2-morpholinoethanesulphonic acid

Endpoint summary

Description of key information

The systemic toxicity of the test substance was investigated in a experimental study according to OECD TG 422 under GLP-conditions. Based on the observation the NOAEL for systemic toxicity of male/female rats is 1000 mg/kg bw/day. The study was performed with the hydrate form of the substance (CAS 1266615-59-1). Taking into account a correction for the water content (7 %) the NOAEL for the anhydrous form (CAS 4432-31-9) is 930 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 Toxicity Study with the Reproduction/Developmental Toxicity Screening Test

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017-03-07 to 2017-06-13

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

version of 29 July 2016

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA Health Effects Test Guidelines: OPPTS 870.3650 Combined Repeated Dose Toxicity with the Reproduction/Developmental Toxicity Screening Test

Version / remarks:

July 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

Hsd.Han

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt., 1103 Budapest, Cserkesz u. 90
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11-12 weeks (both sexes)
- Weight at study initiation: males: 327-381 g
females: 202-244 g
- Fasting period before study: no
- Housing: before mating: 2 animals of the same sex/cage; mating: 1 male and 1 female/cage; pregnant females: individually; males after mating: 2/cage;
Type III polypropylene/polycarbonate
- Diet: ad libitum, ssniff SM R/M-Z+H complete diet
- Water: ad libitum, tap water
- Acclimation period: 19 days

DETAILS OF FOOD AND WATER QUALITY: The food is considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. The supplier provided an analytical certificate of the standard diet for the batch used. Water quality control analysis and microbiological assessment are performed once in every six months by Government Office of Capital Budapest Department of Public Health and Medical Officer Service.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+/- 3
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Details on route of administration:

The test item was administered orally by gavage. The route of application was selected in compliance with international guidelines. The oral route is a possible route of human exposure to the test item.

Vehicle:

water

Remarks:

distilled

Details on oral exposure:

- PREPARATION OF DOSING SOLUTIONS:
The test item was solved in distilled water in concentrations of 20, 60 and 200 mg/mL. Dosing solutions were prepared not longer than for four days before the administration and stored at room temperature until use.

- VEHICLE
- Concentration in vehicle: 20, 60 and 200 mg/mL
- Amount of vehicle: 5 mL/kg body weight
- Batch no. of Aqua purificata (distilled water): 1702-5502, 1702-5510, 1703-5503 (supplier: Parma Produkt Kft., Budapest, Hungary)

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical control of dosing formulations was performed by LC/MS/MS in the Analytical Laboratory of Test Facility twice during the study. Recoveries of the test item in the dosing formulations ranged from 100 - 105% of the nominal concentrations.
Stability and homogeneity in distilled water over the range of relevant concentration has been demostrated at room temperature for at least four days (recoveries from 98% to 105%), i.e. the maximum period of solutions administered.

Duration of treatment / exposure:

56-66 days (depending on mating effectiveness)

Frequency of treatment:

daily

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

12 male and 12 female per dose and control

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on results from a 14-day dose-range finding experiment that used the same concentrations
- Rationale for animal assignment: random

Positive control:

none

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (starting on Day 0)

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 (body weight gain only)

WATER CONSUMPTION AND COMPOUND INTAKE: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: approx. 16 hours after last treatment (food deprived)
- Anaesthetic used for blood collection: Yes (isofluran)
- Animals fasted: Yes (approx. 16 hours)
- How many animals: 5 males and 5 females per group (randomly selected)
- Parameters examined:
- white blood cell (leukocyte) count (WBC)
- red blood cell (erythrocyte) count (RBC)
- hemoglobin concentration (HGB)
- hematocrit (HCT)
- Mean Corpuscular (erythrocyte) Volume (MCV)
- Mean Corpuscular (erythrocyte) Hemoglobin (MCH)
. Mean Corpuscular (erythrocyte) Hemoglobin Concentration (MCHC)
- platelet (thrombocyte) count (PLT)
- reticulocytes (RET)
- differential white blood cell count
- activated partial thromboplastin time (APTT)
- prothrombin time (PT)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: approx. 16 hours after last treatment (food deprived)
- Animals fasted: Yes (approx. 16 hours)
- How many animals: 5 males and 5 females per group (randomly selected)
- Parameters examined:
- alanine aminotransferase activity (ALT)
- aspartate aminotransferase activity (AST)
- total bilirubin concentration (TBIL)
- creatinine concentration (CREA)
- Urea concentration (UREA)
- glucose concentration (GLUC)
- cholesterol concentration (CHOL)
- bile acids (BAC)
- sodium concentration (Na+)
- potassium concentration (K+)
- albumin concentration (ALB)
- total protein concentration (TPROT)
- T4 (in parental males at termination day 55)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
Functional operation battery was performed on 5 animals per sex and group during the last exposure week but before blood sampling. Investigations included sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity. General physical conditions and behaviour of animals were tested (modified Irwin test).

IMMUNOLOGY: No

OTHER: none

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed, and any abnormality was recorded including details of the location, color, shape and size. Special attention was paid to the organs of the reproductive system. The number of implantation sites was recorded (see reproductive toxicity study). The ovaries, uterus with cervix, vagina, testes, epididymides (total and cauda), prostate, and seminal vesicles with coagulating glands, adrenal glands and pituitary and all organs showing macroscopic lesions of all adult animals were preserved. Testes and epididymides were preserved in modified Davidson solution, all other organs in 4 % buffered formaldehyde solution. Thyroid gland was preserved from all adult males and females and from one male and one female pup per litter for the intended subsequent histopathological examination. Thyroid and parathyroid were preserved together with larynx.

All organs showing macroscopic lesions and the following organs were preserved in 4 % buffered formaldehyde solution (except testes and epididymides, see above) for five male and five female animals randomly selected from each group:
- adrenal glands
- bone with bone marrow and joint (femur)
- brain (representative regions: cerebrum, cerebellum, pons and medully oblongata)
- eyes (lachrymal gland with Harderian glands)
- female mammary gland
- gonads (testis with epididymides, ovaries, uterus with fallopian tube and vagina)
- gross lesions
- heart
- Kidneys
- large intestines (caecum, colon, rectum, incl. Peyer's patches)
- liver
- lungs (with main stem bronchi)
- lymph nodes (submandibular, mesenteric)
- muscle (quadriceps)
- esophagus
- pancreas
- pituitary
- prostate
- salivary glands (submandibular)
- sciatic nerve
- seminal vesicle with coagulating gland
- skin
- small intestines (representative regions: duodenum, ileum, jejunum)
- spinal cord (at three levels: cervical, mid-thoracic and lumbar)
- spleen
- sternum
- stomach
- thymus
- thyroid + parathyroid
- trachea
- urinary bladder

HISTOPATHOLOGY : Yes (control and high dose group)
Full histopathological examinations were performed on the following preserved organs and tissues of selected animals in the control and high dose groups (5 per sex):
- adrenal glands
- aorta
- bone marrow
- brain
- cecum
- colon
- duodenum
- eyes + optic nerves
- esophagus
- harderian glands
- heart
- ileum
- jejunum
- kidneys
- lachrymal glands
- liver
- lungs
- mesenteric lymph nodes
- muscle (quadriceps)
- pancreas
- pituitary
- prostate
- rectum
- salivary glands (subm.)
- sciatic nerve
- skin
- spinal cord
- spleen
- sternum
- stomach - forestomach
- subm. lymph nodes
- thymus
- thyroid + parathyroid
- trachea
- urinary bladder

Histopathological examinations were performed on the following preserved organs and tissues of ALL animals in the control and high dose groups (12 per sex):
- ovaries (Primodial, secondary and teriary follicles; Corpora lutea)
- uterus
- vagina
- testes
- epididymides
- seminal vesicle with coagulating gland
- thymus (one male in low dose group due to hemorrhage

Other examinations:

At the time of termination, body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all male adult animals were determined. Absolute organ weight was recorded. Relative organ weight (to body and brain weight) were calculated and reported.

In addition, for five males and females randomly selected from each group, adrenals, brain, heart, kidneys, liver, spleen and thymus were weighed.
The thyroid weight after fixation was not determined in the absence of changes in thyroid hormones levels.

Statistics:

Depending on variance homogeneity between groups (Bartlett's test), parametric or non-parametric (Kruskal-Wallis test) ANOVA was performed, with subsequent inter-group comparisons (Duncan multiple range test or Mann-Whitney U-Test) in case of significant ANOVA results. If applicable, the Chi-square test was performed.

Clinical signs:

no effects observed

Description (incidence and severity):

Daily clinical observation:
No treatment-related signs of systemic toxicity were detected at any dose level at the daily clinical observations (100, 300 and 1000 mg/kg bw/day, male or female).

Detailed weekly clinical observation:
The behavior and physical condition of animals was not affected by the test item at any dose level (100, 300 or 1000 mg/kg bw/day) based on the weekly detailed clinical observations during the entire treatment period.

Mortality:

no mortality observed

Description (incidence):

There was no mortality in any group during the course of study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test item related effects were noted on the mean body weight and body weight gain values at 100, 300 or 1000 mg/kg bw/day. There were no significant differences between the control and test item treated groups in the body weight or body weight gain at any occasion.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no test item related differences in the mean daily food consumption in any test item treated group when compared to the control during the study. There were no significant differences between the control and test item treated groups in the mean daily food consumption at any occasion.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

There were no pathological changes in the examined hematological and blood coagulation parameters in any of the groups (male and female, 100, 300 or 1000 mg/kg bw/day). The examined hematological and blood coagulation parameters were comparable in male and female animals of control and all test item treated groups and statistical significance was not observed.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test item related adverse effects on the examined clinical chemistry parameters at 100, 300 or 1000 mg/kg bw/day (male or female).
Some sporadic statistically differences in some parameters were not related to dose and considered of no toxicological relevance.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Functional observations did not demonstrate any test item related changes. The behavior, physical condition and reactions to different type of stimuli of animals selected for examination are considered to be normal in all groups (100, 300 and 1000 mg/kg bw/day, control).

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test item related adverse effects on the examined organ weights in male or female animals at 100, 300 or 1000 mg/kg bw/day.
Kidney weights (absolute and relative) were reduced in a single male rat in the mid dose group. This minor change was not related to doses, the values met the historical controls and no corresponding histopathological correlate was observed. Therefore, this is considered to have no toxicological relevance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Macroscopic findings related to the effect of the test item were not detected in organs or tissues of male or female animals at 100, 300 and 1000 mg/kg bw/day at necropsy. Some findings were noted in single animals of both sexes across most groups including controls (i.e. thymic hemorrhage and slight hydrometra). In the absence of related histopathological alterations (inflammatory or other pathological lesion) they were judged not to be toxicologically relevant.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological examinations did not reveal any test item related alterations in the organs or tissues of male or female animals at 1000 mg/kg bw/day. No test item related alterations in organs and tissues and no morphological evidence of acute or subacute injury to the various organs were observed.
There was no morphological evidence of acute or subacute injury (degeneration, inflammation, necrosis, etc.) of the stomach, the small and large intestines, the liver, the pancreas, the cardiovascular system, the urinary system, the immune system, the hematopoietic system, the skeleton, the muscular system, the male and female reproductive system or the central or peripheral nervous system in the animals.The cytomorphology of the endocrine glands were the same in the control and the treated animals.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Thyroid hormone levels:
There were no significant differences with respect to the control in the T4 thyroid hormone levels in parental male animals or in offspring sampled on postnatal day 13 at any dose levels.

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: highest dose tested

Dose descriptor:

NOAEL

Effect level:

930 mg/kg bw/day (nominal)

Sex:

male/female

Remarks on result:

other: conversion to anhydrous form taking into account a correction for the water content (7%)

Key result

Critical effects observed:

no

Conclusions:

Under the conditions of the present study, the test item did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage. Based on these observations the NOAEL for systemic toxicity of male/female rats was determined to be 1000 mg/kg bw/day.

Executive summary:

A study according OECD TG 422 was performed to investigate possible effects of the test item on reproduction and development when repeatedly administered orally to rats compared to control animals. Four groups of Wistar rats consisting of 12 animals per group and sex were administered by gavage once daily doses of 0 (vehicle only), 100, 300 and 1000 mg/kg bw/day. The suitability of distilled water as vehicle for the test item was analytically verified up front as the test item was stable in distilled water at room temperature for at least four days. The concentration of the substance in the dosing formulations administered to the animals was confirmed twice during the study. All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before necropsy (altogether 56 or 57 days). Females were additionally exposed through the gestation period and up to lactation days 12-20, i.e. up to the day before necropsy (altogether for 56 to 66 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Estrous cycle was monitored by examining vaginal smears before the treatment for two weeks and for two weeks from the beginning of the treatment period (two weeks pre-mating period) and during the mating period until evidence of mating. The dams were allowed to litter and rear their offspring up to day 13 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on post-natal day 13 or shortly thereafter. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from 2-8 pups per litter on post-natal day 4, from all dams and from 4-7 pups per litter at termination on post-partum/post-natal day 13 and from all parent male animals at termination. All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all adult male animals were determined. Histopathology examination was performed on ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in the control and high dose groups (male or female). Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, blood coagulation, clinical chemistry, gross necropsy, and organ weighing as well as full histopathology in the control and high dose groups.

There was no mortality in any group during the course of study. Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations. At the same intervals, the behavior and physical condition of the animals was not impaired at each dose level (100, 300 or 1000 mg/kg bw/day) during the entire treatment period. Test item related changes of the body weight or body weight gain were not detected. The body weight development was not disturbed and comparable in the control and test item treated groups. The mean daily food consumption was not affected by the test item in male or female animals at all test item groups during the entire study (pre-mating, post-mating, gestation and lactation periods). There were no test item related differences between the control and test item treated groups in the examined parameters of reproductive performance, and in the delivery parameters of dams (100, 300 and 1000 mg/kg bw/day). Clinical pathology examinations (hematology, blood coagulation, clinical chemistry and thyroid hormone levels) did not reveal toxicological relevant alterations related to the test item. Specific macroscopic alterations related to the test item were not found at necropsy. There were no test item related changes in the weights (absolute and relative to body or brain weights) of selected organs in the animals at any dose level.

Histopathological examinations of the selected organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) did not reveal any test item related changes at the highest dose of 1000 mg/kg bw/day. During full histopathology, there were no changes related to the test item in organs or tissues of selected animals (male or female) at 1000 mg/kg bw/day. No adverse findings on the offspring’s development were detected (mortality, clinical signs and body weight, anogenital distance and nipple retention in male pups, necropsy).

Under the conditions of the present study, the substance did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage and the test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female rats at the doses of 100, 300 or 1000 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows:

NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day

NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day

NOAEL for F1 Offspring: 1000 mg/kg bw/day

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

930 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

OECD TG 422, GLP

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

A study according OECD TG 422 was performed to investigate possible effects of the test item on reproduction and development when repeatedly administered orally to rats compared to control animals. Four groups of Wistar rats consisting of 12 animals per group and sex were administered by gavage once daily doses of 0 (vehicle only), 100, 300 and 1000 mg/kg bw/day. The suitability of distilled water as vehicle for the test item was analytically verified up front as the test item was stable in distilled water at room temperature for at least four days. The concentration of the substance in the dosing formulations administered to the animals was confirmed twice during the study. All animals of the parent (P) generation were dosed prior to mating (14 days) and throughout mating. In addition, males received the test item or vehicle after mating up to the day before necropsy (altogether 56 or 57 days). Females were additionally exposed through the gestation period and up to lactation days 12-20, i.e. up to the day before necropsy (altogether for 56 to 66 days). Observations included mortality, clinical signs, body weight, food consumption, mating, pregnancy and delivery process, as well as development of offspring. Estrous cycle was monitored by examining vaginal smears before the treatment for two weeks and for two weeks from the beginning of the treatment period (two weeks pre-mating period) and during the mating period until evidence of mating. The dams were allowed to litter and rear their offspring up to day 13 post-partum. Litters were weighed and offspring were observed for possible abnormalities and were euthanized on post-natal day 13 or shortly thereafter. Blood samples were collected for determination of serum levels of thyroid hormones (T4) from 2-8 pups per litter on post-natal day 4, from all dams and from 4-7 pups per litter at termination on post-partum/post-natal day 13 and from all parent male animals at termination. All parental animals were subjected to gross pathology one day after the last treatment. The body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all adult male animals were determined. Histopathology examination was performed on ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in the control and high dose groups (male or female). Five dams and the male mating partners were randomly selected from each group to examine further signs of toxicity such as functional observations, hematology, blood coagulation, clinical chemistry, gross necropsy, and organ weighing as well as full histopathology in the control and high dose groups.

There was no mortality in any group during the course of study. Clinical signs of systemic toxicity related to the test item were not detected at any dose level, neither at the daily nor at the detailed weekly clinical observations. At the same intervals, the behavior and physical condition of the animals was not impaired at each dose level (100, 300 or 1000 mg/kg bw/day) during the entire treatment period. Test item related changes of the body weight or body weight gain were not detected. The body weight development was not disturbed and comparable in the control and test item treated groups. The mean daily food consumption was not affected by the test item in male or female animals at all test item groups during the entire study (pre-mating, post-mating, gestation and lactation periods). There were no test item related differences between the control and test item treated groups in the examined parameters of reproductive performance, and in the delivery parameters of dams (100, 300 and 1000 mg/kg bw/day). Clinical pathology examinations (hematology, blood coagulation, clinical chemistry and thyroid hormone levels) did not reveal toxicological relevant alterations related to the test item. Specific macroscopic alterations related to the test item were not found at necropsy. There were no test item related changes in the weights (absolute and relative to body or brain weights) of selected organs in the animals at any dose level.

Histopathological examinations of the selected organs (ovaries, uterus, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland) did not reveal any test item related changes at the highest dose of 1000 mg/kg bw/day. During full histopathology, there were no changes related to the test item in organs or tissues of selected animals (male or female) at 1000 mg/kg bw/dayNo adverse findings on the offspring’s development were detected (mortality, clinical signs and body weight, anogenital distance and nipple retention in male pups, necropsy).

Under the conditions of the present study, the substance did not cause signs of systemic toxicity in parental male and female Hsd.Han: Wistar rats at 100, 300 or 1000 mg/kg bw/day doses administered by oral gavage and the test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) in parental male and female rats at the doses of 100, 300 or 1000 mg/kg bw/day. The development of the F1 offspring was not impaired at any dose level from birth to post-natal day 13 after repeated oral administration of dams. Based on these observations the NOAEL were determined as follows:

NOAEL for systemic toxicity of male/female rats: 1000 mg/kg bw/day

NOAEL for reproductive performance of male/female rats: 1000 mg/kg bw/day

NOAEL for F1 Offspring: 1000 mg/kg bw/day

The study was performed with the hydrate form of the substance (CAS 1266615-59-1). Taking into account a correction for the water content (7 %) the NOAEL for the anhydrous form (CAS 4432-31-9) is 930 mg/kg bw/day.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on this data, the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the fifteenth time in Regulation (EU) 2020/1182.