6-methyl-3,4-dihydro-2H-1,4-benzoxazine

Endpoint summary

Description of key information

OECD 422 Combined Repeated Dose Toxicity study with Reproduction/Developmental Toxicity screening test:

It is concluded that the oral administration of 6 -methyl-3,4 -dihydro-2H-1,4 -benzoxazine to Han Wistar rats was generally tolerated in the adult animals but caused signs of decreased activity and partially closed eyelids at 150 mg/kg/day, which, due to the isolated, transient occurrence was considered non-adverse. In males, there was a 29% reduction of body weight gain at 150 mg/kg/day which was considered adverse. Due to the adverse effect on body weight gain in males at 150 mg/kg/day, the no observed adverse effect level (NOAEL) of the test substance for systemic toxicity was considered to be 50 mg/kg/day for males and 150 mg/kg/day for females.

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 Toxicity Study and Reproductive/Developmental Toxicity Screening

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 September 2019 - 17 January 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2016

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Test item identity (including alternative names): 6-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine
- Intended use: Industrial chemical.
- Appearance: Yellowish, clear oil
- Storage conditions: Refrigerated (2 to 8°C), under argon and protected from light. Containers were kept sealed and flushed with argon after every use. Prolonged exposure to air and light was avoided.
- Supplier: Sponsor
- Batch number: 1394901004
- Expiry date: 1 January 2020
- Purity: >99% (by HPLC area % 225 nm bandwidth 50 nm)

Species:

rat

Strain:

Wistar

Remarks:

Han Wistar (RccHan™; WIST)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo RMS Ltd.
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Males 84 to 90 days old; Females 98 to 104 days old.
- Weight at study initiation: Males 308 to 341 g; Females 193 to 242 g.
- Fasting period before study:
- Housing:
* Cages- Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropriate intervals. Solid (polycarbonate) bottom cages were used throughout the study except during pairing. Grid bottomed cages were used during pairing. These were suspended above absorbent paper which was changed daily.
* Bedding- Solid bottom cages contained softwood based bark-free fiber bedding, which was changed at appropriate intervals each week.
* Aspen chew block- A soft white untreated wood block; provided to each cage throughout the study (except during lactation) and replaced when necessary.
* Plastic shelter- Provided to each cage throughout the study (except during pairing and lactation) and replaced at the same time as the cages.
* Paper shavings- Approximately two handfuls of paper shavings were provided to each cage as nesting material from Day 20 after mating and throughout lactation. Shavings were replaced at the same frequency as the bedding.
- Diet: SDS VRF1 Certified pelleted diet, ad libitum.
- Water: Potable water from the public supply via polycarbonate bottles with sipper tubes; ad libitum.
- Acclimation period: Males six days before commencement of treatment; Females 20 days before commencement of treatment.


DETAILS OF FOOD AND WATER QUALITY:
Certificates of analysis for the diet are scrutinized and approved before any batch of diet was released for use. Certificates of analysis were routinely provided by the water supplier. Certificates of analysis were also received from the suppliers of the softwood based bark-free fiber bedding and Aspen chew blocks. No specific contaminants were known that may have interfered with or prejudiced the outcome of the study and therefore no special assays were performed.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air supply: Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): Artificial lighting, 12 hours light: 12 hours dark.

Route of administration:

oral: gavage

Details on route of administration:

- Route: Oral gavage using a suitably graduated syringe and a rubber catheter inserted via the mouth.
- Treated at: Constant doses in mg/kg/day.
- Volume dose: 5 mL/kg body weight.
- Individual dose volume: Calculated from the most recently recorded scheduled body weight.
- Frequency: Once daily at approximately the same time each day.

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
Formulation procedures were performed under yellow light. Starting with the lowest concentration, the required amount of test item was weighed and then mixed with the vehicle (approximately 50% of the final volume). The mixture was magnetically stirred until the test material was uniformly mixed. The remaining vehicle was added to achieve the required volume and the formulation was mixed using a magnetic stirrer until homogeneous. A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.

PREPARATION
- Rate of preparation of diet (frequency): Weekly.
- Storage of formulation: Ambient temperature (15 to 25°C).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

- Stability and homogeneity: The suitability of the proposed mixing procedures was determined and specimen formulations at 2 and 200 mg/mL were analyzed to assess the stability and homogeneity of the test item in the liquid matrix.
- Achieved concentration: Samples of each of the first and last preparation formulations were analyzed for achieved concentration of the test item.

Duration of treatment / exposure:

Males: Two weeks before pairing up to necropsy after minimum of five weeks.
Females: Two weeks before pairing, then throughout pairing and gestation until Day 12 of lactation (necropsy on Day 13 of lactation).

Frequency of treatment:

Daily

Dose / conc.:

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

Remarks:

Group 1

Dose / conc.:

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

Remarks:

Group 2

Dose / conc.:

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

Remarks:

Group 3

Dose / conc.:

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

Remarks:

Group 4

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
Doses levels were selected in consultation with the Sponsor based on the results of a 14-day preliminary toxicity study in the Han Wistar rat (Covance Study No. XY88WS). In that study, a dose level of 300 mg/kg/day was not tolerated, resulting in adverse signs including swaying, flattened gait, splayed hind limbs, reduced activity and piloerection. Macroscopically, lesions were identified in the stomach of the majority of the animals.
At 75 or 150 mg/kg/day, signs were generally limited to the first three days of treatment and consisted of piloerection, decreased activity and partially closed eyelids, with a few isolated incidences throughout the 14-day treatment period. Body weight gain was initially reduced but improved from Day 4, and food intake was slightly lower than the pretreatment values throughout treatment. After 14 days, liver and kidney weights were higher in males given 150 mg/kg/day and spleen weights were higher in females given 150 mg/kg/day, but there were no macroscopic findings.
It was therefore considered that 150 mg/kg/day was a suitable high dose for this study. The lower doses of 17 and 50 mg/kg/day (approximate factor of three between doses) were chosen in order to assess dose responsiveness of any effects and to obtain a clear no-observed-adverse-effect level (NOAEL).

- Rationale for animal assignment: weight of animals

Positive control:

No

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes.
Mortality check was performed near the start and end of each working day.

CLINICAL OBSERVATIONS: Yes
Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.

BODY WEIGHT: Yes
F males:
Before dosing on the day that treatment commenced (Day 1) and weekly thereafter
On the day of necropsy.

F0 females:
Before dosing on the day that treatment commenced (Day 1) and weekly before pairing.
Days 0, 7, 14 and 20 after mating.
Day 1, 4, 7, and 13 of lactation.
On the day of necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption:
Weekly, from the day that treatment commenced.
Food consumption was not recorded for males and females during the period when paired for mating (Week 3) but recommenced for males in Week 4.
For females after mating food consumption was performed to match the body weight recording:
Days 0-6, 7-13 and 14-19 after mating
Days 1-3, 4-6 and 7-12 of lactation

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / Not specified

WATER CONSUMPTION:
Fluid intake was assessed by daily visual observation. No significant effect was observed, and consequently quantitative measurements were not performed.

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes; At termination
- Anaesthetic used for blood collection: Yes, light general anesthesia induced by isoflurane
- Animals fasted: Not specified
- How many animals: The five lowest numbered surviving males per group; The first five lactating females with a surviving litter per group
- Parameters checked:
• Hematocrit (Hct)*
• Hemoglobin concentration (Hb)
• Erythrocyte count (RBC)
• Absolute reticulocyte count (Retic)
• Mean cell hemoglobin (MCH)*
• Mean cell hemoglobin concentration (MCHC)*
• Mean cell volume (MCV)
• Red cell distribution width (RDW)
• Total leucocyte count (WBC)
• Differential leucocyte count:
• Neutrophils (N)
• Lymphocytes (L)
• Eosinophils (E)
• Basophils (B)
• Monocytes (M)
• Large unstained cells (LUC)
• Platelet count (Plt)

CLINICAL CHEMISTRY: Yes; At termination
- Anaesthetic used for blood collection: Yes, light general anesthesia induced by isoflurane
- Animals fasted: Not specified
- How many animals: The five lowest numbered surviving males per group; The first five lactating females with a surviving litter per group
- Parameters checked:
• Alkaline phosphatase (ALP)
• Alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Total bilirubin (Bili)
• Bile acids (Bi Ac)
• Urea
• Creatinine (Creat)
• Glucose (Gluc)
• Total cholesterol (Chol)
• Triglycerides (Trig)
• Sodium (Na)
• Potassium (K)
• Chloride (Cl)
• Calcium (Ca)
• Inorganic phosphorus (Phos)
• Total protein (Total Prot)
• Albumin (Alb)

Sacrifice and pathology:

- Method of Sacrifice
Adult animals: Carbon dioxide asphyxiation (no exposure to carbon dioxide took place until after the completion of blood sampling for clinical pathology and thyroid hormone assays).
- Sequence: To allow satisfactory inter-group comparison.

- Necropsy
All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
Time of Necropsy
F0 males: After Week 5 investigations completed.
F0 females failing to produce a viable litter: Day 25 after mating.
F0 females whose litter died before Day 13: On or after day the last offspring died.
F0 females: Day 13 of lactation.

Other examinations:

ESTROUS CYCLE
- Dry smears: For 15 days before pairing using cotton swabs.
- Wet smears: Using pipette lavage during the following phases:
For 14 days before treatment (all females including spares); animals that failed to exhibit 4-5 day cycles were not allocated to study.
After pairing until mating.
For four days before scheduled termination.

MATING PROCEDURE
- Pairing commenced: After a minimum of two weeks of treatment.
- Male/female ratio: 1:1 from within the same treatment groups.
- Duration of pairing: Up to two weeks.
- Daily checks for evidence of mating: Ejected copulation plugs in cage tray and sperm in the vaginal smear.
- Day 0 of gestation: When positive evidence of mating was detected.
- Male/female separation: Day when mating evidence was detected.
- Pre-coital interval: Calculated for each female as the time between first pairing and evidence of mating.

PARTURITION OBSERVATIONS AND GESTATION LENGTH
- Duration of gestation: Time elapsing between the detection of mating and commencement of parturition.
- Parturition observations: From Day 20 after mating, females were inspected three times daily for evidence of parturition. The progress and completion of parturition was monitored, numbers of live and dead offspring were recorded, and any difficulties observed were recorded.

THYROID HORMONE ANALYSIS
- Occasion: At termination:
All surviving F males.
All surviving F females (no samples were obtained from animals which failed to litter or with total litter loss).
- Conditions: No overnight deprivation of food.
- Anesthetic: Adults: Isoflurane.
- Blood sample site: Sublingual vein.
- Parameters: Thyroid stimulating hormone (TSH)
Thyroxine (T4)
- Anticoagulant: None.
- Blood volume: Adults: 1.0 mL.
- Blood tubes: Greiner Minicollect tubes with clotting activator.
- Processing: Samples were kept at ambient temperature (15 to 25°C) for a minimum of 30 minutes prior to centrifugation.
- Centrifugation conditions: At 2000g for ten minutes at 4°C.
- Aliquot volumes:
Aliquot 1: T4 - 0.2 mL of serum
Aliquot 2: TSH - residual serum
- Final storage conditions: Deep frozen (approximately -60°C to -90C), pending analysis.
- Fate of samples: Dispatched to the Department of Biomarkers, Bioanalysis and Clinical Sciences, Covance.

Statistics:

All statistical analyses were carried out separately for males and females.
Data relating to food consumption were analyzed on a cage basis. For all other adult parameters, the analyses were carried out using the individual animal as the basic experimental unit.

The following sequence of statistical tests was used for grip strength, motor activity, body weight, food consumption, organ weight and clinical pathology data: Bartlett's test for variance homogeneity (Bartlett, 1937), Williams’ test (Williams, 1971; 1972), Dunnett's test (Dunnett, 1955; 1964) , Kruskal-Wallis’ test (Kruskal and Wallis, 1952; 1953), Wilcoxon rank sum tests (Wilcoxon, 1945), Shirley's test (Shirley, 1977), Steel's test (Steel, 1959), Fisher’s exact tests (Fisher, 1973).

Clinical signs:

no effects observed

Description (incidence and severity):

After dosing on Day 1, all animals receiving 150 mg/kg/day displayed signs of decreased activity and partially closed eyelids. No similar signs were recorded on any other occasion. Transient chin rubbing and salivation were recorded in animals receiving 150 mg/kg/day. These signs are commonly observed in studies where the test item is administered by oral gavage and, consequently, are considered of no toxicological significance.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

• A control male was found dead on Day 13 with no prior signs recorded.
• A female No in 150 mg/kg/day was killed for welfare reasons on Day 21 of gestation due to general skin pallor, a hunched posture, ungroomed coat and chromodacryorrhea.
• Two females were killed prematurely due to total litter loss (one in control and in 150 mg/kg/day group).
• Two females failed to litter and were therefore prematurely sacrificed on Day 25 of gestation (one control and one in 50 mg/kg/day).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males: Overall body weight gain (Day 1 to 36) was statistically significantly low, when compared with controls, in males receiving 150 mg/kg/day (71% of control).
Females: effect on body weight gain was less apparent; before pairing, body weight gain was lower than controls in females receiving 50 or 150 mg/kg/day but without dose response. During gestation and lactation, body weight gain was higher than controls at all BN-02 dose levels, but again there was no dose response.

Food efficiency:

effects observed, treatment-related

Description (incidence and severity):

Overall group mean food intake was lower than control in males and in females before pairing at 150 mg/kg/day (93 and 92% of control in males and females, respectively), which was attributed to low food consumption during the first week of treatment. Food intake was unaffected in females during gestation or lactation.

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

The hematological examination performed after 5 weeks of treatment for males and on Day 13 of lactation for females revealed no toxicologically significant differences from controls.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The biochemical examination of the blood plasma performed revealed a treatment-related trend towards reduced plasma glucose concentration in males receiving 17, 50 or 150 mg/kg/day and in females receiving 150 mg/kg/day, with the extent of the difference from control being more apparent in males. There was also a reduction of creatinine concentration in males receiving 150 mg/kg/day, which was not present in females.
Phosphorus concentration was statistically significant lower than control and potassium concentration was statistically significantly higher than control in females receiving 150 mg/kg/day. These findings were not apparent in males. All other differences from control were minor, lacked dose-relationship or were confined to one sex and were therefore attributed to normal biological variation.

Urinalysis findings:

not specified

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

- Sensory Reactivity Observations and Grip Strength: Sensory reactivity and grip strength were unaffected by treatment.
- Motor Activity: There was no effect of treatment upon motor activity. All differences from control were transient and/or without dose relationship, and were considered unrelated to treatment.

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The analysis of organ weights performed after six weeks of treatment for males and on Day 13 of lactation for females revealed, when compared with controls, statistically significantly increased liver weights in males and females receiving 150 mg/kg/day. All other inter-group differences from control, including those attaining statistical significance, were minor, lacked dose-relationship or were confined to one sex and were therefore attributed to normal biological variation.

Gross pathological findings:

no effects observed

Description (incidence and severity):

The macroscopic examination performed revealed no test item related lesions. The incidence and distribution of all findings were considered to be unrelated to treatment.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No findings related to the treatment with the test substance administrated by oral gavage were seen in Han Wistar rats. The incidence and distribution of all findings were considered to be unrelated to treatment.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No findings related to the treatment with the test substance administrated by oral gavage were seen in Han Wistar rats. The incidence and distribution of all findings were considered to be unrelated to treatment.

Other effects:

no effects observed

Description (incidence and severity):

- Estrous Cycles, Pre-Coital Interval, Mating Performance, Fertility and Gestation Length
All females allocated to study showed normal 4/5 day estrous cycles during the acclimatization period.
Estrous cycles, pre-coital interval, gestation length and index, mating performance and fertility were considered unaffected by treatment with the test substance. All females showed diestrus at termination.

- Thyroid Hormone Analysis
Serum thyroxine (T4) concentrations in adult males and offspring on Day 13 of age were considered to be unaffected by treatment.
In female offspring of parental animals receiving 150 mg/kg/day, serum T4 concentration was statistically significantly lower than control but there was no similar finding in male offspring. Conversely, in adult males receiving 150 mg/kg/day, T4 concentration was higher than control. Given the difference in the direction of the variation from control between the adults and offspring, the lack of a dose relationship and the lack of findings in male offspring, these findings were attributed to normal biological variation. As there was considered to be no effect of treatment, no further analysis of T4 or TSH was required.

Details on results:

The oral administration of the test substance to rats at dose levels of 17, 50 or 150 mg/kg/day was generally well tolerated. There was no adverse effect of treatment upon the clinical condition of the animals, their behavior in the arena, sensory reactivity or grip strength. A reduction of body weight gain and food intake seen at 150 mg/kg/day in males throughout treatment, and also in females before pairing was considered to be a non-specific indicator of toxicity. This effect was considered adverse in males only.

Five premature deaths occurred during the study, however as three of these occurred in the control group, they were unrelated to treatment. After dosing on Day 1, all animals receiving 150 mg/kg/day displayed signs of decreased activity and partially closed eyelids. No similar signs were recorded on any other occasion, therefore this single, transient occurrence was considered non-adverse.

There were no histopathological correlates for the high liver weights, or any findings in the kidney to account for the reduced plasma glucose and creatinine concentrations or the variations to plasma and potassium, which were therefore considered non-adverse.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

no

Formulation Analysis:

The mean concentrations of 6 -methyl-3,4 -dihydro-2H-1,4 -benzoxazine in the first and last test formulations analyzed were in the range -1.5 to +1.0% of the nominal concentration.  These results were therefore within applied limits if -15%/+10% of the nominal concentration, demonstrating accurate formulation.  The difference from mean remained within 5%, confirming the precision of analysis.

Conclusions:

It is concluded that the oral administration of the test substance to Han Wistar rats was generally tolerated in the adult animals but caused signs of decreased activity and partially closed eyelids at 150 mg/kg/day, which, due to the isolated, transient occurrence was considered non-adverse. In males, there was a 29% reduction of body weight gain at 150 mg/kg/day which was considered adverse. Due to the adverse effect on body weight gain in males at 150 mg/kg/day, the no observed adverse effect level (NOAEL) of 6-methyl-3,4-dihydro-2H-1,4-benzoxazine for systemic toxicity was considered to be 50 mg/kg/day for males and 150 mg/kg/day for females.

Executive summary:

Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was conducted (Covance Laboratories Limited, 2020, Study TP20CQ) to assess the general toxicity and reproductive toxicity of the test substance in the Han Wistar rat. The study was conducted in accordance with OECD 422 guideline and in compliance with GLP.

 

Three groups of ten male and ten female rats received the test substance at doses of 17, 50 or 150 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 12 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 13 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, corn oil, at the same volume dose as treated groups.

 

The oral administration of the test substance to rats was generally well tolerated. There was no adverse effect of treatment upon the clinical condition of the animals, their behavior in the arena, sensory reactivity or grip strength. A reduction of body weight gain and food intake seen at 150 mg/kg/day in males throughout treatment, and also in females before pairing was considered to be a non-specific indicator of toxicity. This effect was considered adverse in males only. Five premature deaths occurred during the study they were unrelated to treatment. After dosing on Day 1, all animals receiving 150 mg/kg/day displayed signs of decreased activity and partially closed eyelids. No similar signs were recorded on any other occasion, therefore this single, transient occurrence was considered non-adverse.

 

There were no histopathological correlates for the high liver weights, or any findings in the kidney to account for the reduced plasma glucose and creatinine concentrations or the variations to plasma and potassium, which were therefore considered non-adverse.

 

Due to the adverse effect on body weight gain in males at 150 mg/kg/day, the no‑observed‑adverse‑effect level (NOAEL) of 6 -methyl-3,4 -dihydro-2H-1,4 -benzoxazine for systemic toxicity was considered to be 50 mg/kg/day for males and 150 mg/kg/day for females. The NOAEL for reproductive/developmental toxicity was 150 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP compliant guideline sub-acute study 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

In a GLP compliant, OECD test guideline 422 sub-acute orat toxicity test it wass concluded that the oral administration of the test substance to Han Wistar rats was generally tolerated in the adult animals but caused signs of decreased activity and partially closed eyelids at 150 mg/kg/day, which, due to the isolated, transient occurrence was considered non-adverse. In males, there was a 29% reduction of body weight gain at 150 mg/kg/day which was considered adverse. Due to the adverse effect on body weight gain in males at 150 mg/kg/day, the no observed adverse effect level (NOAEL) of the substance for systemic toxicity was considered to be 50 mg/kg/day for males and 150 mg/kg/day for females.

Justification for classification or non-classification

GLP compliant guideline study with a klimisch score of 1