Cyclohexanol, 1-[2-amino-1-(4-methoxyphenyl)ethyl]-, hydrochloride (1:1)

Endpoint summary

Description of key information

The acute toxic class method was started at the dose level of 2000 mg/kg in female animals (n=3). All animals died, so the test was continued at the dose level of 200 mg/kg in female animals (n=3). No mortality occurred, so the test was repeated at the same dose level in male animals (n=3). No male animals died therefore the study was terminated after the 14 day observation period.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was performed according to recommended guidelines.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Husbandry
Animal health: Only animals in acceptable health condition were used for the test. It was certified by the veterinarian.
Number of animal room: 243/al
Housing: 3 animals I cage
Cage type: Ill. type polypropylene/polycarbonate
Bedding: laboratory bedding
Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 22 ± 3 °C
Relative humidity: 30-70%

Water Supply
The animals received tap water as for human consumption, ad libitum, from 500 ml bottle.

Route of administration:

oral: gavage

Vehicle:

not specified

Doses:

The acute toxic class method was started at the dose level of 2000 mg/kg in female animals (n=3).
The test was continued at the dose level of 200 mg/kg in female animals (n=3) and then the test was repeated at the same dose level in male animals (n=3).

No. of animals per sex per dose:

3

Control animals:

no

Statistics:

No statistical analysis was performed.

Preliminary study:

The acute toxic class method was started at the dose level of 2000 mg/kg in female animals (n=3): all animals died.

Sex:

female

Dose descriptor:

LD100

Effect level:

ca. 2 000 mg/kg bw

Based on:

test mat.

Sex:

female

Dose descriptor:

LD0

Effect level:

ca. 200 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD0

Effect level:

ca. 200 mg/kg bw

Based on:

test mat.

Mortality:

All treated animals died after the treatment at the dose level of 2000 mg/kg. Death of animals occurred 4 hours, 10 minutes and 62 minutes after the application, respectively. Decreased activity, tremor, convulsions, ventral position and severe dyspnoea were observed immediately before the death.

Clinical signs:

other: In dose group of 2000 mg/kg the following clinical symptoms were observed: decreased activity (3/3), tremor (2/3) on the head, convulsions (2/3) on the upper part of the body, ventral position (2/3), squatting position (3/3), piloerection (2/3), dyspnoea

Gross pathology:

Dead animals
In the female dose group of 2000 mg/kg, point-like haemorrhages (No.: 4697,4720) and reddish mottled colour (No.:4726) were observed in the lungs. The liver was dark red in animal No.: 4720 and congestive in another one (No.:4726). In animal No.: 4720 hyperaemic (reddish) mucous membrane was found in the stomach and the wall of the intestines was edematous. This lately alteration was noticed in animal No.: 4726, too.

Surviving animals
In the male dose group of 200 mg/kg, pulmonary emphysema (No.: 4602,4618) and pinprick-sized (No.: 4599) haemorrhages were found in the lungs. In the female dose group of 200 mg/kg, pulmonary emphysema (No.: 4692,4754) and pinprick-sized haemorrhages (No.: 4740) were detected in the lungs. Besides, pale liver (No.: 4754) and a slight hydrometra (No.: 4740) occurred in this group.
In summary, macroscopic alterations related to the toxic effect of the test item were not found either in the dead or in the surviving animals.

Interpretation of results:

Toxicity Category IV

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral LD50 value of the test item Venlafaxin 2nd Intermediate was estimated between 200 mg/kg and 2000 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

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

The key study shows that (i) LD100 is equal to or lower than 2000 mg/kg while (ii) LD0 is equal to or higher than 200 mg/kg: therefore, the LD50 value is included in this range. At 200 mg/kg female animals were symptom-free and male rats showed mild symptoms which disappear the next day. Moreover, venlafaxine hydrochloride, API that is structural analogue of the test material from which it is synthetized, has a LD50 value equal to 336 mg/kg.

According to CLP Regulation (1272/2008) the cut-off value between the hazard categories 3 and 4 for acute oral toxicity is lined up at 300 mg/kg. Even if a LD50 value was not clearly established for VP*HCl, considering the lack of relevant symptoms at the lower dose (200 mg/kg) and the LD50 value of venlafaxine hydrochloride greater than 300 mg/kg, VP*HCl is classified as Acute Tox 4 in accordance with CLP Regulation.

Justification for selection of acute toxicity – oral endpoint
The effect level is considered higher than 300 mg/kg bw.

Justification for classification or non-classification

According to Directive 67/548/EEC and to Regulation (EC) n. 1272/2008, the substance should be classified for oral acute toxicity as Xn; R22 and Acute Tox 4 H302.