[(±)-(4-amino-2-hydroxy-4-oxobutyl)trimethylammonium] chloride

Endpoint summary

Description of key information

Key study: OECD guideline. GLP study.
A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rat study was conducted according to OECD guideline 422. Under the conditions of this study, the no observed adverse effect level (NOAEL) for the test substance for parental/adult and F1 effects is considered to be 1000 mg/kg bw/day

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

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 3 January 2013 to 30 April 2013

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline. GLP study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633
- Age at study initiation: Young adult rats, approximately 11 weeks old at starting and 13 weeks at mating. The age range within the study was kept to the minimum.
- Weight at study initiation: Males: 366 g – 421 g, Females: 214 g - 247 g; did not exceed ± 20% of the mean weight for each sex at onset of treatment.
- Housing: Rodents were group-housed, up to 4 animals of the same sex and dose group/cage, with the exception of the mating and gestation/delivery period, when they were paired or individually housed, respectively. Group housing allowed social interaction and the deep wood sawdust bedding allowed digging and other normal rodent activities (i.e. nesting).
- Diet (e.g. ad libitum): Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and Maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany, ad libitum.
- Water (e.g. ad libitum): tap water from municipal supply, ad libitum.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.0 – 24.0°C
- Humidity (%): 32 - 58%
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 3 January 2013 To: 18 February 2013

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was formulated in Distilled water at 15.6, 62.5 and 250 mg/mL. Formulations were prepared weekly intervals, based on the stability test performed at the Test Site. Analysis of test item formulation samples of 15.6 mg/mL, 62.5 mg/mL and 250 mg/mL showed no decrease of concentration within 15 days and can be considered as stable for at least 15 days stored in room temperature.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples were taken from test item formulations and from the control on 3 occasions, during the first and last weeks and approximately midway during the treatment, one set to analyze and one set as a back-up, if required for any confirmatory analyses.

The measured concentrations of the test item evaluated for each test item-dose group varied between 97.9 and 101.5%. No test item was detected in the control samples. These results were within acceptable ranges (90 % - 110%).

Duration of treatment / exposure:

Males were dosed for 28 days (14 days pre-mating and 14 days mating/post-mating period).

Females were dosed for 14 days pre-mating, for up to 5 days mating period, through gestation and up to the day of necropsy (at least 4 days post-partum dosing).

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0, 62.5, 250 and 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

12 animals/sex/group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose levels and the vehicle were selected based on available data, formulation and analytical trials and information from previous experimental work, including the results of a repeated dose range finding study in the rat (the test item administered by oral gavage to Wistar rats for 7 consecutive days at dose levels of 62.5, 250 and 1000 mg/kg bw in distilled water at a dose volume of 4 mL/kg bw, was not associated with any overt adverse effects that could be clearly related to test item administration).

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were inspected for signs of morbidity and mortality twice daily, at the beginning and the end of the working day. General clinical observations were performed daily, after treatment at approximately the same time with minor variations, or in the afternoon (pm) as practical during the working day, as no peak period of effects was noted after dosing during the first days of treatment.

All animals were monitored for pertinent behavioural changes, signs of difficult or prolonged parturition and all signs of toxicity including mortality. Any changes were recorded including onset, degree and duration of signs as applicable.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: More detailed examinations were made once before the first exposure (to allow for within-subject comparisons), then at least weekly, in the morning (am) or before treatment. These observations were made outside the home cage in a standard arena, at similar times as practical. The animals were monitored for changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern), or changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (e.g. excessive grooming, repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. self-mutilation, walking backwards); special attention were directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. No such clinical signs were observed during the study.

BODY WEIGHT: Yes
- Time schedule for examinations: All adult animals were weighed with accuracy of 1 g for randomization purposes, then on Day 0, afterwards at least weekly and at termination. Parent females were weighed on gestation Days GD 0, 7, 14 and 20 and on postpartal Days PPD0 (within 24 hours after parturition), PPD4 and PPD5 (before termination). Body weights of the female animals were additionally weighed on gestational Days GD10 and 17 in order to give accurate treatment volumes, but these data were not evaluated statistically.

FOOD CONSUMPTION :
Animal food consumption was determined by re-weighing the non-consumed diet with a precision of 1 g on Day 7 then at least weekly.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The fundus of eyes of all animals was examined before treatment. Five male and 5 female Control and High dose animals (“subgroup A”) randomly selected from groups 1 and 4, during the last week of treatment prior to necropsy (males, Day 26 pm, females, PPD 3 pm). Mydriasis was produced after instillation of a mydriatic agent (eye drops "Humapent") into the conjunctival sac. The examination was performed using a Gowlland ophthalmoscope. As no ophthalmoscopic alterations were found, no additional examination was performed in other animals.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: For terminal blood sampling of animals selected (subgroup B).
- Anaesthetic used for blood collection: Yes. Blood samples were collected by cardiac puncture under pentobarbital anaesthesia, immediately prior to scheduled necropsy.
- Animals fasted: Yes
- How many animals: 5 males and 5 females/group, “subgroup B”:
- Parameters checked: Red Blood Cell (erythrocyte) count, White Blood Cell (leukocyte) count, Haemoglobin concentration, Haematocrit (relative volume of erythrocytes), Mean Corpuscular (erythrocyte) Volume, Mean Corpuscular (erythrocyte) Haemoglobin, Mean Corpuscular (erythrocyte) Haemoglobin Concentration, Red Cell (erythrocyte) volume, Platelet (thrombocyte) count, Mean Platelet Thrombocyte volume, Reticulocyte count, Neutrophil, Lymphocyte, Monocyte, Basophil, Eosinophil, Large Unstained Cells, Activated Partial Thromboplastin Time, Prothrombin Time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: For terminal blood sampling of animals selected (subgroup B).
- Anaesthetic used for blood collection: Yes. Blood samples were collected by cardiac puncture under pentobarbital anaesthesia, immediately prior to scheduled necropsy.
- Animals fasted: Yes
- How many animals: 5 males and 5 females/group, “subgroup B”:
- Parameters checked: Blood sugar concentration, Total Bilirubin concentration, Urea concentration, Cholesterol concentration, Creatinine concentration, Phosphorus concentration, Sodium concentration, Potassium concentration, Calcium concentration, Chloride concentration, Total Protein concentration, Albumin concentration, Alb/glob ration, Aspartate Aminotransferase activity, Alanine Aminotransferase activity, Alkaline. Phosphatase – activity, Gamma Glutamyltransferase –activity, Bile acids.

URINALYSIS: Yes
- Time schedule for collection of urine: Urine sampling (approximately 18 – 19 hours sampling period) was performed prior to necropsy (males on Day 28; females on PND 5).
- Parameters checked: Leukocyte, nitrite, pH, protein, glucose, urobilinogen, bilirubin, ketones, Blood/Erythrocytes, Specific gravity, sediment, volume, appearance.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Dose groups that were examined: 5 males and 5 females/group, “subgroup A”: Assessment of any potential test item related neurotoxicity was performed during the last exposure week (males on Day 26 am; females on PPD 3 am). In order to avoid hyperthermia of pups, dams were removed from the pups for not more than approximately 30-40 minutes.
- Battery of functions tested: Selected animals were subjected to the functional observation battery, including qualitative assessment of the grip strength, and to measurements of the landing foot splay and fore/hind grip strength.

To measure the landing foot splay, the fore/hind paws of the rat were painted with ink and the rats were dropped from a horizontal position onto the appropriate record sheet covering the examination table. The distance between the two resulting ink spots was measured.

Fore/hind grip strength measurements were conducted using a grip strength meter , an instrument designed to quantify objectively rodent muscular strength, in order to identify and assess quantitatively any potential effect of test item. The rats were held appropriately such that the fore limbs were allowed to grip the support bar and gently pulled back until they released the bar; the device measured the maximum grip strength. This was performed 3 times for each animal on each test day. The procedure was repeated with the hind limbs with the appropriate grip support; results are tabulated with individual and mean data.

Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity were conducted and the general physical condition and behaviour of animals were tested. A modified Irwin test was performed. Parameters such as, but not limited to body position, locomotor activity, respiration rate, respiration type, piloerection, head searching compulsive biting or licking, circling, upright walking, retropulsion, jumping, exophthalmos, twitches, clonic convulsions, tonic convulsions, tremor, startle, transfer arousal, spatial locomotion, gait, posture, limb position, finger approach, finger withdrawal, touch escape response, diarrhoea, diuresis, visual placing, grip strength, body tone, corneal reflex, pinna, toe pinch, grasping reflex, positional struggle, skin, mucous membrane colour, salivation, palpebral closure, lachrymation, limb tone, abdominal tone, tail pinch, righting reflex, and/or vocalisation were evaluated.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
Gross necropsy was performed on all animals. Terminally, after completion of the treatment, animals were euthanised under pentobarbital anaesthesia, followed by exsanguination. After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed macroscopically. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate. Special attention was paid to the organs of the reproductive system. The number of implantation sites and of corpora lutea was recorded in the females as applicable.

HISTOPATHOLOGY: Yes
For the adult animals, detailed histological examination was performed on the selected list of retained organs in the Control and High dose groups and all macroscopic findings (abnormalities) from all animals. The weighed organs and all organs showing macroscopic lesions of all adult animals were preserved. The eyes with the optic nerve were retained in modified Davidson’s fixative. Testes and epididymides were preserved in Bouin’s solution, all other organs in 10% buffered formalin solution. In addition, for 5 animals/sex/group (subgroup B), the following organs and tissues, or representative samples, were preserved: Gross findings, adrenals, aorta, brain, epididymides, eyes with optic nerves, oesophagus, femur with marrow, heart, kidneys, large intestine, lacrimal glands, harderian glands, liver, lungs with bronchi, lymph nodes, mammary gland (inguinal), ovaries with oviduct, pancreas, pituitary, prostate, salivary gland (mandibular), sciatic nerve, seminal vesicles, coagulating glands, skeletal muscle (quadriceps), skin and subcutis (inguinal), small intestine, spinal cord (cervical, lumbar, and thoracic levels), spleen, sternum with marrow, stomach, testes, thymus, thyroid with parathyroids, tongue, trachea (with main stem bronchi), urinary bladder, uterus, vagina.

Special attention was paid to evaluation of the stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. Detailed histological examination of the ovaries covered the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.

Other examinations:

ORGAN WEIGHTS:
At the time of termination, body weight and weight of the following organs of all parental animals were determined:

- With a precision of 0.01 g: uterus (with and without cervix), vagina, testes, epididymides, prostate, seminal vesicles with coagulating glands, brain
- With a precision of 0.001 g: ovaries, pituitary

From subgroup B animals, the following organs were weighed in addition to the ones previously mentioned:

- With a precision of 0.01 g: heart, kidneys, liver, spleen and thymus.
- With a precision of 0.001 g: adrenals.

For all organs, paired organs were weighed individually. Individual and/or paired absolute organ weight are reported for each animal and adjusted for the body and brain weights. Paired organ weights as applicable were summarised. Relative organ weight (to body and brain weight) were calculated and reported.

Statistics:

The statistical evaluation of appropriate data was performed with the statistical program package SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant, Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed as feasible.

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:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
There was no mortality during the study. No test item-related adverse effects or systemic clinical signs were noted following administration of daily by oral gavage under the conditions of this study, or in the animals. In one female animal in the Control group thin fur on both forelimbs, left axillary, lumbar area or on the thorax ventral area was observed from Day 25. In a Low dose female thin fur on both forelimbs or on the thorax ventral area was observed from Day 30. In one female animal in the Low dose group, slight decreased activity, hunched back position, piloerection, slight opacity in both eyes and dark brownish discharge (moderate) in urogenital area was observed from Day 33.

BODY WEIGHT AND WEIGHT GAIN
No test item related effects were noted on the mean body weight and body weight gain values following daily administration of the test item at dose levels up to and including 1000 mg/kg bw/day, during the treatment period. A higher increase in body weight gain was recorded for treated males between Days 21 and 27 (p<0.05 or 0.01) compared to the control animals. However, the overall body weight gain values (Days 0-27) were comparable to the control.

FOOD CONSUMPTION
There were no test item-related differences in the mean daily food consumption in any test-item treated group (62.5, 250 or 1000 mg/kg bw/day) when compared to the Control. Compared to control, differences attaining statistical significance were noted for males at 250 mg/kg bw/day (Mid dose) and 1000 mg/kg bw/day (High dose) between Days 21 and 28 (p<0.05 and 0.01, respectively). The individual values remained within the normal ranges and the finding was not considered toxicologically significant or to reflect an adverse effect.

OPHTHALMOSCOPIC EXAMINATION
No test item related changes compared to pre-treatment were noted during ophthalmoscopy examination of 5 male and 5 female Control and High dose animals during the last week of treatment prior to necropsy (males, Day 26 pm, females, PPD 3 pm), thus no additional evaluation was required in other dose groups .

HAEMATOLOGY
When compared to the controls, there were no differences that were considered toxicologically significant in the treated animals. Variations were noted in a few parameters in the female animals, on occasion attaining statistical significance, including for example statistically higher mean Red Blood Cell (erythrocyte) count (RBC) in the Low dose (p<0.05), lower than control Mean Platelet Thrombocyte volume (MPV) in the High dose (p<0.01) and lower Eosinophil ratio (EOS%) in the Mid and High dose groups (p<0.05). Evaluation of the mean and individual results in comparison with the control data did not reveal any test-item related cause of the changes noted, and/or no consistent dose or gender-related response was observed. Therefore, these differences observed between the Control and treated groups were considered to be incidental or individual findings, which were not related to treatment, were generally comparable with the expected physiological range and of no toxicological significance.

CLINICAL CHEMISTRY
In the animals evaluated at the completion at termination (on Day 28 in males and on PPD5 in females), there were no toxicologically significant changes or adverse effects on the animal serum chemistry that could be ascribed to the test item administration in the conditions of this study. A few clinical chemistry parameters showed on occasion statistically significant variations, i.e. slightly lower than control sodium concentration (Na+) (p<0.05) in high dose males or higher than control glucose concentration (Glucose) (p<0.05) in Mid and High dose females. However, there was no dose or gender response or the values were within the physiological ranges. For this reason, these variations were not considered toxicologically significant or related to treatment.

URINALYSIS
Test item administration daily by oral gavage at up to and including 1000 mg/kg bw/day did not result in any test item-related effects considered adverse at urinalysis performed prior to necropsy in the animals. The urine volume showed minor variations, without statistically significant in the animals, however, with no dose or gender-dependent, and not considered to be of toxicological importance in correlation with test item administration in the conditions of this study. The few other minor variations observed did not attain statistical significance and/or were regarded as normal background changes.

NEUROBEHAVIOUR
There were no toxicologically significant changes in the animal behaviour, general physical condition, in the reactions to different type of stimuli, grip strength or motor activity in the control or treated groups, at the evaluation performed towards the end of the treatment period.

Increased vocalization was observed on occasion in the animals (2/5, 2/5, 1/5 and 1/5 in males and 0/5, 2/5, 2/5 and 2/5 in females, Control/Low dose/Mid dose/High dose, respectively), slightly increased startle (one male in Control group and in the Low dose) and slightly decreased righting reflex (one male in the Low dose group) when subjected to the modified Irwin test (functional observation battery). However, no treatment-related differences to the Control, or dose, or gender related response, were noted, and this sign was considered to be without toxicological significance and within the normal biological variation with respect to behaviour, reactions to different type of stimuli or manipulations.

No toxicologically significant changes, or effects considered adverse or related to test item administration were noted in the landing foot splay or grip strength tests. When compared to Control, there were no statistically or toxicologically significant differences in the mean grip strength (g) or landing foot splay (cm) values of the forelimbs or hind limbs.

ORGAN WEIGHTS
There were no toxicologically significant effects on organ weights. Compared to controls, slightly lower weights of pituitary glands were recorded for males at 250 mg/kg bw/day (Mid dose). The difference was approximately 15% and attained statistical significance (p<0.05) for absolute values, body weight and brain weight related mean values. The changes were not associated with any findings in clinical pathology or microscopic changes and were regarded as physiological variation.

GROSS PATHOLOGY
There was no evidence of the test item-related macroscopic findings at dose levels of 62.5, 250 and 1000 mg/kg bw/day. Incidental or common background observations including small testes and epidydimides, single cyst of the vagina, uterine dilation, enlargement of the spleen, raised red area of the glandular mucosa in the stomach and thin fur at the dorsal thoracic/lumbar/forelimbs regions were recorded at necropsy. All these changes were observed without notable incidence and/or cross control or treated animals and were not toxicologically meaningful.

HISTOPATHOLOGY: NON-NEOPLASTIC
No test item-related microscopic effects were observed at dose levels of 62.5, 250 and 1000 mg/kg bw/day. Microscopic evaluation of the brains or pituitaries, male gonads as well as testicular interstitial cell structure, the spermatogenic cells representing different phases of the development and differentiation of the spermatozoa were similar in Control and High Dose males. The follicular, luteal and interstitial compartments of the ovary as well as epithelial capsule and stroma were similar histological structure in both Control and High Dose females. Minimal to moderate tubular degeneration/atrophy and/or minimal to mild reduced sperm content in the epidydimides in 3/12 Control males, mild tubular dilatation of the left testis in 1/12 Low dose male, mild acinar cell debris in 1/12 Control male or cell mixed mononuclear infiltrate/inflammation of the prostate in 2/12 High Dose males, were regarded as incidental. All other changes were incidental or a common background.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Conclusions:

Under the conditions of this study, the no observed adverse effect level (NOAEL) for the test item is considered to be 1000 mg/kg bw/day.

Executive summary:

A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rat study was conducted according to OECD guideline 422. Male and female Wistar rats were treated for 2 weeks pre-mating, then during the mating/postmating period, males for 28 days and females throughout gestation period and up to and including postpartum/lactation Day PPD5, at the following dose levels: 0, 62.5, 250 and 1000 mg/kg bw/day. The measured concentration of the test item evaluated for each test item-dose group varied between 97.9 and 101.5%. No test item was detected in the control samples. These results were within acceptable ranges (90 - 110 %). Parameters measured during the study included signs of morbidity and mortality twice daily, daily or detailed weekly observation of clinical signs, neurological and ophthalmoscopic assessment, weekly body weight and food consumption, and clinical pathology evaluation, including haematology, coagulation, clinical chemistry and urinalysis. In addition, the reproductive performance and indices, pregnancy, parturition and postpartum/lactation period were monitored in the adult animals, and viability, clinical signs and development were evaluated in their F1 offspring until PND4. Pups were examined at euthanasia. At termination of the adults, necropsy with macroscopic examination was performed; weights of selected organs were recorded and representative tissues/organs were sampled and preserved in appropriate fixatives. For the adult animals, detailed histological examination was performed on the selected list of retained organs in the Control and High dose groups. Daily administration of the test item by oral gavage to Wistar rats did not result in test item related mortality or clinical adverse effects at daily, weekly or neurological assessment, in ophthalmological changes, or changes in the body weight, food consumption, haematology, coagulation, clinical chemistry, or urinalysis parameters at dose levels of 62.5, 250, or 1000 mg/kg bw/day during the treatment period under the conditions of this study. No test item related, or adverse effects were noted at evaluation of the reproductive parameters during mating and gestation, delivery and post-partum/lactation period until PPD5, under the conditions of this study. There were no adverse effects ascribed to test item administration on the F1 offspring viability, clinical signs, development or at observations following euthanasia. There were no test item-related changes observed in organ weights, at necropsy or at histopathology for the adult animals of either sex. Under the conditions of this study, the no observed adverse effect level (NOAEL) for the test substance is considered to be 1000 mg/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Klimisch 1 and the study was carried out in accordance with internationally valid GLP principles.

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

Key study: OECD guideline. GLP study.

A Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rat study was conducted according to OECD guideline 422. Under the conditions of this study, the no observed adverse effect level (NOAEL) for the test substance for parental/adult and F1 effects is considered to be 1000 mg/kg bw/day

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available.

Justification for classification or non-classification

Based on the available data, the substance is not classified for repeated dose toxicity.