Registration Dossier

Administrative data

Description of key information

A Combined 28 -day repeated dose and reproduction / developmental screening (2013) is availa ble on butane-1,4-diylbis(oxy-2-hydroxypropane-3,1-diyl) bisacrylate.

Based on this study, the no-observed adverse effect level (NOAEL) is of 150 mg/kg/day in both males and females based on systemic effects observed at 150 mg/kg/day.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted March 1996
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3650, adopted July 2000
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-11 wks;
- Weight at study initiation: Males: 321-352 g; Females: 184-214 g
- Fasting period before study: no
- Housing: individually in Makrolon type M III cages (floor area app. 800cm²)
- Diet (e.g. ad libitum): Kliba maintenance diet mouse-rat "GLP" ad lib.
- Water (e.g. ad libitum): ad lib.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light):12h/12h
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
The suspension of Laromer 8765 in corn oil was prepared daily by weighing the appropriate amount of test substance and adding corn oil up to the desired volume, which was subsequently released with a magnetic stirrer. During administration of the test substance, preparations were kept homogeneous by stirring with a magnetic stirrer.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility of the test substance
- Amount of vehicle (if gavage): 4 ml/kg b.w.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The various analyses confirmed
- the stability of the test substance in corn oil at room temperature over a period of 7 days
- the homogeneous distribution of the test substance in corn oil
- the correctness of the prepared concentrations of the test-substance preparations in corn oil was determined at start, end and once throughout the study (see report 01Y0446/01X037)
Duration of treatment / exposure:
males: 35 days
females: 55 days
Frequency of treatment:
daily (no administration to animal being in labor)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
500mg/kg (up to day 5), 300mg/kg (from day 6 onward)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on range finding study (10C0446/01S014): no pathological changes in 3 female Wistar rats treated with 500mg/kg for three weeks, animals moribund after 1 week exposure to 1000mg/kg due to ulcerations in the fore and glandular stomach.
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yess
- Time schedule: before, within 2h and 2-5h after treatment, additional check in the afternoon on workdays
- Cage side observations: morbidity, pertinent behavioral changes, signs of overt toxicity, littering and lactation bevhavior

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
- Observations: abnormal behavior during “handling”, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, impairment of gait, lacrimation, palpebral closure, exophthalmus, feces (appearance/consistency), urine, pupil size

BODY WEIGHT: Yes
- Time schedule for examinations: males and females without evidence of mating: weekly; females with evidence of mating: weekly prior to mating, on GD0, 7, 14, 20, on parturition days 0 and 4

FOOD CONSUMPTION:
- Food consumption for each animal determined was determined weekly, except during mating

WATER CONSUMPTION:
- Time schedule for examinations: monitored daily by visual inspection

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on the day of necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (16-20h)
- How many animals: 5 parental animals per sex and group
- The following parameters were examined: Leukocyte count, Erythrocyte count, hemoglobin, hemtocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, differential blood count, reticulocytes, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on the day of necropsy
- Animals fasted: Yes (16-20h)
- How many animals: 5 parental animals per sex and group
- The following parameters were examined: ALT, AST, ALP, GGT, sodium, potassium, chlorid, inorganic phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, bile acids

URINALYSIS: Yes
- Time schedule for collection of urine: day31 (males), day 50 (females)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes during collection
- How many animals: 5 parental animals per sex and group
- The following parameters were examined: pH, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity, sediment, color, turbity, volume

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: day 29 (males), day 53 (females)
- Dose groups that were examined: 5 animals per sex and group (only females with litter)
- Battery of functions tested: home cage and open field observation, motor activity, sensory motor test / reflexes (including: Reaction to an object being moved towards the face, touch sensitivity, vision (Visual placing response), pupillary reflex, pinna reflex, auditory startle response, righting response, behavior during handling, vocalization, pain perception (Tail pinch), grip strength of forelimbs and hindlimbs, landing foot-splay test)
Sacrifice and pathology:
SACRIFICE
- Male animals: All surviving animals on day 36
- Maternal animals: All surviving animals on day 56
- 6 males and 3 females died prematurely and were necropsied as soon as possible after their death and assessed by gross pathology.
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
The following tissues were weighed
- in all animals: epididymides, testes
- in 5 males and females of each group: adrenal glands, brain, heart, kidneys, liver, spleen, thymus
The following tissues were examined histotechnically in at least 5 animals per sex of the control and high dose group, unless noted otherwise, and in all animals that died prematurely:
adrenal glands, gross lesions (all affected animals in all dosage groups), bone marrow (femur), brain, cecum, cervix, coagulation glands, colon, duodenum, epididymides, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes (auxillary and mesenteric), ovaries, oviducts, prostate gland, peyer's patches, rectum, sciatic nerve, seminal vesicles, spinal cord, spleen, stomach (all animals from all dose groups), testes, thymus, thyroid glands, trachea, urinary bladder, uterus, vagina
Other examinations:
Reproductive performance: see entry in chapter 7.8.1
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Respiration sounds were observed in 3 males of the mid dose, in all males of the high dose group, and in 1 high dose female on study days 7 (only males) and 21. Piloerection was observed in each 2 high dose males and females and one mid dose male and female on different days throughout the study.
Immediately after dosing, animals from all treatment groups showed salivation due to bad taste or local irritation of the upper digestive tract. This finding was assessed as non-adverse.
Mortality:
mortality observed, treatment-related
Description (incidence):
6 males and 2 females were found dead on different days (days 4, 5, 6, 16, 34, 34 for the males, and days 51 and 53 for the females), 1 female was sacrificed in moribund condition on day 55.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For the surviving high dose and mid dose male animals mean body weight was significantly lower on post-mating day 7 (-8.6% and -4.3%, respectively). In addition, body weight change values of high dose male animals were significantly lower during the pre-mating days 0-7 (-85.3%) and 0-13 (-42.1%). These deviations to the control values were regarded to be treatment-related. No changes in body weight parameters were determined for female animals in all groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related adverse findings were noted with regard to food consumption during the entire study period.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test substance-related adverse findings were noted.
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In mid and high dose males, absolute and relative neutrophil counts were increased whereas relative lymphocyte counts were decreased. Total white blood cell counts were not significantly altered in the mentioned individuals. However, in the mid dose males absolute and relative neutrophil accounts as well as relative lymphocyte counts were within historical control ranges. Therefore, in the mentioned alterations in this test group of the differential blood cell counts were regarded as incidental and not treatment-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among clinical chemistry parameters were observed.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among urinalysis parameters were observed.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related effects were observed.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance related effects were observed.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Most of the animals having died spontaneously showed erosions/ ulcers on the forestomach, in one animal the macroscopic finding was not confirmed histologically. 7 males and all females of the high dose group showed erosions / ulcers in the forestomach, in one animal of each sex this finding was observed in the glandular stomach. One high dose female had a mass in the forestomach, that correlated to severe inflammation/ edema, as confirmed during histopathologic examination. In the mid dose group, 9 males and 6 females had erosions / ulcers in the forestomach, and again this finding was observed in one animal of each sex in the glandular stomach. In the low dose, 5 males and 2 females were affected.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related erosions/ ulcers were observed in many treated animals often correlating to the macroscopic finding. In many animals, an inflammatory or hyperplastic reaction to an erosion or ulcus was observed, characterized by varying degrees of edema in the submucosa, inflammatory cell
infiltrates of varying composition (neutrophils, lymphocytes, plasma cells) and hyperplasia of the squamous epithelium of the forestomach forming both elongating rete ridges as well as papillary projections into the lumen of the stomach. The hyperplasia was accompanied by hyperkeratosis.

Foci on the pancreatic lymph node observed macroscopically in some male animals of mid dose group and one high dose male correlated histologically to cyst and/ or lympho- reticular hyperplasia.

All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
male
Basis for effect level:
other: lower terminal body weight and premature deaths, most likely due to the irritant properties of the test substance
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
150 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: Premature deaths, most likely due to the irritant properties of the test substance.
Dose descriptor:
LOAEL
Remarks:
local effects
Effect level:
50 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: erosions / ulcers in the stomach
Critical effects observed:
yes
Lowest effective dose / conc.:
50 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the oral administration by gavage of test substance to male and female Wistar rats revealed local pathological findings in the
stomach at a dose level of 50 mg/kg bw/d and above. This finding was related to the irritating potential of the test substance.
Signs of systemic toxicity were observed at a dose level of 150 mg/kg bw/d (impaired body weight data in male animals) and above (premature deaths in both sexes), which were assumed to be related to the test substance administration.
Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 50 mg/kg bw/d for male animals and 150 mg/kg bw/d for female animals. With regard to effects in the stomach the NOAEL for local effects could not be set.
Executive summary:

Test substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0), 50 mg/kg bw/d (test group 1), 150 mg/kg bw/d (test group 2) and 500 mg/kg bw/d (test group 3). Because of clinical findings and the premature death of 3 male animals in test group 3, the dose was reduced from 500 to 300 mg/kg bw/d from study day 6 onwards.

The objective of the study was to detect possible effects of the test substance on the integrity and performance of male and female reproductive systems including gonadal function, mating behavior, conception, gestation and parturition. Furthermore, it was intended to obtain information about the general toxicological profile including target organs and the no observed adverse effect level (NOAEL) after repeated oral administration. The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females followed by an additional treatment until one day before sacrifice.

After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear.

Note: As a result of the premature death in 3 male animals of test group 3 (500 and 300 mg/kg bw/d) 3 male animal were mated in a 1:2 ratio, i.e. male animal No. 31 was mated with female animal Nos. 131 and 132, male No. 34 with female Nos. 133 and 134 and male animal No. 39 with Nos. 139 and 140. As a result of the premature death of male animal No. 39, female animal No. 140 was mated with male animal No. 36 from study day 16 onwards.

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating and mating. During gestation and lactation period, F0

females were weighed on gestation days (GD) 0, 7, 14 and 20, after the day of parturition (postnatal day [PND] 0) and on PND 4.

The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2 and examined

macroscopically for external and visceral findings.

Clinicochemical and hematological examinations as well as urinalyses were performed in 5 animals per sex and group towards the end of the administration period. Towards the end of the administration period a functional observational battery was performed and motor activity was measured in the first 5 surviving parental males and the first 5 surviving females with litter (in order of delivery) per group.

All F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

In the high dose group, six male animals and 2 female animals were found dead during the study; in addition, 1 female animal was sacrificed moribund on gestation day 27. Respiration sounds were observed in 5 male and 3 female on several days during the

study, labored respiration was observed in 2 male animals and 1 female animal on few study days and gasping respiration was observed in 1 male animal on day 6 of the postmating phase and in 1 female animal on day 20 of the gestation phase.

Piloerection were observed in 2 male animals and 2 female animals on several days during the study. Encrusted left eye was observed in 1 male animal on post-mating day 6. Blood in bedding and inability to deliver was seen in 1 female animal during the gestation phase from day 25 to day 27, light-brown vaginal discharge was observed on gestation day 27. Mean body weight was lower in male animals on post-mating day 7 (-8.6%). Mean body weight change values were decreased in male animals during the premating

days 0-7 (-85.3%) and 0-13 (-42.1%). Increased absolute and relative neutrophil counts in males and dcreased relative lymphocyte counts in males were observed. At pathology : mean terminal body weight was lower in male animals, i.e. -8%. Erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 9 of 10 male and all female animals. Erosions or ulcers in the glandular stomach were observed in 3 of 10 males.

In the intermediate group, respiration sounds were observed in 3 male and 2 female animals on several days during the study, labored respiration was observed in 3 male animals on few study days during the mating phase. Piloerection were in 1 male animal on day 8 and 9 of the mating phase and in 1 female animal on day 26 of the gestation phase. Mean body weight was significantly lower in male animals on mating day 8 (-4.3%). No test substance-related adverse findings were observed in clinical pathology. Erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 9 of 10 male and in 7 of 10 female animals.

Erosions or ulcers in the glandular stomach were observed in 1 of 10 female animals.

In th low dose group, only erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 6 of 10 male and 1 of 10 female animals.

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the oral administration by gavage of test substance to male and female Wistar rats revealed local pathological findings in the

stomach at a dose level of 50 mg/kg bw/d and above. This finding was related to the irritating potential of the test substance.

Signs of systemic toxicity were observed at a dose level of 150 mg/kg bw/d (impaired body weight data in male animals) and above (premature deaths in both sexes), which were assumed to be related to the test substance administration.

Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 50 mg/kg bw/d for male animals and 150 mg/kg bw/d for female animals. With regard to effects in the stomach the NOAEL for local effects could not be set.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is considered as reliable with a klimisch score of 1.

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

Combined repeated dose and reproduction / developmental screening (2013)

Test substance was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0), 50 mg/kg bw/d (test group 1), 150 mg/kg bw/d (test group 2) and 500 mg/kg bw/d (test group 3). Because of clinical findings and the premature death of 3 male animals in test group 3, the dose was reduced from 500 to 300 mg/kg bw/d from study day 6 onwards.

The objective of the study was to detect possible effects of the test substance on the integrity and performance of male and female reproductive systems including gonadal function, mating behavior, conception, gestation and parturition. Furthermore, it was intended to obtain information about the general toxicological profile including target organs and the no observed adverse effect level (NOAEL) after repeated oral administration. The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation in females followed by an additional treatment until one day before sacrifice.

After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear.

Note: As a result of the premature death in 3 male animals of test group 3 (500 and 300 mg/kg bw/d) 3 male animal were mated in a 1:2 ratio, i.e. male animal No. 31 was mated with female animal Nos. 131 and 132, male No. 34 with female Nos. 133 and 134 and male animal No. 39 with Nos. 139 and 140. As a result of the premature death of male animal No. 39, female animal No. 140 was mated with male animal No. 36 from study day 16 onwards.

A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals. Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating and mating. During gestation and lactation period, F0

females were weighed on gestation days (GD) 0, 7, 14 and 20, after the day of parturition (postnatal day [PND] 0) and on PND 4.

The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2 and examined

macroscopically for external and visceral findings.

Clinicochemical and hematological examinations as well as urinalyses were performed in 5 animals per sex and group towards the end of the administration period. Towards the end of the administration period a functional observational battery was performed and motor activity was measured in the first 5 surviving parental males and the first 5 surviving females with litter (in order of delivery) per group.

All F0 parental animals were sacrificed by decapitation, under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

In the high dose group, six male animals and 2 female animals were found dead during the study; in addition, 1 female animal was sacrificed moribund on gestation day 27. Respiration sounds were observed in 5 male and 3 female on several days during the

study, labored respiration was observed in 2 male animals and 1 female animal on few study days and gasping respiration was observed in 1 male animal on day 6 of the postmating phase and in 1 female animal on day 20 of the gestation phase.

Piloerection were observed in 2 male animals and 2 female animals on several days during the study. Encrusted left eye was observed in 1 male animal on post-mating day 6. Blood in bedding and inability to deliver was seen in 1 female animal during the gestation phase from day 25 to day 27, light-brown vaginal discharge was observed on gestation day 27. Mean body weight was lower in male animals on post-mating day 7 (-8.6%). Mean body weight change values were decreased in male animals during the premating

days 0-7 (-85.3%) and 0-13 (-42.1%). Increased absolute and relative neutrophil counts in males and dcreased relative lymphocyte counts in males were observed. At pathology : mean terminal body weight was lower in male animals, i.e. -8%. Erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 9 of 10 male and all female animals. Erosions or ulcers in the glandular stomach were observed in 3 of 10 males.

In the intermediate group, respiration sounds were observed in 3 male and 2 female animals on several days during the study, labored respiration was observed in 3 male animals on few study days during the mating phase. Piloerection were in 1 male animal on day 8 and 9 of the mating phase and in 1 female animal on day 26 of the gestation phase. Mean body weight was significantly lower in male animals on mating day 8 (-4.3%). No test substance-related adverse findings were observed in clinical pathology. Erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 9 of 10 male and in 7 of 10 female animals.

Erosions or ulcers in the glandular stomach were observed in 1 of 10 female animals.

In th low dose group, only erosion/ ulcer and/or related squamous hyperplasia or inflammation/edema in the forestomach were observed in 6 of 10 male and 1 of 10 female animals.

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the oral administration by gavage of test substance to male and female Wistar rats revealed local pathological findings in the

stomach at a dose level of 50 mg/kg bw/d and above. This finding was related to the irritating potential of the test substance.

Signs of systemic toxicity were observed at a dose level of 150 mg/kg bw/d (impaired body weight data in male animals) and above (premature deaths in both sexes), which were assumed to be related to the test substance administration.

Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 50 mg/kg bw/d for male animals and 150 mg/kg bw/d for female animals. With regard to effects in the stomach the NOAEL for local effects could not be set.

Justification for classification or non-classification

No organ damage or changes in clinical chemistry, urine or hematological parameters were observed. Reduced body weight and premature deaths were most likely the result of excessive local irritation and not of systemic toxicity, an effect which is already covered by the classifications for eye damage and skin sensitization. Even following the precautionary principle and assuming that some systemic toxicity occured in parallel to local irritation, no target organ was identified (with the only effect being reduced body weight) and the LOAEL (150 mg/kg) do not justifiy classification for single target organ toxicity after repeated exposure according to the Regulation EC n°1272/2008.