(4aR*, 8aR*)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-one hydrochloride (1:1)

Endpoint summary

Description of key information

Repeated dose toxicity: oral: The potential toxicity of T002102 after repeated oral exposure was assessed in a 28 days repeated dose, GLP-compliant study, performed according to the OECD Guideline 407 and EU Method B.7 (K1, RCC, 2002).The NOAEL and NOEL is established as 41.85 mg/kg/day.The test substance is classified as STOT RE 2 according to CLP classification.

Repeated dose toxicity: inhalation: A key study is available for the oral route of exposure. According to the REACH regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicity: dermal: A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

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

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2001-08-23 to 2001-10-04

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD guideline 407 "Repeated dose 28-Day Oral Toxicity Study in Rodents" and EU method B.7. "Repeated dose (28 day) toxicity (oral)" without deviation.

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Certificate from the Swiss GLP Monitoring Authorities

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: HanBrl:WIST (SPF), RCC Ltd. Biotechnology & Animal Breeding Division, CH-4414 Fűllinsdorf/Switzerland
- Age at delivery: 6 weeks
- Weight at acclimatization: 131-151 grams (males; mean 139 grams); 113-131 grams (females; mean 123 grams)
- Fasting period before study: no data
- Housing: In groups of 5 in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding.
- Diet (e.g. ad libitum): ad libitum, pelleted standard Provimi Kliba 3433 (batch no.73/01) rat maintenance diet
- Water (e.g. ad libitum): ad libitum, community tap water from Itingen
- Acclimation period: 7 days, under test conditions after health examination. Music during the light period

ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 22 ± 3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 2001-09-06 To: 2001-10-04

Route of administration:

oral: gavage

Vehicle:

other: PEG 300

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- The test substance formulations were prepared weekly. The test substance was weighed into a glass beaker on a tared Mettler balance and the vehicle added (w/v). The mixtures were prepared using a magnetic stirrer and stored in a glass beaker at room temperature. Homogeneity of the test substance in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg body weight
- Lot/batch no. (if required): 412565/1 51301
- Expiry date: 2006-05-01
- Storage conditions: at room teperature (17-23°C) in the original container in the dark

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken after experiment start. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed by RCC Ltd. (Environmental Chemistry & Pharmanalytics Division) according to an HPLC analytical method.

Duration of treatment / exposure:

28 days

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

6.46 mg/kg/day after correction based on analytical verification

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

41.85 mg/kg/day after correction based on analytical verification

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5 males and 5 females per dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on the results of a non-GLP, 5-day, dose-range-finding study (RCC Study Number 821698) in which the test substance was administered by gavage to 2 rats per group and sex.

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once before commencement of administration; twice daily on days 1-3; and once daily on days 4-28

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before commencement of administration and once weekly (weeks 1-3) thereafter.
- Parameters: the animals were observed in their home cages, outside their home cages in a standard arena and in the hand.

BODY WEIGHT: Yes
- Time schedule for examinations: weekly during pretest, treatment and before necropsy.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule: recorded once during the pretest period and weekly thereafter
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks, collected early in the working day to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube.
- Anaesthetic used for blood collection: light isoflurane
- Animals fasted: The animals were fasted for approximately 18 hours before blood sampling, but allowed access to water ad libitum.
- How many animals: all animals
- Parameters examined included: erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, reticulocyte fluorescene ratios, nucleated erythrocytes (normoblasts), Heize bodies, methemoglobin, total leukocyte count, differential leukocyte count, red blood cell morphology, thromboplastin time and activated partial thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks, collected early in the working day to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube.
- Anaesthetic used for blood collection: light isoflurane
- Animals fasted: The animals were fasted for approximately 18 hours before blood sampling, but allowed access to water ad libitum.
- How many animals: all animals
- Parameters examined included: glucose, urea, creatinine, total bilirubin, total cholesterol, triglycerides, phospholipids, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatinine kinase, alkaline phosphatase, gamma-glutamyl transferase, sodium, potassium, chloride, calcium, phosphorous inorganic, albumin, total protein, globulin and the albumin/globulin ratio.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals.
- Dose groups that were examined: all dose groups
- Battery of functions tested: During week 4 a modified Irwin screen test was performed on all animals which resided at the study at that time point. The following tests were performed: appearance (piloerection, salivation, hunched posture); motor (ataxia, tremor/twitching, prostration, circling, spasm); behavior (hyperactivity, somnolence, increased exploration, reduced grooming, vocalization); respiration (dyspnea, tachypnea, bradypnea); reflexes (blink, pinna, iridic light reflex, push-off (hind leg), pain response, startle/hearing); miscellaneous (lacrimation, limbs cyanotic, mydriasis, miosis, exophthalmos, reduced muscle tone, soft feces, bedding dark yellow); grip strength; locomotor activity.
- grip strength: forelimb and hind limb strength measurements were pêrformed using a push-pull strain gauge. The animals were placed with the forpaws inside a triangular grasping ring and with the hind paws outside a triangular grasping ring. Using one hand, the animals were held towards the base of the tail and steadily pulled away or towards the ring until the grip was broken. Each measurement was repeated three times, the means were calculated and recorded.
- locomotor activity: locomotor (decreased or increased) activity was measured quantitatively with Activity Monitor AM 1052 system. Animals were randomized and monitoried during the fourth treatment week for a 60-minute period and the total activity of this time period was recorded. Low beams count was reported in 15-minute intervals as well as the total activity of the measuring period.

Mortality/viability:
-Time schedule: twice daily

Sacrifice and pathology:

GROSS PATHOLOGY:
- Necropsy: All animals were weighed and necropsied after 4 weeks. Descriptions of all macroscopic abnormalities were recorded. All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguination.
- Samples of tissues and organs were collected from all animals at necropsy and fixed in neutral phosphate buffered 4% formaldehyde solution
- following tissues and organs were collected: adrenal glands, aorta, bone, bone marrow, cecum, colon, duodenum, epididymides, esophagus; eyes with optic nerve, Harderian gland, Ileum (with Peyer's patches), Jejunum (with Peyer's patches), kidneys, larynx, lacrimal gland, liver, lungs, lymph nodes, mammary gland area, nasal cavity, ovaries, pancreas, pituitary gland, prostate gland, rectum, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, stomach, testes, thyroid, tongu, trachea, urinary bladder, uterus, vagina, gross lesions.

Organ weights:
- The following organ weights were recorded: brain, heart, liver, thymus, kidneys, adrenals, spleens, testes, epididymides, and ovaries. The organ-to-terminal body weight ratio, as well as organ-to-brain weight ratios were determined.

HISTOPATHOLOGY:
- Slides of adrenal glands, bone marrow, brain, cecum, colon, duodenum, epididymides, heart, Ileum with Peyer's patches, Jejunum with Peyer's patches, kidneys, liver, lungs, lymph nodes, ovaries, prostate gland, rectum, sciatic nerve, seminal vesicles, spinal vesicles, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus, vagina, and gross lesions were collected at scheduled sacrifice from the animals of control and high-dose groups and were examined by a pathologist. As test substance-related morphological changes were detected in the organs of the high-dose animals, the same organs (liver and thyroids) from the animals of the mid- and low-dose groups were examined.

Other examinations:

none

Statistics:

The following statistical methods were used to analyze the grip strength, locomotor activity, body weight, organ weights and ratios, as well as clinical laboratory data:
The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the treated groups and the control groups for each sex (or Student's T-test, as appropriate).
The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
Fisher's exact-test was applied to the macroscopic findings.
Student's t-test was applied to grip strength and locomotor activity.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

- Salivation was noted in 2 males on day 19 and in 1 male on days 20-21 and days 23-28 of treatment at 200 mg/kg/day. This finding was considered to be test substance-related.
- Dark yellow bedding, considered to be possibly caused by discoloration of the urine, was noted in males and females treated with 200 mg/kg/day.
- soft feces was noted from day 10 onwards in males and females of all groups. This finding was considered to be due to the vehicle (PEG300)
- All other dose levels were without findings of toxicological relevance.
- Detailed clinical observations:
- test item treated females were unaffected by treatment during behavioral observations at weeks 1-3
- Salivation was noted during treatment week 3 in two males treated with 200 mg/kg/day. This finding was considered to be test item related

Mortality:

no mortality observed

Description (incidence):

All animals survived until scheduled necropsy.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test substance-related differences in mean body weights or body weight gain were noted at any dose level tested when compared with the controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The mean daily food consumption of the test substance-treated rats compared favorably with those of the controls.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- No test substance-related differences in the hematology parameters were noted in males or females at any dose level tested.
- In females treated with 200 mg/kg/day, the nucleated erythrocyte (normoblasts) count was significantly increased (p<0.05), and exceeded the 95% tolerance limits of the historical control data. However, there were neither effects on the erythrocyte count or on the reticulocyte ratios, nor were similar changes seen in the males. this finding was therefore considered to be irrelevant.
- Significantly reduced methemoglobin levels were noted in males treated with 50 mg/kg/day (p<0.01) and 200 mg/kg/day (p<0.01), whereas significantly increased levels were noted in females treated with 200 mg/kg/day. These contrary differences were considered to be incidental, as all remained within the 95% tolerance limits of the historical control values and concomitant changes were not seen in related parameters.
- The significantly reduced white blood cell counts noted in males and females treated with 10 mg/kg/day (p<0.01) were caused by significantly reduced lymphocyte counts (p<0.01). In the absence of a dose-response relationship, these changes were considered to be incidental.
All remaining differences when compared with the control values were considered to be incidental.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

- Increased cholesterol levels and increased phospholipids were noted in males and females treated with 200 mg/kg/day. Whereas the differences in both parameters in males attained statistical significance (p<0.05), only phospholipids were significantly increased in females (p<0.05). Triglycerides were slightly higher in females treated with 200 mg/kg/day. These changes were considered to be test substance-related.
- The activity of gamma glutamyltransferase was increased in males treated with 200 mg/kg/day (p<0.01) when compared to the controls.
- Increased total bilirubin (p<0.05) was noted in females treated with 200 mg/kg/day, but this difference was considered to be caused by a low control value. Increased phosphorus levels (p<0.05) were noted in males and females treated with 200 mg/kg/day. Increased calcium (p<0.05) was seen in females treated with 200 mg/kg/day when compared with the controls. These differences remained within the 95% tolerance limits of the historical control data, and were considered to be unrelated to the test substance.
- Decreased chloride (p<0.01) levels were seen in females treated with 200 mg/kg/day when compared with the controls, and exceeded the 95% tolerance limits of the historical control data, but this was not seen in males at this dose level and was considered to be incidental.
- All other differences when compared with the control values were not dose dependent and therefore, are considered to be unrelated to the test substance.

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

- test item treated females were unaffected by treatment during behavioral observations at weeks 1-3
- Salivation was noted during treatment week 4 in 1 male treated with 200 mg/kg/day. This finding was considered to be test substance-related. All other dose levels were without findings of toxicological relevance.
- The fore- and hindlimb grip strength of the treated rats were unaffected. Although the mean hindlimb grip strength of the males treated with 200 mg/kg/day was significantly lower (p<0.05) than that of the controls, the forelimb grip strength compared favorably and the hindlimb grip strength of the female rats treated with 200 mg/kg/day was significantly greater than that of the controls. These contrary findings were considered to be unrelated to the test substance.
- The mean locomotor activity of the treated rats was unaffected. A significant reduction in the total locomotor activity of the female treated with 200 mg/kg/day (p<0.05) was not seen in the males treated with 200 mg/kg/day, and a significant increase during 15-30 minutes in the females treated with 10 mg/kg/day (p<0.05) was not dose-dependent. These differences were considered to be unrelated to the test substance.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

- Slightly elevated liver weights were noted in males and females treated with 200 mg/kg/day when compared with the controls. The liver-to-body weight ratio noted in the males, and the absolute liver weight and liver-to-body weight ratio in females (p<0.01), as well as the liver-to-brain weight ratio in females (p<0.05), attained statistical significance when compared with that of the controls.
- All other organ weights and ratios were considered to be similar to the respective controls.

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no gross findings (renal pelvis dilation, thickened thymus, enlarged lymph nodes) which were considered to distinguish test substance-treated rats from those of the control rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

- A number of findings were noted at the end of the treatment period. From these findings, the following distinguished test substance-related rats from those of the control group:
- Liver: centrilobular hypertrophy was noted in 4 of 5 males and 4 of 5 female rats in the 200 mg/kg/day group. The severity of this finding was minimal.
- Thyroid gland: minimal to slightly increased incidence of follicular cell hypertrophy was noted in males and females treated with 200 mg/kg/day when compared with the controls.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Description (incidence and severity):

HISTORICAL CONTROL DATA (if applicable):
- Hematology and clinical chemistry data were compared to the historical control data.

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No test substance-related effects at 41.85 mg/kg/day

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No test substance-related adverse effects were observed at 41.85 mg/kg/day dose level in both males and females.

Dose descriptor:

LOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: see 'Remark'

Critical effects observed:

yes

Lowest effective dose / conc.:

200 mg/kg bw/day (nominal)

System:

other: hepatobiliary and endocrine system

Organ:

liver

thyroid gland

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Results of the analytical verification:

The chemical analysis determined concentration, homogeneity and stability of T002102 in PEG300.

- Acclimatization/Pretest

The mean concentrations of the homogeneity samples were found to be 87.7%, 96.8% and 103.5% of the nominal concentrations of dose group 2 (2 mg/ml), dose goup 3 (10 mg/ml), and dose group 4 (40 mg/ml), respectively. The individual concentrations varied in the range from -5% to +7% of the mean concentrations. Therefore, the test item was found to be homogeneously distributed in the vehicle. T002102 is stable in the vehicle under storage conditions for two hours. The 7-day storage stability samples of dose group 2 and 3 are not within the range as accepted at RCC (+/-10% of the mean value of the respective content samples).

-Administration/Test

The overall mean concentrations of the homogeneity samples were found to be 90.1%, 95.4% and 98.9% of the nominal concentrations of dose group 2 (2 mg/ml), dose group 3 (10 mg/ml), and dose group 4 (40 mg/ml), respectively. The individual concentrations varied in the range from -2% to +2% of the mean concentrations. Therefore, the test item was found to be homogeneously distributed in the vehicle.

Expert report (De Smedt et al, 2016): the test item formulations are prepared weekly. The measured concentration of the dose formulation sample, in the dose groups 10 and 50 mg/kg body weight/day were resp. 64.6% and 83.7% of the nominal concentration (resp. 2 and 10 mg/mL) in the stability test after 7 days. Since these results were outside the accepted range of +/- 10%, it was decided to correct the NOAEL and NOEL rather than to repeat this study. The NOAEL and NOEL were established at 50 mg/kg body weight/day, hence a correction factor 83.7% was applied. In conclusion, both the NOAEL as the NOEL for this study are considered to be 41.85 mg/kg body weight/day.

Conclusions:

Based on the results of this study, 41.85 mg/kg body weight/day of test substance was established as the no-observed-effect-level (NOEL) and as the no-observed-adverse-effect-level (NOAEL).
Based on CLP classification, the substance should be considered to be classified as STOT RE 2.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

41.85 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

hepatobiliary

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral:

The effect of repeated exposure to T002102 following oral administration was examined in a subacute toxicity study in SPF-bred Wistar rats of both sexes. The substance was administered daily by oral gavage at 10, 50 and 200 mg/kg/day (nominal concentrations), formulated in polyethylene glycol 300 at 5mL/kg bw. 10 Wistar rats per dose (5 males and 5 females) were exposed for a period of 28 days.

Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during the acclimatization and treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 4.

At the end of the dosing period, blood samples were withdrawn for hematology and plasma chemistry analyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.

From the animals of the low and middle dose groups, thyroids and liver were examined to establish a no-effect level. Oral administration of T002102 to Wistar rats at doses of 10, 50 and 200 mg/kg/day (nominal concentrations), for 28 days resulted in no deaths, no clinical signs of toxicological relevance in females, no changes in the parameters of the functional observational battery of females, no effects on the grip strength and locomotor activity, no effects on food consumption and body weight, no effects on hematology parameters, and no macroscopical findings.

Substance-related findings were restricted to sporadic salivation in male rats at high dose level (during daily and weekly observations as well as functional observational battery), findings in the clinical biochemistry parameters indicative of minor changes in lipid metabolism of males and females at high dose level, increased liver weights in males and females at high dose level, and microscopical findings in the liver (minimal centrilobular hypertrophy) and thyroid gland (follicular cell hypertrophy) in males and females at high dose level.

Based on the results of this study, 41.85 mg/kg body weight/day of test substance was established as the no-observed-effect-level (NOEL) and as the no-observed-adverse-effect-level (NOAEL).

 

Repeated dose toxicity: inhalation

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicity: dermal
A key study is available for the oral route of exposure. According to the REACH regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for classification or non-classification

Based on the results of the repeated dose toxicity via the oral route and the criteria of the CLP Regulation, T002102 should be classified as STOT repeated exposure category 2 (H373). Significant toxic effects (LOAEL) were observed at 200 mg/kg bw (nominal concentration). This value is situated within the guidance value ranges for classification in category 2 for STOT RE (28 days study: > 30 and ≤ 300 mg/kg bw).