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Description of key information

The key studies are an acute oral toxicity study in rats and an acute  dermal toxicity in rats both with an LD50 of >2000 mg/kg.

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 29 to May 19, 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterize
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Version / remarks:
July 1992
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
GLP compliance:
yes
Remarks:
OECD Principles of Good Laboratory Practice, Statutory Instrument No. 654, 1997, ISBN 0-11-064105-1
Test type:
fixed dose procedure
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK., Margate, Kent, England
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 175 - 232g
- Fasting period before study: overnight
- Housing: The dose range-finding animal was housed singly in a cage with dimensions 42 x 27 x 20 cm, and the main study animals were housed 5 per cage per sex with dimensions 59 x 38.5 x 20 cm
- Diet: Rat and Mouse No. 1 Maintenance Diet, supplied by Special Diets Services Limited, 1 Stepfield, Witham, Essex, CMS 3AD was available ad libitum throughout the study except for a period of food deprivation overnight prior to dosing until as soon as practicable after dosing.
- Water: Domestic mains quality water was available ad libitum throughout the study
- Acclimation period: 5 days before commencement of study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): During the study, mean environmental maximum and minimum temperatures were 22°c and 19°C
- Mean Humidity (%): 50 %
- Air changes (per hr): 15 minimum
- Photoperiod (hrs dark / hrs light):12/24
Route of administration:
oral: gavage
Vehicle:
maize oil
Details on oral exposure:
The available toxicity data suggested that an initial dose level of 2000 mg/kg would be suitable. The main study dose level was selected based on the results from the dose range-finding study.

The test material was administered orally in a single dose by means of a gavage at a constant dose volume of 10 ml/kg.
The dose was calculated based on the weight of the animal on the day of dosing.
Doses:
dose level: 2000 mg/kg
No. of animals per sex per dose:
A preliminary dose range-finding, using one female, at 2000 mg/kg indicated that this dose level would be suitable for the main study. 5 females and 5 males were used for this main study.
Control animals:
no
Details on study design:
The dose was calculated based on the weight of the animal on the day of dosing.

Formulations were administered within approximately 1 hour of preparation and were magnetically stirred during dosing.
All the animals were checked for viability early in the morning and again as late as possible on each day until sacrifice on Day 8 (dose range-finding) or Day 15 (main study).
Statistics:
No formal statistical analysis was conducted
Preliminary study:
The available toxicity data suggested that an initial dose level of 2000 mg/kg would be suitable. The main study dose level was selected based on the results from the dose range-finding study.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no premature decedents during the study
Clinical signs:
Clinical signs were noted from approximately 5 to 6 hours after dosing and on Day 2. These signs were limited to wet, stained perigenital area and soft jelly­ like faeces

Body weight:
Body weight performance was considered to have been satisfactory.

Body Weight (g) Gain

Day 1 Day 2 Day 3 Day 4 Day 8 Day 15 (Days 1-15)
Dose Level Animal
(mg/kg)/Sex
2000/male 6 222 240 249 251 269 297 75
7 232 248 256 260 281 310 78
8 229 250 253 258 278 307 78
9 230 248 256 264 283 304 74
10 222 244 245 251 264 289 67
Mean 227 246 252 257 275 301 74
±SD 5 4 5 6 8 8 5


2000/female 11 175 186 179 190 200 208 33
12 194 198 192 203 203 235 41
13 178 185 178 193 203 209 31
14 190 199 190 196 214 223 33
15 207 221 212 222 236 239 32
Mean 189 198 190 201 211 223 34
±SD 13 15 14 13 15 14 4
Gross pathology:
There were no abnormalities detected at necropsy.

Dose Level
(mg/kg) Animal/Sex Necropsy Finding Day of Death
2000 6-10male No abnormalities detected 15
11-15 female No abnormalities detected 15
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study following a single oral administration of L-744,341 to Sprague-Dawley rats, no mortality and no toxicity occurred at 2000 mg/kg
Executive summary:

There were no premature decedents or major clinical signs noted during the obsevation period.

Body weight performance was considered to be satisfactory, and there were no abnormalities detected at necropsy.

Under the conditions of the study following a single oral administration of L-744,341 to Sprague-Dawley rats, no mortality and no toxicity occurred at 2000 mg/kg
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
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:
2015-01-07 to 2015-01-21
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Based on OECD test guideline and GLP compliant.
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Commission Regulation (EC) No 440/2008, B3: "Acute Toxicity (Dermal)"
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF Guidelines (2000), including the most recent revisions.
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Species Rat, Wistar strain, Crl:WI (Han) (outbred, SPF-Quality). Recognized by international guidelines as the recommended test system (e.g. OECD, EC). Source: Charles River Deutschland, Sulzfeld, Germany.

Number of animals: 5 males and 5 females (females were nulliparous and non-pregnant).
Age and body weight: Young adult animals (approx. 10 weeks old) were selected. Body weight variation did not exceed +/- 20% of the sex mean.

Conditions
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, at least 10 air changes/hour, and a 12-hour light/12-hour dark cycle. Any variations to these conditions were maintained in the raw data and had no effect on the outcome of the study.

Accommodation
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).
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).

Diet
Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).

Water
Free access to tap water.

Diet, water, bedding and cage enrichment evaluation for contaminants and/or nutrients was performed according to facility standard procedures. There were no findings that could interfere with the study.
Type of coverage:
open
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% Aqueous carboxymethyl Not indicated cellulose
Details on dermal exposure:
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.
*. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).
Duration of exposure:
24 hours, after which dressings were removed and the skin cleaned of residual test substance using tap water.
Doses:
2000 mg/kg (10 mL/kg) body weight.
No. of animals per sex per dose:
5/sex/group
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Animals were subjected to daily observations and weekly determination of body weight. Mortality/viability was observed twice daily. Animals were weighed 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.
- Terminal sacrifice was performed on day 15
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Lethargy, flat posture, hunched posture, piloerection, chromodacryorrhoea (snout) and/or ptosis were noted for the animals on Day 1.

White staining and/or scales were seen in the treated skin-area of the animals between Days 2 and 11.
Body weight:
The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity.
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 dermal LD50 value of Montelukast Backbone Diol in Wistar rats was established to exceed 2000 mg/kg body weight.

Based on these results, Montelukast Backbone Diol 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:
LD50
Value:
2 000 mg/kg bw

Additional information

Acute toxicity oral: .

There were no premature decedents or major clinical signs noted during the observation period., body weight performance was considered to be satisfactory, and there were no abnormalities detected at necropsy.Un

under the conditions of the study following a single oral administration of the substance to Sprague-Dawley rats, no mortality and no toxicity occurred at 2000 mg/kg. Acute dermal toxicity: No mortality occurred. Clinical signs: Lethargy, flat posture, hunched posture, piloerection, chromodacryorrhoea (snout) and/or ptosis were noted for the animals on Day 1. White staining and/or scales were seen in the treated skin-area of the animals between Days 2 and 11. The changes noted in body weight gain in males and females were within the range expected for rats used in this type of study and were therefore considered not indicative of toxicity. No abnormalities were found at macroscopic post mortem examination of the animals.

Justification for classification or non-classification

The key studies are an acute oral toxicity study and an acute dermal toxicity in rats with an LD50 of >2000 mg/kg.

Based on these results, Montelukast Backbone Diol 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).