6-amino-2-(2,4-dimethylphenyl)-1H-benz[de]isoquinoline-1,3(2H)-dione

Endpoint summary

Description of key information

The oral LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

18 July 2016 to 09 August 2016

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)

Version / remarks:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008 (including most recent amendments)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF 12 Nousan, Notification No 8147

Version / remarks:

2000 (including the most recent partial revisions)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

- Purity/composition correction factor: Yes, correction factor is 1.031 according to active ingredient

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Crl:WI (Han) (outbred, SPF-Quality)
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Young adult animals (approximately 9 to 10 weeks old)
- Weight at study initiation: 165 to 187 g (mean 174 g). Body weight variation did not exceed ± 20 % of the sex mean.
- Fasting period before study: Yes. Animals were deprived of food overnight prior to dosing and until 3 to 4 hours after administration of the test material. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labelled cages (height 18 cm) containing sterilised sawdust as bedding material and paper as cage-enrichment
- Diet: ad libitum pelleted rodent diet
- Water: ad libitum
- Acclimation period: At least 5 days

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

IN-LIFE DATES: Not reported

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

1 % aqueous solution

Details on oral exposure:

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at the testing facility and on test material data supplied by the Sponsor.

MAXIMUM DOSE VOLUME APPLIED: Dosed at 10 mL/kg bw

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Limit dose

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

2 dose groups, each containing 3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Animals were observed for mortality/viability twice daily. Body weights were recorded on Days 1 (pre-administration), 8 and 15. Clinical signs were observed 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.
- 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 (the method used is not intended to allow the calculation of a precise LD50 value).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

act. ingr.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

No mortality occurred.

Clinical signs:

Orange discoloration of the faeces and/or urine was noted for all animals between Days 1 and 3. This was considered to be due to the colour of the test material.

Body weight:

The mean body weight gain shown by the surviving 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 the animals.

The oral LD50 value 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.

Interpretation of results:

other: Not classified in accordance with EU criteria

Conclusions:

Under the conditions of this study, the oral LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.

Executive summary:

The acute oral toxicity potential of the test material to the rat was investigated in accordance with the standardised guidelines OECD 423, EU Method B1 tris, US EPA OPPTS 870.1100 and JMAFF 12 Nousan Notification No 8147 under GLP conditions using the Acute Toxic Class Method.

The test material was administered by oral gavage to two consecutive 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. Orange discoloration of the faeces and/or urine was noted for all animals between Days 1 and 3. This was considered to be due to the colour of the test material. The mean body weight gain shown by the animals over the study period was considered to be normal and no abnormalities were found at macroscopic post mortem examination of the animals.

Under the conditions of this study, the oral LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

One study is available, conducted in accordance with standardised guidelines under GLP conditions. The quality of the database is therefore considered to be high.

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

Oral

The acute oral toxicity potential of the test material to the rat was investigated in accordance with the standardised guidelines OECD 423, EU Method B1 tris, US EPA OPPTS 870.1100 and JMAFF 12 Nousan Notification No 8147 under GLP conditions using the Acute Toxic Class Method. The study was awarded a reliability score of 1 in accordance with the criteria set forth by Klimisch et al. (1997).

The test material was administered by oral gavage to two consecutive 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. Orange discoloration of the faeces and/or urine was noted for all animals between Days 1 and 3. This was considered to be due to the colour of the test material. The mean body weight gain shown by the animals over the study period was considered to be normal and no abnormalities were found at macroscopic post mortem examination of the animals.

Under the conditions of this study, the oral LD50 value in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does not require classification with respect to acute toxicity via the oral route.