Benzonitrile, 4-[(1,6-dihydro-4-hydroxy-6-oxo-2-pyrimidinyl)amino]-

Endpoint summary

Description of key information

Repeated dose toxicity - oral: In a combined 28-day repeated dose toxicity study with the reproduction/developmental toxicity screening test, the test substance was administered daily to rats up to a dose level of 1000 mg/kg body weight/day (OECD 422; Van Otterdijk, 2016). The NOAEL is established as at least 1000 mg/kg body weight/day. The substance is therefore not classified as STOT RE, according to CLP Regulation.

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 tothe 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:

2015-09-18 to 2015-11-27

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)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.3650 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test)

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

no

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

No testing guidelines were applicable for the pilot phase, as this part of the study was intended for dose level selection purposes only.

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I15CB0987
- Expiration date of the lot/batch: 2016-07-29 (pilot phase); 2015-12-05 (main phase)
- Purity test date: 2016-05-19 (pilot phase), 2015-08-17 (main phase)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Solubility and stability of the test substance in the solvent/vehicle: Stability of formulations over 6 hours at room temperature under normal laboratory light conditions (concentration range 1-200 mg/ mL) was confirmed as part of the analytical method development and validation study (Project 509773).

FORM AS APPLIED IN THE TEST (if different from that of starting material): suspension (Groups 2, 3 and 4).

OTHER SPECIFICS: correction factor is 1.00

Species:

rat

Strain:

Wistar

Details on species / strain selection:

This species and strain of rat was recognized as appropriate for general and reproduction toxicity studies. Charles River Den Bosch had general and reproduction/developmental historical data in this species from the same strain and source. This animal model had been proven to be susceptible to the effects of reproductive toxicants.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approx. 10-12 weeks (females, at start pretest); approx 10-12 weeks (males, at start treatment)
- Weight at study initiation: 200-243 g (females); 294-368 g (males)
- Fasting period before study: no
- Housing:
Pretest: Females were housed in groups of 5 females/cage in Macrolon plastic cages (MIV type, height 18 cm).
Pre-mating: Animals were housed in groups of 5 animals/sex/cage in Macrolon plastic cages (MIV type, height 18 cm).
Mating: Females were caged together with males on a one-to-onebasis in Macrolon plastic cages (MIII type, height 18 cm).
Post-mating: Males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 animals/cage. Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet
- Water (e.g. ad libitum): Free access to tap-water
- Acclimation period: At least 5 days prior to start of pretest (females) or treatment (males).

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10 room air changes/hour
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES:
From: 2015-09-18 (females, start pretest); 2015-10-02 (males, start treatment), 2015-11-08/09/10/11/12/14 (pups, delivery of litters)
To: 2015-11-02 (males, necropsy); 2015-11-20/23/24/26 (pups, necropsy on PND 13-15); 2015-11-13/16/23/24/25/27 (females, necropsy on PND 14-16)

Route of administration:

oral: gavage

Details on route of administration:

Method: Oral gavage, using a plastic feeding tube.
Frequency: Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

Vehicle:

propylene glycol

Remarks:

specific gravity 1.036

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- Formulations (w/w) were prepared daily within 6 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle (1.036). A correction was made for the purity/composition of the test item. A correction factor of 1 was used. Formulations were placed on a magnetic stirrer during dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch and on information provided by the Sponsor.
- Concentration in vehicle: 0 mg/mL (Group 1; control), 20 mg/mL (Group 2), 60 mg/mL (Group 3), 200 mg/mL (Group 4)
- Amount of vehicle (if gavage): 5 mL/kg body weight. Actual dose volumes were calculated according to the latest body weight.
- Lot/batch no. (if required): no data
- Purity: no data

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses were conducted on a single occasion during the treatment phase (2015-10-14; Day 13 of treatment), according to a validated method (Test Facility Study no. 509773). Sextuplicate samples (i.e. 3 sets of duplicate samples) were collected. Two sets of duplicate samples were stored as reserve samples. Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Once analytical results were approved in the raw data by the Principal Scientist, the reserve samples were destroyed. In addition to the criteria mentioned in the validated analytical method, each calibration curve was accepted if the average of the retention times and response factors of the data points used to construct the calibration line were within a range of ±10% compared to those obtained during the method validation. The accuracy of preparation was considered acceptable if the mean measured concentrations were 85-115% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Stability of the test item under test conditions was demonstrated in the method validation study (Test Facility Study no. 509773).

Duration of treatment / exposure:

31 days (males); 52-56 days (females that delivered); 42-45 days (females which failed to deliver)
Pups were not dosed directly but could have potentially been exposed to the test item in utero, via maternal milk or from exposure to maternal urine/faeces.

Frequency of treatment:

Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

Group 1 (control)

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

Group 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

Group 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

Group 4

No. of animals per sex per dose:

10 animals/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels were based on the results of a 10-day range finding study with T002326 (Test Facility Study no. 508974). At the administered dose levels of 500 and 1000 mg/kg/day, no mortality occurred. No toxicologically relevant clinical signs were noted. Body weight and food intake and organ weights were considered unaffected by treatment, and no necropsy findings were noted. Dose levels of 100, 300 and 1000 mg/kg/day were selected in consultation with the Sponsor.
- Rationale for animal assignment (if not random): randomized

Positive control:

no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily (early in the morning and close to the end of the working day).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily from treatment onwards up to the day prior to necropsy, detailed clinical observations were made in all animals. Once prior to start of treatment and at weekly intervals during the treatment period this was also performed outside the home cage in a standard arena. The time of onset, grade and duration of any observed sign was recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of treatment and weekly thereafter. Mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on PND 1, 4, 7 and 13. Body weight gain was calculated and reported.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Weekly, except for males and females which were housed together for mating and for females without evidence of mating. Food consumption of mated females was measured on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on PND 1, 4, 7 and 13. Relative food consumption was calculated and reported.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable

FOOD EFFICIENCY: No

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations: Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy from the selected 5 animals/sex/group
- Anaesthetic used for blood collection: Yes, Isoflurane
- Animals fasted: Yes, the animals were deprived of food overnight (with a maximum of 24 hours) before blood sampling, but water was available
- How many animals: 5 animals/sex/dose
- Parameters examined:
The following haematology parameters were determined in blood prepared with K3-ETA as an anti-coagulant: White blood cells (WBC); Neutrophils; Lymphocytes; Monocytes; Eosinophils; Basophils; Red blood cells; Reticulocytes; Red blood cell distribution width (RWD); Haemoglobin; Haematocrit; Mean corpucular volume (MCV); Mean corpuscular haemoglobin (MCH); Mean corpucular haemoglobin concentration (MCHC); Platelets

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy from the selected 5 animals/sex/group
- Animals fasted: Yes, the animals were deprived of food overnight (with a maximum of 24 hours) before blood sampling, but water was available
- How many animals: 5 animals/sex/dose
- Parameters examined:
All parameters were determined in plasma, except for bile acids which were determined in serum: Alanine aminotransferase (ALAT); Aspartate aminotransferase (ASAT); Alkaline Phosphatase (ALP); Total protein; Albumin; Total bilirubin; Bile acids; Urea; Creatinine; Glucose; Cholesterol; Sodium; Potassium; Chloride; Calcium; Inorganic Phosphate (Inorg. Phos)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes (Functional Observations)
- Time schedule for examinations: at the end of the treatment period
- Dose groups that were examined: all dose groups
- Battery of functions tested: Hearing ability; pupillary reflex; static righting reflex; grip strength; motor activity

IMMUNOLOGY: No

Sacrifice and pathology:

SACRIFICE
All animals surviving to the end of the observation period were deeply anaesthetized using isoflurane and subsequently exsanguinated.
- Male animals: following completion of the mating period (a minimum of 28 days of dose administration)
- Female animals: on PND 14-16 (females which deliver); on post-coitum day 25 (females which failed to deliver)

GROSS PATHOLOGY: Yes
- After sacrifice, all animals were subjected to a full post mortem necropsy, with special attention being paid to the reproductive organs. Descriptions of all macroscopic abnormalities were recorded.
- The number of implantation sites were recorded for all paired females. - Samples of the following tissues and organs of 5 selected animals/sex/group were collected and fixed in 10% buffered formalin: Adrenal glands (M/F), (Aorta) (M/F), Brain - cerebellum, mid-brain, cortex (7 levels) (M/F), Caecum (M/F), Cervix (F), Clitoral gland (F), Colon (M/F), Coagulation gland (M), (Cowper’s gland) (M), Duodenum (M/F), Epididymides (M), Eyes (with optic nerve (if detectable) and Harderian gland) (M/F), Mammary gland area (males and females) (M/F), Femur including joint (M/F), (Glans penis) (M), (Levator ani plus bulbocavernosus muscle complex (LABC)) (M), Heart (M/F), Ileum (M/F), Jejunum (M/F), Kidneys (M/F), (Lacrimal gland, exorbital) (M/F), (Larynx) (M/F), Liver (M/F), Lung, infused with formalin (M/F), Lymph nodes - mandibular, mesenteric (M/F), (Nasopharynx) (M/F), (Esophagus) (M/F), Ovaries (F), (Pancreas) (M/F), Peyer's patches [jejunum, ileum] if detectable (M/F), Pituitary gland (M/F), Preputial gland (M), Prostate gland (M), Rectum (M/F), (Salivary glands - mandibular, sublingual) (M/F), Sciatic nerve (M/F), Seminal vesicles (M), Skeletal muscle (M/F), Skin) (M/F), Spinal cord -cervical, midthoracic, lumbar (M/F), Spleen (M/F), Sternum with bone marrow (M/F), Stomach (M/F), Testes 4 (M), Thymus (M/F), Thyroid including parathyroid if detectable (M/F), (Tongue) (M/F), Trachea (M/F), Urinary bladder (M/F), Uterus (F), Vagina (F), All gross lesions (M/F)
- Samples of the following tissues and organs of all remaining animals, males that fail to sire and females which fail to deliver, were collected and fixed in 10% buffered formalin: Cervix (F), Clitoral gland (F), Coagulation gland (M), Cowper’s glands (M), Epididymides 4 (M), Glans penis (M), Levator ani plus bulbocavernosus muscle complex (LABC) (M), Mammary gland area (males and females) (M/ F), Ovaries (F), Preputial gland (M), Prostate gland (M), Seminal vesicles (M), Testes 4 (M), Thyroid including parathyroid if detectable (M/F), Uterus (F), Vagina (F), All gross lesions (M/F)

HISTOPATHOLOGY: Yes
- All organ and tissue samples were processed, embedded and cut at a thickness of 2-4 micrometers. These slides were stained with haematoxylin and eosin. The additional slides of the testes (to examine staging of spermatogenesis) were stained with PAS/haematoxylin.
- The following slides were examined by a pathologist:
1) The preserved organs and tissues of the selected 5 animals/sex of Groups 1 and 4.
2) Additional slides of the testes of the selected 5 males of Groups 1 and 4 and all males that failed to sire.
3) All gross lesions of all animals (all dose groups).
4) Thyroid gland of all selected males and females of Groups 2 and 3, based on (possible) treatment-related changes in this organ in Group 4.
5) The reproductive organs of two Group 3 pairs that failed to sire or deliver healthy pups: male no. 22 / female no. 62 (not pregnant) and male no. 29 / female no. 69 (implantation sites only). For female no. 56 / male no. 16, reproductive organs were also examined histopathologically. However, mating was overlooked for this pair.
- All abnormalities were described and included in the report. An attempt was made to correlate gross observations with microscopic findings.
- A peer review on the histopathology data was performed by a second pathologist.

Statistics:

The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off be fore printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg, pale faeces was noted among all females from Week 2 of the premating phase onwards, and for all males on the last day before necropsy.
Salivation seen after dosing among animals at 1000 mg/kg during the treatment period was considered to be a physiological response rather than a sign of systemic toxicity considering the nature and minor severity of the effect and its time of occurrence (i.e. after dosing). This sign may be related to the taste of the test item.
Other clinical signs noted occurred within the range of background findings to be expected for rats of this age and strain which are housed and treated under the conditions in this study. At the incidence observed, these were considered signs of no toxicological relevance.

Mortality:

no mortality observed

Description (incidence):

No mortality occurred during the study period.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No toxicologically relevant changes in body weights and body weight gain were noted.
The statistically significantly lower body weight gain of females at 1000 mg/kg during the second week of the premating period was slight in nature and with continuation of treatment body weight gain was similar to controls for these females. As such, this change was considered to be of no toxicological significance.
Other variations in body weights and body weight gain among treated groups remained similar to control levels throughout treatment.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption before or after allowance for body weight was similar between treated and control animals

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):

Haematological parameters of selected rats were considered unaffected by treatment.
Any statistically significant changes in haematology parameters were considered to be unrelated to treatment as these occurred in the absence of a dose-related trend.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Females at 1000 mg/kg had a statistically significantly higher mean cholesterol level (approximately 42% higher than the control mean).
No further (statistically significant) changes in clinical biochemistry parameters occurred that were considered to be related to treatment. One control male had a very high alanine and aspartate aminotransferase activity (ALAT and ASAT). There were no morphological correlates that would support or explain this incidental finding.
Thyroid hormone analyses: Serum levels of T4 and TSH in F0 males were considered unaffected by treatment.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

Hearing ability, pupillary reflex and static righting reflex were normal in all selected animals. Grip strength and motor activity showed no variations that were considered to be related to treatment. All groups showed a similar motor activity habituation profile with a decreasing trend in activity over the duration of the test period.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

All organ weight differences observed, including those that reached statistical significance, were not considered to be of toxicological relevance.
The statistically significant increase in glans penis to body weight ratio at 1000 mg/kg was small in nature and occurred in the absence of any organ weight changes in other accessory sex organs or any histopathological changes in reproductive organs. Hence, this variation was not considered to be of toxicological relevance.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Macroscopic observations at necropsy did not reveal any alterations that were considered to have res ulted by treatment with the test item.
Incidental findings among control and treated animals were within the background range of findings that are encountered among rats of this age and strain, and did not show a dose-related trend. These necropsy findings were therefore considered to be unrelated to treatment.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Hypertrophy of follicular cells of the thyroid gland was recorded at a slightly increased severity in males and females at 1000 mg/kg.
Remaining histologic changes were considered to be incidental findings. There was no test item related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations.

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Critical effects observed:

no

Conclusions:

In conclusion, treatment with JNJ-4370561-AAA (T002326) by oral gavage in male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg revealed no adverse (parental) toxicity up to 1000 mg/kg.
Based on these results, a (parental) No Observed Adverse Effect Level (NOAEL) of at least 1000 mg/kg was derived. Therefore, the substance is not classified as STOT RE according to the CLP Regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

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 toxicity: oral

A combined repeated dose toxicity study with the reproduction/developmental toxicity screening test was performed in rats, in which male and female rats were exposed to 0 (vehicle), 100, 300, 1000 mg/kg bw/day via gavage (OECD 422, Van Otterdijk, 2016). The vehicle used was propylene glycol and the test solutions were prepared daily and administered within 6 hours after preparation.

The test item did not cause mortality during the study. Salivation was seen after dosing among animals at 1000 mg/kg during the treatment. This was considered to be a physiological repsonse rather than a sign of systemic toxicity . The effect might be related to the taste of the test item. There were no adverse effects observed in body weight and body weight gain, food consumption, behaviour, hematology, organ weight including organ / body weight ratios and gross pathology. The serum levels of T4 and TSH in F0 males were considered unaffected by treatment.

Females at 1000 mg/kg had a statistically significantly higher mean cholesterol level (approximately 42% higher than the control mean); no further significant changes in clinical biochemistry parameters occurred that were considered to be related to treatment. Hypertrophy of follicular cells of the thyroid gland was recorded at a slightly increased severity in males and females at 1000 mg/kg. Remaining histologic changes were considered to be incidental findings.

Based on the abovementioned considerations, the NOAEL was considered to be at least 1000 mg/kg bw/day. Therefore, the substance is not classified as STOT RE according to the CLP Regulation.

Repeated 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 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 available data and according to the criteria of the CLP Regulation, T002326 should not be classified as STOT RE via the oral route.