N-cyclohexylcyclohexanamine 2-[1-[[[(1R)-1-[3-[(1E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(2-hydroxypropan-2-yl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetate

Endpoint summary

Description of key information

Two studies, acute oral and dermal were performed on rats with results predicting the LD50 >2000 mg/kg bw.

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:

24 December 2014 to 13 January 2015

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)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Qualifier:

according to guideline

Guideline:

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

GLP compliance:

yes

Test type:

acute toxic class method

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: approx. 11 weeks old
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean.
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance.
- Housing: 3 animals per cage in labeled Makrolon cages.
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 5 days before start of treatment

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

IN-LIFE DATES: From: Dec 24th, 2014 To: Jan 13th, 2015

Route of administration:

oral: gavage

Vehicle:

other: 1% Aqueous carboxymethyl cellulose

Details on oral exposure:

Using all available information on the toxicity of the test material, 2000 mg/kg was chosen as the starting dose.
dose level: 2000 mg/kg
concentration: 10 ml/kg body weight

Doses:

dose level: 2000 mg/kg ( females)

No. of animals per sex per dose:

2 groups of 3 females each

Control animals:

no

Details on study design:

The toxicity of the test substance 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.

Statistics:

No statistical analysis was performed.

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.
Scheduled necropsy Day 15 after treatment.

Clinical signs:

other: Hunched posture was noted for all animals between Days 1 and 4. Additionally, piloerection was noted for three animals on Day 1.

Gross pathology:

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

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 value of Montelukast dicyclohexylamine salt 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, Montelukast dicyclohexylamine salt 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 (2011) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

7th January 2015 - 21st January 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: Body weight variation did not exceed +/- 20% of the sex mean.
- Housing: Individually housed in labeled Makrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Lignocel S 8-15, JRS - J.Rettenmaier & Söhne 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 (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: Acclimatization period was at least 5 days before start of treatment under laboratory conditions. During the acclimatization period the animals were group housed in Makrolon cages (MIV type, height 18 cm).

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

Type of coverage:

occlusive

Vehicle:

other: 1% Aqueous carboxymethyl cellulose

Details on dermal exposure:

TEST SITE
- Area of exposure: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.
-The formulation was applied on an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After 24 hours dressings were removed and the skin cleaned of residual test substance using tap water.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Single dosage, on Day 1. 2000 mg/kg (10 mL/kg) body weight

Duration of exposure:

24 hrs.

Doses:

Single dosage, on Day 1. 2000 mg/kg (10 mL/kg) body weight.

No. of animals per sex per dose:

5 males and 5 females (females were nulliparous and non-pregnant).

Control animals:

no

Details on study design:

- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Mortality/Viability observed twice daily and body weights observed days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales:
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).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: Number of animals: 5; Number of deaths: 0
Female: Number of animals: 5; Number of deaths: 0

Clinical signs:

other: Signs of toxicity related to dose levels: Lethargy, flat posture, hunched posture, piloerection, chromodacryorrhoea (snout) and/or ptosis were noted for the animals on Day 1. Additionally, chromodacryorrhoea of the left eye was noted for one male animal

Gross pathology:

Effects on organs: No macroscopic abnormalities were observed for animals killed at study termination on Day 15.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute lethal dermal dose to rats was demonstrated to be > 2,000 mg/kg bodyweight.

Based on these results, Montelukast dicyclohexylamine salt does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments),
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Justification for classification or non-classification

Two studies, acute oral and dermal were performed on rats with results predicting the LD50 >2000 mg/kg bw.

Based on these results, Montelukast dicyclohexylamine salt does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to the:

- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments),

- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).