4-[3-(1-naphthylamino)propyl]morpholine

Endpoint summary

Description of key information

A single acute oral toxicity study (rats) is available for the registered substance. Acute oral and dermal toxicity studies are also available for the commercial product containing the registered substance (ca. 28%).

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:

April 22, 2016 to August 04, 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

RCCHan:WIST

Sex:

female

Details on test animals or test system and environmental conditions:

Acclimatisation period: 6 - 20 Days
Housing: individually in polypropylene solid bottom cages with Corn Cob bedding material. Water bottle (polypropylene water bottle with stainless steel nozzle).
Enrichment: Wooden Block
Identification: tail tattoo
Feed and Water: ad libitum (with exception of overnight fasting at study termination and 3 hours post dosing)
Temperature: between 20 and 23 degrees C
Humidity: 49-58%
Airchanges: 17 per hour
Photoperiod: 12 hours light/dark per day (light period: 6am to 6pm)

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

Single dose with a constant dose volume of 10mL/kg bw

Doses:

550, 1750, 2000 and 5000 mg/kg bw

No. of animals per sex per dose:

550: 1
1750: 3
2000:1
5000: 3

Control animals:

no

Details on study design:

An initial study was performed using a single animal at a dose of 2000 mg/kg bw. THis animal was observed for behaviour and mortality. It was found dead on study day 2. The main study therefore proceeded with a single animal dosed at 550 mg/kg bw.
This animal survived and so 3 animals were then dosed with 1750 mg/kg bw and 3 animals dosed with 5000 mg/kg bw (see note below regarding the dose level choice).
Animals were monitored for clinical signs and mortality at 0.5, 1, 2, 3, 4, and 5-6 hours post administration of test material and then twice daily each day for the remainder of the observation period (14 days post dosing).
At study termination, all surviving animals were humanely Euthenized via carbon dioxide administration. All rats on the study (including those that died during the observation period) were subjected to a gross pathological exam.
- External examination
- opening of abdominal and thoracic cavities,
- stomach opened and contents rinsed/removed; examination of mucosal surface for signs of irritation

Statistics:

LD50 determined using AOT 425 StatPgm. Methodology: Dixon's maximum likelihood method

Preliminary study:

The animal dosed with 2000 mg/kg bw died within 24 hours of dosing

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 3 100 mg/kg bw

Based on:

test mat.

95% CL:

> 1 750 - < 5 000

Mortality:

2000 mg/kg bw: 1 animal dosed, died within 24 hours of dosing
550 mg/kg bw: 1 animal dosed, no mortality
1750 mg/kg bw: 3 animals dosed, no mortality
5000 mg/kg bw: 3 animals dosed, 1 died within first 6 hours, the remaining two died within 24 hours post dosing

Clinical signs:

other: 550 mg/kg bw: no clinical signs 1750 mg/kg bw: Lethargy observed in all 3 rats for the first 3 days post dosing. Then behaviour returned to normal 2000 and 5000 mg/kg bw: Lethargy observed in all rats post-dosing prior to death.

Gross pathology:

550 and 1750 mg/kg bw: no abnormality detected (internal and external exam)
2000 mg/kg: no external abnormalities; liver was pale (rated as mild)
5000 mg/kg bw: no external abnormalities; liver was congested (rated as minimal)

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The LD50 was determined to be 3110 mg/kg bw per day with a 95% confidence limit of 1750 to 5000 mg/kg bw.

Executive summary:

An acute oral toxicity study (Up-and-Down Procedure) was conducted using eight female Wistar rats given a single oral dose of 4-(3-(1-Naphthylamino)propyl)morpholine mixed in corn oil. Initially a limit test was conducted with the dose level of 2000 mg/kg body weight in rat N° 1. This rat was found dead on day 2. Hence, a Main Test was conducted with the starting dose level of 550 mg/kg body weight in rat N° 2. This rat survived; hence the six additional female Wistar rats received doses of 1750 (rat N° 3, 6 and 8) and 5000 (rat N° 4, 7 and 9) mg/kg body weight according to the Up and Down Procedure.

No signs of toxicity were observed in the rats treated with 550 (rat N° 2) mg/kg body weight. Lethargy was observed in the rats treated with 2000 (rat N° 1), 1750 (rat N° 3, 6 and 8) and 5000 (rat N° 4, 7 and 9) mg/kg body weight. Rat N° 1, 4, 7 and 9 were found dead by day 2.

All surviving rats gained body weight by the end of the study.

External and internal examination of found dead and terminally sacrificed rats did not reveal any lesions of pathological significance. Internal examination of found dead rats revealed mild pale liver (rat N° 1) and minimal congestion of liver (rat N° 4, 7 and 9). Lesions observed in found dead rats could be correlated with the test item used in the present study.

The acute oral LD50 of the 4-(3-(1-Naphthylamino)propyl)morpholine was estimated to be 3110 mg/kg body weight (Based on an assumed sigma of 0.5) in female Wistar rats with an approximate 95% confidence interval is 1750 to 5000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 110 mg/kg bw

Quality of whole database:

Good

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

In the OECD guideline acute oral toxicity study (rats, up/down procedure) the LD50 of 4-(3-(1-naphthylamino)propyl)morpholine was determined to be >2000 mg/kg bw (3110 mg/kg bw). This is consistent with data generated previously on the commercially available product (Mortrace MP, containing 28% of the registered substance), where the LD50 was approximately 6770 mg/kg bw (males and females).

No dermal acute toxicity data exist for the 4-(3-(1-naphthylamino)propyl)morpholine itself, however data do exist for the commercial product (Mortrace MP). The dermal toxicity of this product was assessed using rabbits in a limit dose study (2000 mg/kg bw, 3 male and 3 female rabbits). No mortality was observed in this study.

Given the low order of oral toxicity and the absence of toxicity when the commercial product was tested at the limit dose via the dermal route, it is considered appropriate to waive the acute dermal toxicity study in accordance with column 2 of the REACH text.

Justification for classification or non-classification

LD50 (Oral, rat, female) is >2000 mg/kg bw and so the CLP criteria for acute toxicity are not met.

Where GHS category 5 for acute toxicity applies, this substance would be considered as meeting the criteria for Acute Category 5 due to the LD50 of 3110 mg/kg bw.