1-benzyl-N-phenylpiperidin-4-amine

Endpoint summary

Description of key information

Acute toxicity: oral

In a GLP compliant K1 acute oral toxicity study in female Crl:WI (Han) (SPF) rats, following the acute toxic class method in accordance with the OECD Guideline 423, EU Method B.1 tris and EPA OPPTS 870.1100, the LD50 was established to exceed 2000 mg/kg body weight (Latour, 2017).

In addition, in a supporting K4 study in rats, an acute oral LD50 value of 311 mg/kg body weight was established (Schellekens, 1990).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

2016-11-03 to 2016-11-22

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF No 8147, 11/2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: I15JB3618
- Expiration date of the lot/batch: 2019-10-09 (retest date)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: no data
- Solubility and stability of the test substance in the solvent/vehicle: no data

OTHER SPECIFICS: correction factor is 1

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 6 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 9-10 weeks old
- Weight at study initiation: 162-194 grams
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Makrolon cages (MIV type; height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS- J. Rettenmaier & Sohne GmbH + CO. KG, Rosenberg, Germany) and paper as cage enrichment (Enviro-dri, Wm. Lillico &Son (Wonham Mill Ltd.), Surrey, United Kingdom).
- 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 before start of treatment under laboratory conditions.

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

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Remarks:

specific gravity 1.036

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 2000 mg/kg
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at Charles River Den Bosch and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve),
1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (turbid solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).

MAXIMUM DOSE VOLUME APPLIED: 10mL/kg

DOSAGE PREPARATION (if unusual): The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficiently for these kinds of studies. Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The toxicity of the test item was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 2000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups.

Doses:

2000 mg/kg (10 mL/kg) body weight

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Mortality/Viability - Twice daily.
Body weights - Days 1 (pre-administration), 8 and 15.
Clinical signs - At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The signs were graded according to fixed scales and the time of onset, degree and duration were recorded:
Maximum grade 4: grading slight (1) to very severe (4)
Maximum grade 3: grading slight (1) to severe (3)
Maximum grade 1: presence is scored (1).
- Necropsy of survivors performed: yes - At the end of the observation period, all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necropsy. Descriptions of all internal macroscopic abnormalities were recorded.

Statistics:

No statistical analysis was performed

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred

Clinical signs:

Hunched posture, piloerection and/or salivation was noted for all animals on Days 1 and/or 2.

Body weight:

The mean body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of all animals.

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of T000293 in Wistar rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.
Based on these results, T000293 does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Study with supporting results, no data on methodology, test item or test system. Only a summary report is available.

Principles of method if other than guideline:

No data on methodology, test system, test item

GLP compliance:

not specified

Test type:

other: No data

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 20 rats, nu further data on source
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

VEHICLE
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: no data
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: no data

DOSAGE PREPARATION (if unusual): no data

Doses:

80, 160, 320 and 640 mg/kg body weight

No. of animals per sex per dose:

5 rats per group; 4 groups

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: no data
- Frequency of observations and weighing: mortality: no data; clinical observations: no data
- Necropsy of survivors performed: no data

Statistics:

No data

Sex:

not specified

Dose descriptor:

LD50

Effect level:

311 mg/kg bw

Based on:

test mat.

95% CL:

>= 129 - <= 748

Mortality:

640 mg/kg bw: 4/5 rats died within 1 hour
320 mg/kg bw: 4/5 rats died within 1 hour
160 mg/kg bw: 0/5
80 mg/kg bw: 0/5

Clinical signs:

160 mg/kg bw: light tremors during first 3 hours after treatment
80 mg/kg bw: normal behaviour

Body weight:

No data

Gross pathology:

No data

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The oral LD50 for the substance T000293 is 311.0 (129-748) mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

311 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

An acute oral toxicity study with T000293, according to the acute toxic class method (OECD Guideline 423, EU Method B.1 tris and EPA OPPTS 870.1100) in female Crl:WI(Han) (SPF) rats was performed (Latour, 2017). The test item was administered by oral gavage to two subsequent groups of three female Wistar rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Hunched posture, piloerection and/or salivation was noted for all animals on Days 1 and/or 2.

The mean body weight gain shown by the animals over the study period was considered to be normal.

No abnormalities were found at macroscopic post mortem examination of all animals.

The oral LD50 value of JNJ-1594008-AAA (T000293) in Wistar rats was established to exceed 2000 mg/kg body weight.

In addition, a supporting K4 study in rats is available. In this study, rats were exposed to either 80, 160, 320 or 640 mg/kg body weight (5 rats per group).

At 80 mg/kg 0/5 animals died and behavior was normal

At 160 mg/kg 0/5 animals died but light tremors were observed during the first 3 hours after treatment

At 320 and 640 mg/kg 4/5 animals died within 1 hour

An acute oral LD50 value of 311 mg/kg body weight was established (Schellekens, 1990).

An Expert Report of Janssen Research & Development, a division of Janssen Pharmaceutica N.V. provides an expert judgement of both acute oral toxicity studies with T000293 (De Smedt and Lampo, 2018).

Expert conclusion: Based on the high mortalities (4/5 rats 1 hour after application) and the observation of tremors at dose 160 mg/kg, it is suggested to take 311 mg/kg bw as LD50 value.

Justification for classification or non-classification

Based on the available LD50 value of 311 mg/kg body weight and the criteria of the CLP Regulation, T000293 should be classified as acute oral toxicant category 4 and should be labelled as H302: Harmful if swallowed.