Registration Dossier

Administrative data

Description of key information

For the oral route of administration a read across to a reliable GLP study that was performed according OECD TG 423 is provided. The LD50 exceeds 2000 mg/kg bw/day.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
Mar 12 - May 15, 1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: For this endpoint information from a structural similar compound is available. This study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 423.
Reference:
Composition 1
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: F. Winkelmann, Borchen, Germany- Age at study initiation: 5 to 8 weeks - Weight at study initiation: 172 (158 - 186) g - Fasting period before study: 17 hours before until up to 4 hours after treatment- Housing: separately in type III Makrolon cages - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum): ad libitum- Acclimation period: 5 days ENVIRONMENTAL CONDITIONS- Temperature (°C): 20 to 21 °C - Humidity (%): 54 to 68 %- Photoperiod (hrs dark / hrs light): 12 hour light - 12 hour dark regimeIN-LIFE DATES: From: day 1 To: day 15
Route of administration:
oral: gavage
Vehicle:
other: Methocel K4M Premium solution
Details on oral exposure:
VEHICLE- Concentration in vehicle: 100 g/L- Amount of vehicle (if gavage): 20 mL/kg- Justification for choice of vehicle: excellent vehicle performance in long range historical dataMAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 (m) / 5 (f)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days- Frequency of observations: for at least 6 hours after administration and then daily up to end of study- Frequency of weighing: on days 2, 4, 6, 8, 11, 13, and 15 of the experimental part.- Necropsy of survivors performed: yes- Other examinations performed: clinical signs, body weight, gross pathology
Statistics:
Standard statistical methods have been applied for data processing.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All rats survived the observation period.
Clinical signs:
No signs of toxicity were seen in the 3 male and 3 female rats after treatment with 2000 mg/kg.
Body weight:
On female rat showed inhibition of body weight development. The body weight development of the other rats was inconspicuous during the study.
Gross pathology:
The gross pathological examination revealed no organ alterations.
Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
Based on the result of this study, it is concluded that the test material has no acute toxic potential and that the LD50 value is higher than 2000 mg/kg after single oral administration in rats.
Executive summary:

Study design

The test material was tested for acute toxicity in rats after single oral administration of 2000 mg/kg body weight. The study was performed according to the OECD Guideline for Testing of Chemicals No. 401.

Results

No signs of toxicity were seen in the rats (5 males, 5 females) after treatment with 2000 mg/kg of the test item.
On female rat showed inhibition of body weight development. The body weight development of the other rats was inconspicuous during the study. There were no deaths during the course of the study.
The gross pathological examination revealed no organ alterations.

Conclusion

Based on the result of this study, it is concluded that the test material has no acute toxic potential and that the LD50value is higher than 2000 mg/kg after single oral administration in male/female rats.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
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
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for read across

Endpoint:Acute Oral Toxicity

Type of read across:one-to-one

Test Compound (with data):CAS: 174350-05-1

Dossier Compound (without data):CAS: 124729-02-6

The read across is based on the following similarity measures:


(1) Chemical similarity:
The test compound (CAS: 174350-05-1) provides all main chemical features present in the dossier compound (CAS: 124729-02-6). Both substances share typical structural features for liquid crystals, i.e. one phenyl ring coupled via single bond to a cyclohexyl ring.

Comparing dossier and test compound yields the same substitution pattern at the phenyl ring, i.e. a Fluor substitution (dossier compound: n=2, test compound: n=2) and a para ethoxy substituent.

The cylohexyl ring of both compounds shows a para alkyl substitution of different chain length (dossier cpd.: n=5; test cpd.: n=3). Thus, the only difference in terms of chemical structure is the length of the alkyl chain connected to the core structure. Overall, this almost perfect match results in a high chemical similarity score of 1.00 (Tanimoto).

(2) Physicochemical similarity
The high chemical similarity yields almost identical physicochemical key parameters relevant for bioavailability as listed in the table below.


Assay

Test Compound
CAS: 174350-05-1

Dossier Compound
CAS: 124729-02-6

Cyclohexyl phenyl core

yes

yes

Terminal alkyl chain at the cyclohexyl ring

propyl

pentyl

Terminal alkoxy chain at the phenyl ring

ethoxy

ethoxy

Liquid crystalline properties

yes

yes

Fluoro Substitution at the phenyl ring

yes (n=2)

yes (n=2)

Water solubility

130 µg/L
(EU A.6)

30 µg/L (EU A.6)

logP

> 5.7
(OECD 117, EU A.8)

> 6.5
(OECD 117, EU A.8)

Mutagenicity in vitro

negative (OECD 471)

negative (OECD 471)

Read Across

Acute oral toxicity

Rats, single dose, oral
LD50 > 2000 mg/kg bw /d
(OECD 423)

LD50 > 2000 mg/kg bw/d (Read Across)




Conclusion
The Dossier Compound shows a data gap for acute oral toxicity; however, a chemical analogue provides data for this endpoint. Both the Dossier Compound and the Test Compound show a very high chemical similarity and almost identical physicochemical parameters leading to similar bioavailability. No additional alerting reactive fragments are found in the dossier compound.

Based on these findings it is justified to use the data from the chemical analogue (Acute oral toxicity in rats: LD50 > 2000 mg/kg bw/d (GLP, OECD TG 423)) to fill the data gap for the dossier compound.





Justification for selection of acute toxicity – oral endpoint
This study was performed according to GLP and the methods applied are fully compliant with OECD TG 423.

Justification for selection of acute toxicity – dermal endpoint
On 15 July 2014 the Competent Authorities for REACH and CLP (Caracal) have agreed that substances that are not toxic in acute oral tests need no longer be tested for acute dermal toxicity. Caracal agreed on proposals to amend REACH Annex VIII (point 8.5.3) so that substances that have not shown oral acute toxicity up to a limit dose of 2000mg/kg bodyweight would not also require dermal data. The test material does not provide evidence for acute oral toxicity. The LD50 exceeds 2000 mg/kg bw. Therefore no further testing for dermal toxicity is justified.

Justification for classification or non-classification

According to the results of the acute oral test, a classification and labelling is not required for this substance.