2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolane-4-methanol

Endpoint summary

Description of key information

• Acute toxicity: Oral

In an acute oral toxicity study in female Crl:WI (Han) (SPF) rats, following the acute toxic class method in accordance with the OECD Guideline 423 and EU Method B.1 tris, the LD50 was established to exceed 2000 mg/kg. According to the OECD 423 guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight.

• Acute toxicity: Inhalation

No reliable acute toxicity study via the inhalation route was available. However, this endpoint is waived as specific data are available for the oral and dermal exposure routes.

• Acute toxicity: Dermal

In an acute dermal toxicity study in male and female Crl:WI (Han) (SPF) rats, following the standard acute method according to OECD Guideline 402 and EC method B.3, the LD50 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:

From 2015-06-16 to 2015-07-03

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)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: M14IB5308
- Expiration date of the lot/batch: 21 November 2015 (retest date)
- Purity: 99.6%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 6 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 8 weeks old
- Weight at study initiation (day 1): 149 - 166 grams
- Fasting period before study: animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test item. Water was available ad libitum.
- Housing: group housing of 3 animals per cage in labeled Makrolon cages (MIV 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): ad libitum, pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): ad libitum, free access to tap water.
- Acclimation period: at least 5 days before start of treatment under laboratory conditions, health inspection at least prior to dosing. It was ensured that the animals were healthy and without any abnormality that might affect the study integrity.
- 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.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24 °C
- Humidity (%): 40-70%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

propylene glycol

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Justification for choice of vehicle: the vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036)(turbid solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92).

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION:
- The preparations (w/w) were kept at room temperature and were dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
- Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

3 females per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days (until day 15)
- Frequency of observations and weighing:
mortality/viability: twice daily;
body weights: days 1 (pre-administration), 8 and 15;
clinical signs: 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:
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).
- Necropsy of survivors performed: yes, at the end of the observation period all animals were sacrificed by oxygen/carbon dioxide procedure and subjected to necorpsy. Descriptions of all internal macroscopic abnormalities were recorded.

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.

Clinical signs:

other: Hunched posture and piloerection were noted for three animals on days 1 and for one animal on day 2.

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of JNJ-16479489-AAA (T001159) 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, JNJ-16479489-AAA (T001159) 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:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

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:

From 2015-11-17 to 2015-12-01

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

other: limit test with a single dose

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: M14IB5308
- Expiration date of the lot/batch: 03 February 2016 (retest date)
- Purity: 99.6%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: 5 male and 5 female rats (nulliparous and non-pregnant), Wistar strain Crl:WI (Han) (outbred, SPF-Quality); Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx. 10 weeks old)
- Weight at study initiation: 180-277 grams
- Housing:group housed in Makrolon cages (MIV type, height 18 cm) during acclimatization period; 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): ad libitum, free access to pelleted rodent diet
- Water (e.g. ad libitum): ad libitum, free access to tap water
- Acclimation period: at least 5 days before start of treatment under laboratory conditions


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

IN-LIFE DATES: From: 2015-11-17 To: 2015-12-01

Type of coverage:

not specified

Vehicle:

propylene glycol

Details on dermal exposure:

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial preparations performed at WIL Research Europe and on test item data supplied by the Sponsor. The vehicle was chosen from (in order of preference): water (Elix) (test item did not dissolve), 1% aq. carboxymethyl cellulose (test item did not dissolve), propylene glycol (spec.gravity 1.036) (turbid solution), polyethylene glycol 400 (spec. gravity 1.125) and corn oil (spec. gravity 0.92). There was no information available regarding the solubility or stability in vehicle.

DOSAGE PREPARATION
The preparation (w/w) was kept at room temperature and dosed within 4 hours after adding the vehicle to the test item. Homogeneity was assessed by visual inspection of the solutions and the formulations were stirred during dosing, which ensures homogeneity sufficient for these kinds of studies.
Adjustment was made for specific gravity of the vehicle. No correction was made for purity of the test item as the correction factor is 1.

TEST SITE
- Clipping: One day before exposure (Day -1) an area of approximately 5x7 cm on the back of each animal was clipped.
- Area of exposure: approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females
- % coverage: no data
- Type of wrap if used: 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 removal of dressing, the skin was cleaned of residual test item using tap water
- Time after start of exposure: 24 h

Duration of exposure:

24 h

Doses:

2000 mg/kg (single dosing)

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

Observations:
Observation period: until day 15 after treatment
- Mortality/Viability: Twice daily.
- Body weights: Days 1 (pre-administration), 8 and 15.
- 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).
- Necropsy 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.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

other: Piloerection was noted for one male and one female animal on Day 2. Chromodacryorrhoea was noted for three male and one female animals on Day 1 or 2. Scales, scabs and erythema maculate were seen in the treated skin-area and flanks of the animals during t

Gross pathology:

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

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 value of JNJ-16479489-AAA (T001159) in Wistar rats was established to exceed 2000 mg/kg body weight. Based on these results, the substance 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) 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:

LD50

Value:

2 000 mg/kg bw

Additional information

• Acute oral toxicity:

An acute oral toxicity study with T001159 according to the acute toxic class method in female Crl:WI (Han) (SPF) rats (OECD guideline 423 and EU Method B.1 tris) was performed (Latour, 2015). A single dose of 2000 mg/kg bw was applied. The substance was formulated in propylene glycol at a concentration of 200 mg/mL. The rats received a single oral dose of test item, and were observed during 14 days following administration. Lethality and viability were observed twice daily, and bodyweight was monitored at day 1 (prior to administration), 8 and 15. Clinical signs were observed at periodic intervals on the day of dosing (day 1) and once daily thereafter. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

No mortality occurred during the study. Hunched posture and piloerection were noted for three animals on day 1 and for one animal on day 2.

The body weight gain over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.

No abnormalities were found at macroscopic post mortem examination.

The oral LD50 value of T001159 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.

• Acute inhalation toxicity:

In addition to the oral route of exposure, for substances other than gases, the information mentioned under REACH section 8.5.2 to 8.5.3 shall be provided for at least one other exposure route (REACH Regulation, column 2 adaptation of Annex VIII). For this substance a key study is available for the dermal route of exposure. Therefore, an acute inhalation toxicity study should not be performed.  

• Acute dermal toxicity:

An acute dermal toxicity study with T001159 according to the standard acute method in male and female Crl:WI (Han) (SPF) rats (OECD guideline 402 and EU Method B.3 was performed (Latour, 2016). The substance was dissolved in propylene glycol and applied on a clipped area on the back at 2000 mg/kg bw. The test item was then wrapped with a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. After 24 h hours of exposure remainings of the test item were washed-off. The animals were observed during 14 days. Lethality and viability were observed twice daily, and bodyweight was monitored at day 1 (prior to 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. Necropsy of survivors and macroscopic examination were also performed. Internal macroscopic abnormalities were recorded. 

No mortality occurred. Clinical signs observed were: piloerection was noted for one male and one female animal on Day 2. Chromodacryorrhoea was noted for three male and one female animals on Day 1 or 2. Scales, scabs and erythema maculate were seen in the treated skin-area and flanks of the animals during the observation period. No abnormalities were found at macroscopic post mortem examination of the animals.

The dermal LD50 value of T001159 in Wistar rats was established to exceed 2000 mg/kg body weight.

Justification for classification or non-classification

Based on the oral LD50 exceeding 2000 mg/kg bw, T001159 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)

No data were available to decide on the classification for the inhalation route.

Based on the dermal LD50 exceeding 2000 mg/kg bw, T001159 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) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).