data
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period, the body weight was determined on day 0 (start of the administration period) and thereafter at weekly intervals. The difference between the body weight on the respective day of weighing and the body weight on day 0 was calculated as body weight change.


Functional observational battery
A functional observational battery (FOB) was performed in all animals at the end of the administration period starting at about 10:00 h. At least one hour before the start of the FOB the rats were transferred to single-animal polycarbonate cages type III supplied by TECNIPLAST, Hohenpeißenberg, Germany, with wire covers from Ehret, Emmendingen, Germany (floor area of about 800 cm2) and small amounts of bedding material. Drinking water was provided ad libitum, but no food was offered during the measurements. The FOB started with passive observations without disturbing the rats, followed by removal from the home cage, open field observations in a standard arena and sensory motor tests as well as reflex tests. The findings were ranked according to the degree of severity, if applicable. The observations were performed at random. A detailed description of the methods, the ranking and documentation system can be found in PART III (Supplement).
Home cage observations:
The animals were observed in their closed home cages; during this period, any disturbing activities (touching the cage or rack, noise) were avoided during these examinations in order not to influence the behavior of the rats. Attention was paid to:

1. Posture
2. Tremors
3. Convulsions
4. Abnormal movements
5. Gait
6. Other findings


Open field observations:
The animals were transferred to a standard arena (50 × 50 cm with sides of 25 cm height) and observed for at least 2 minutes. The following parameters were examined:

1. Behavior on removal from the cage
2. Fur
3. Skin
4. Salivation
5. Nasal discharge
6. Lacrimation
7. Eyes/ pupil size
8. Posture
9. Palpebral closure
10. Respiration
11. Tremors
12. Convulsions
13. Abnormal movements/ stereotypes
14. Gait
15. Activity/ arousal level
16. Feces excreted within 2 minutes (appearance/ consistency)
17. Urine excreted within 2 minutes (amount/ color)
18. Rearing within 2 minutes
19. Other findings


Sensory motor tests/ reflexes:
The animals were then removed from the open field and subjected to following sensory motor or reflex tests:

1. Reaction to an object being moved towards the face (approach response)
2. Touch sensitivity (touch response)
3. Vision (visual placing response)
4. Pupillary reflex
5. Pinna reflex
6. Audition (auditory startle response)
7. Coordination of movements (righting response)
8. Behavior during handling
9. Vocalization
10. Pain perception (tail pinch)
11. Grip strength of forelimbs
12. Grip strength of hindlimbs
13. Landing foot-splay test
14. Other findings


Motor activity assessment
Motor activity (MA) was also measured from 14:00 h onwards on the same day as the FOB was performed. The examinations were performed using the TSE Labmaster System supplied by TSE Systems GmbH, Bad Homburg, Germany. For this purpose, the rats were placed in new clean polycarbonate cages. For motor activity (MA) measurements, the animals were housed individually in polycarbonate cages type III supplied by TECNIPLAST, Hohenpeißenberg, Germany, with wire covers from Ehret, Emmendingen, Germany (floor area of about 800 cm2) with a small amount of bedding for the duration of the measurement. Eighteen beams were allocated per cage. The number of beam interrupts was counted over 12 intervals for 5 minutes per interval. The sequence in which the rats were placed in the cages was selected at random. On account of the time needed to place the rats in the cages, the starting time was "staggered" for each animal. The measurement period began when the 1st beam was interrupted and finished exactly 1 hour later. No food or water was offered to the rats during these measurements and the measurement room was darkened after the transfer of the last rat. The program requires a file name for the measured data to be stored. This name consists of the reference number and a serial number.


Ophthalmoscopy
Prior to the start of the administration period on day -1 the eyes of all animals and on study day 89 the eyes of the control and high-dose animals were examined for any changes using an ophthalmoscope (HEINE OPTOTECHNIK, Herrsching, Germany) after administration of a mydriatic agent (Mydrum, Bausch & Lomb GmbH, Heidelberg, Germany).


Estrous cycle determination
Estrous cycle length and normality were evaluated daily for all female animals for a minimum of 3 weeks prior to necropsy.


Statistics of clinical examinations
Means and standard deviations of each test group were calculated for several parameters
1. Body weight, body weight change
2. Rearing, grip strength forelimbs, grip strength hindlimbs, foot-splay test, motor activity, estrous cycle

CLINICAL PATHOLOGY
In the morning blood was taken from the retro-bulbar venous plexus from fasted animals. The animals were anaesthetized using isoflurane. The blood sampling procedure and subsequent analysis of blood and serum samples were carried out in a randomized sequence. For urinalysis, the individual animals were transferred to metabolism cages (withdrawal of food and water) and urine was collected overnight. Urine samples were evaluated in a randomized sequence.

Hematology
The following parameters were determined in blood with EDTA K3 as anticoagulant

1 Leukocyte count
(WBC)
2 Erythrocyte count
(RBC)
3 Hemoglobin
(HGB)
4 Hematocrit
(HCT)
5 Mean corpuscular volume
(MCV)
6 Mean corpuscular hemoglobin
(MCH)
7 Mean corpuscular hemoglobin concentration
(MCHC)
8 Platelet count
(PLT)
9 Differential blood count
10 Reticulocytes (RET)


Clotting tests were carried out using a ball coagulometer
1 Prothrombin time (Hepato Quick’s test)
(HQT)

Clinical chemistry

Enzyme (systematic name and system number) parameters
1 Alanine aminotransferase
(ALT)
2 Aspartate aminotransferase
(AST)
3 Alkaline phosphatase
(ALP)
4 g-Glutamyltransferase
(GGT)

Blood Chemistry Parameter
1 Sodium
(NA)
2 Potassium
(K)
3 Chloride
(CL)
4 Inorganic phosphate
(INP)
5 Calcium
(CA)
6 Urea
(UREA)
7 Creatinine
(CREA)
8 Glucose
(GLUC)
9 Total bilirubin
(TBIL)
10 Total protein
(TPROT)
11 Albumin
(ALB)
12 Globulins
(GLOB)
13 Triglycerides
(TRIG)
14 Cholesterol
(CHOL)


Urinalysis

1 pH
2 Protein (PRO)
3 Glucose (GLU)
4 Ketones (KET)
5 Urobilinogen (UBG)
6 Bilirubin (BIL)
7 Blood
8 Specific gravity (SP.GR.) [g/L]
9 Sediment
10 Color, turbidity (COL, TURB)
11 Volume (VOL) [mL]

Sperm parameters

1 Sperm motility
2 Sperm morphology
3 Sperm head count (cauda epididymis)
4 Sperm head count (testis)
Sacrifice and pathology:
PATHOLOGY

Necropsy
The animals were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology.

Organ weights
The following weights were determined in all animals sacrificed on schedule:

1. Anesthetized animals
2. Adrenal glands
3. Brain
4. Cauda epididymis
5. Epididymides
6. Heart
7. Kidneys
8. Liver
9. Ovaries
10. Pituitary gland
11. Prostate
12. Seminal vesicles with coagulation glands
13. Spleen
14. Testes
15. Thymus
16. Thyroid glands
17. Uterus with cervix


Organ/tissue fixation
The following organs or tissues were fixed in 4% neutral-buffered formaldehyde solution or in modified Davidson’s solution:

1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain
6. Cecum
7. Cervix
8. Coagulating glands
9. Colon
10. Duodenum
11. Epididymides, left (modified Davidson’s solution)
12. Esophagus
13. Extraorbital lacrimal glands
14. Eyes with optic nerve (modified Davidson’s solution)
15. Femur with knee joint
16. Harderian glands
17. Heart
18. Ileum
19. Jejunum (with Peyer’s patches)
20. Kidneys
21. Larynx
22. Liver
23. Lungs
24. Lymph nodes (mesenteric and axillary lymph nodes)
25. Mammary gland (male and female)
26. Nose (nasal cavity)
27. Ovaries
28. Oviducts
29. Pancreas
30. Parathyroid glands
31. Pharynx
32. Pituitary gland
33. Prostate
34. Rectum
35. Salivary glands (mandibular and sublingual glands)
36. Sciatic nerve
37. Seminal vesicles
38. Skeletal muscle
39. Skin
40. Spinal cord (cervical, thoracic and lumbar cord)
41. Spleen
42. Sternum with marrow
43. Stomach (forestomach and glandular stomach)
44. Testis, left (modified Davidson’s solution)
45. Thymus
46. Thyroid glands
47. Trachea
48. Urinary bladder
49. Uterus
50. Vagina

The eyes of the animal sacrificed intercurrently were fixed in 4% neutral-buffered formaldehyde solution.

The left testis and left epididymis of all animals sacrificed at scheduled dates were fixed in modified Davidson’s solution, whereas the right testis and epididymis was used for sperm parameters
Other examinations:
Histopathology
Fixation was followed by histotechnical processing, examination by light microscopy

For highest and control dose the following organs were examined:

Organs

1. All gross lesions
2. Adrenal glands
3. Aorta
4. Bone marrow (femur)
5. Brain
6. Cecum
7. Cervix
8. Coagulating glands
9. Colon
10. Duodenum
11. Epididymis, left
12. Esophagus
13. Eyes with optic nerve
14. Female mammary gland
15. Heart
16. Ileum
17. Jejunum
18. Kidneys
19. Liver
20. Lung
21. Lymph nodes
(mesenteric and axillary lymph nodes)
22. Ovaries
23. Pancreas
24. Parathyroid glands
25. Peyer’s patches
26. Pituitary gland
27. Prostate
28. Rectum
29. Salivary glands
(mandibular and sublingual glands)
30. Sciatic nerve
31. Seminal vesicles
32. Skin
33. Spinal cord
(cervical, thoracic and lumbar cord)
34. Spleen
35. Stomach (forestomach and glandular stomach)
36. Testis, left
37. Thymus
38. Thyroid glands
39. Trachea
40. Urinary bladder
41. Uterus
42. Vagina
Statistics:
see below, different statistical test are used depending on the parameter

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Female animal No. 70 of test group 2 (300 mg/kg bw/d) showed a palpable mass through skin (<1.5 cm) on the right shoulder region from study day 23 to study 28. From study day 28 onwards the site was encrusted and from study day 36 onwards ulcerated. Additionally, piloerection and pale skin was observed from day 41 onwards, followed by automutilation from day 42 to day 45. The animal had to be sacrificed in a moribund condition.

Salivation after treatment was observed in 3 female animals, i.e. Nos. 21, 23 and 30, of test group 2 (300 mg/kg bw/d) on study day 27 only.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Female animal No. 70 of test group 2 (300 mg/kg bw/d) was sacrificed moribund on study day 45.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related, adverse changes with regard to food consumption were observed.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No treatment-related findings were observed.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
After the administration period, in females of test groups 2 and 3 (300 and 1000 mg/kg bw/d) prothrombin time (i.e., Hepatoquick’s test [HQT]) was significantly prolonged which was regarded as treatment-related and adverse.

Additionally, in females of test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d) mean corpuscular volume (MCV) was significantly decreased, without any changes of measured red blood cell parameters (i.e., red blood cell [RBC] counts, hemoglobin and hematocrit). MCV means in the mentioned test groups were within, whereas the mean of the controls was above the historical control range (females, MCV 50.3-53.0 fL). Therefore, this alteration was regarded as incidental and not treatment-related.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the administration period, in females of test group 3 (1000 mg/kg bw/d) total protein and albumin were significantly decreased. The globulin median among these individuals was decreased in the same amount as the albumins (-6%) compared to controls, although it was not statistically significantly changed. Additionally, in females of test groups 2 and 3 (300 and 1000 mg/kg bw/d) urea and inorganic phosphate levels were significantly increased, whereas calcium levels were significantly decreased. The urea increase was regarded as adverse although the means and medians were not strictly changed dose-dependently, but the means were above the historical control range (females, urea 5.31-7.04 mmol/L).
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
At the end of the administration period in males of test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d) significant higher levels of blood in the urine, increased transitional epithelial cell counts and increased incidences of granular and epithelial cast in the urine sediment were found. The occurrence of transitional epithelial cells and casts in the urine sediment of males was correlated with the histopathological finding of an alpha-2u-globulinuria which is acknowledged as a species-specific effect in male rats of this age group and not of any relevance for humans
The detection of marginal hemoglobin levels in the urine of only the male sex was not strictly dose-dependent as the occurrence of transitional epithelial cells, casts and the histopathologic grading of the nephropathy in these individuals. The hemoglobin concentration was marginal. The hemoglobin derived most likely from eroded capillaries releasing blood cells into the urine, because in males of the respective test groups also erythrocyte and leukocyte counts in the urine sediment were increased. The hypothesis that this blood content in the urine was related to alpha-2u-globulinuria and not caused by an additional compound effect was supported by no corresponding changes in the urine of females of test groups 1, 2 and 3.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Functional observational battery
Deviations from "zero values" were obtained in several rats. However, as most findings were equally distributed between test-substance treated groups and controls, were without a dose-response relationship or occurred in single rats only, these observations were considered to have been incidental.

Motor activity measurement
Regarding the overall motor activity as well as single intervals, no test substance-related deviations to the control animals were noted for male and female animals of test groups 1-3 (100, 300 and 1000 mg/kg bw/d).
In female animals of test group 1 (100 mg/kg bw/d) interval No. 9 showed a significantly lower value. It was the only changed interval and the overall activity was not influenced. In addition, no dose-response relationship occurred. Thus, a relation to treatment was excluded.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
The significant absolute and relative weight increase of the kidneys in males and the liver in females of test groups 2 and 3 were judged as treatment-related and were consistent with histopathological findings. The significant absolute weight increases of the thyroid glands in males of test groups 1 and 2 (24.0 and 24.3 mg, respectively) were within the historical control range values (18.4 – 28.8 mg) and showed no relevant histopathological findings when compared to the control group. Therefore, the significant weight deviations of the male thyroid glands were regarded as incidental. The significant absolute and relative weight changes of the liver in males of test groups 2 (absolute: 9.665 g; relative: 2.448%) and 3 (absolute: 9.377 g ; relative: 2.469%) were of weak statistical significance. However, they were above the historical control range values (absolute: 6.835 – 9.261 g; relative: 2.045 – 2.39%). Since minimal histopathological findings were noted, these weight deviations were assumed to be possible treatment-related but not adverse.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
A light brown discoloration of the liver was observed only in females of test groups 2 and 3 (3 out of 10, and 6 out of 10, respectively). This finding correlated with a fatty change and was regarded as treatment-related.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Regarding pathology, target organs were the kidneys and the liver of male and female animals.
The kidneys of all males in test groups 1, 2 and 3 (100, 300 and 1000 mg/kg bw/d) showed an alpha2u-nephropathy, characterized by eosinophilic droplets accumulation associated with granular casts (representing exfoliated tubular cells with eosinophilic droplets) and basophilic tubules (representing an attempt to regenerate the injured tubules). This nephropathy was low in test group 1 (100 mg/kg bw/d), and increased in test groups 2 and 3 (300 and 1000 mg/kg bw/d) without showing a dose-dependency between both groups. The significantly increased absolute and relative weights of the kidneys in males of test groups 2 and 3 was attributed to the chronic nephropathy. Alpha2u-globulin is a male and rat specific poor soluble protein synthesized in the male rat liver, filtered by the glomerulus and reabsorbed in the S2 segment of the proximal convoluted tubules where it is slowly hydrolysed. Strong accumulation of this protein can be visible in form of eosinophilic droplets. Although α2u-globulin nephropathy was considered to be treatment-related and adverse, due to the tissue damage, this finding does not represent a risk for humans since they do not synthesize this protein (Durham and Swenberg, 2013). The kidneys of females of test groups 2 and 3 (300 and 1000 mg/kg bw/d) showed a dose-dependent cortical tubular vacuolation consistent with a fatty change. Although no tissue injury was noted, clinical chemistry parameters revealed functional alterations. Therefore, this finding was assumed to represent an adverse effect. A minimal increased incidence of medullar mineralization in test group 3, was judged to be possible treatment-related but not adverse.
The liver of males of test groups 2 and 3 (300 and 1000 mg/kg bw/d) showed a periportal fatty change, which was minimally increased in comparison with the control group and was therefore regarded as possibly treatment-related but not adverse. The liver of females, all test groups showed a treatment-related dose-dependent periportal fatty change. Although no tissue injury was noted, clinical chemistry parameters revealed functional alterations in the mid- and high-dose group. Therefore, the fatty change in females of test groups 2 and 3 was judged as treatment-related and adverse, whereas in test group 1 it was regarded as treatment-related but not adverse.
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Sperm parameters
Concerning motility of the sperms and the incidence of abnormal sperms in the cauda epididymidis as well as sperm head counts in the testis and in the cauda epididymidis, no treatment-related effects were observed.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical biochemistry
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: effects on kidney in all dose groups but considered to be related to Alpha2u-globulin problematic in male rats, therefore judged as test organism specific

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 mg/kg bw/day (actual dose received)
System:
other: hepatobiliary, urinary
Organ:
kidney
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study the oral administration Isononanoic acid, C16-18-alkyl esters by gavage to Wistar rats over a period of 3 months revealed a no observed adverse effect level (NOAEL) for general systemic toxicity of 1000 mg/kg bw/d in male and of 100 mg/kg bw/d in female Wistar rats.