Dihexyl ether

Endpoint summary

Description of key information

acute oral toxicity (rat): LD50 > 2000 mg/kg bw

acute inhalation toxicity: LC50 > 5.13 mg/l
acute dermal toxicity (rat): 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:

June 27 to September 27, 2018

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)

Version / remarks:

adopted 17 December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8–10 weeks
- Weight at study initiation: Step 1: 155–173 g; Step 2: 163–175 g
- Fasting period before study: 17 to 18 hours
- Housing: IVC cages, type III H, polysulphone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water (e.g. ad libitum): tap water, sulphur acidified to a pH value of approximately 2.8, ad libitum
- Acclimation period: at east five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 55 ± 10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27 June 2018 To: 16 August 2018 (step 1)/22 August 2018 (step 2)

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

2000 mg/kg

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were weighed on day 1 (prior to the administration) and on days 8 and 15. Clinical examination was made several times on the day of dosing (at least once during the first 30 minutes and with special attention given during the first 4 hours post-dose). Thereafter, the animals were observed for clinical signs once daily until the end of the observation period. Cageside observations included changes in the skin and fur, eyes and mucous membranes. Also respiratory, circulatory, autonomic and central nervous systems and somatomotor activity and behaviour pattern were examined. Particular attention was directed to observations of tremor, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD0

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

none

Clinical signs:

other: No specific findings in any animal.

Gross pathology:

No specific gross pathological changes were recorded for any animal.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of the present study, a single oral application of the test item Dihexyl ether to rats at a dose of 2000 mg/kg body weight was not associated with signs of toxicity or mortality.
The median lethal dose of Dihexyl ether after a single oral administration to female rats, observed over a period of 14 days is: LD50 cut-off (rat): >5000 mg/kg bw

Executive summary:

Two groups, each of three female WISTAR Crl: WI(Han) rats, were treated with the test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was applied directly.

All animals were examined for clinical signs several times on the day of dosing and once daily until the end of the observation period. Their body weights were recorded on day 1 (prior to the administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study without showing any test-item related signs of toxicity. Throughout the 14-day observation period, the body weight gain of the test animals was within the normal range of variation for this strain. At necropsy, no treatment-related macroscopic findings were observed in any animal of any step.

Therefore the median lethal dose of Dihexyl ether after a single oral administration to female rats, observed over a period of 14 days is: LD50 cut-off (rat): >5000 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 26, 2018 - August 08, 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

2009

Deviations:

no

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: SAGE Labs
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 330-362g (males) and 195-237g (females)
- Housing:c ages confromig to the size recommendations in the "Guide for the Care an Use of Laboratory Animals" (Natl. Res. Council, 2011)
- Diet (e.g. ad libitum): Envigo Teklad Global 16 % Protein Rodent Diet(R) #2016, ad libitum (except during exposure)
- Water (e.g. ad libitum): ad libitum (except during exposure)
- Acclimation period: 15 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-27 °C
- Humidity (%): 53-85 %
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: JUly 20, 2018 To: August 3, 2018

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

ca. 3.18 µm

Geometric standard deviation (GSD):

2.28

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: nose-only inhalation chamber
- Exposure chamber volume: 28 l
- Method of holding animals in test chamber: animals were individually housed in polacarbonate holding tubes which seal to the chamber with an "O" ring during exposure
- Source and rate of air: filtered generator air
- Method of particle size determination: eight-stage 1 ACFM Andersen Ambient Particle Sizing Sampler
- Temperature, humidity, pressure in air chamber: 22 °C, 66-67 %, slight megative pressure

TEST ATMOSPHERE
- Brief description of analytical method used: Samples were colected using 37 mm glass fiber filters (Whatman(TM) GF/B) in a filter holder attached by 1/4 inch Tygon(R) tubing to a vacuum pump. Filter papers were weighed before and after collection to determine the mass collected. This value was devided by the total volume of air sampled to determine the chamber concentration. Sample airflows were measured using a Mass Flow Controller.
- Samples taken from breathing zone: yes

Duration of exposure:

4 h

Concentrations:

5.13 mg/l

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
body weights: prior to test substance exposure and again on Days 1, 3, 7, and 14
observations during exposure: continuously
cage side observations: at least once daily
- Necropsy of survivors performed: yes/no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.13 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Key result

Sex:

male/female

Dose descriptor:

LC0

Effect level:

>= 5.13 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

none

Clinical signs:

other: No signs of gross toxicity, adverse clincal effects or abnormal behaviour.

Body weight:

no effects on the body weight

Gross pathology:

no gross abnormalities

Interpretation of results:

GHS criteria not met

Conclusions:

Under the consdition of this study, the single exposure acute inhalation LC50 of the test substance is greater than 5.17 mg/l in male and female rats.

Executive summary:

An acute inhalation toxicity test was conducted with rats to determine the potential for the test substance to produce toxicity from a single exposure via the inhalation (nose-only exposure) route. Under the condition of this study, the single exposure acute inhalation LC50 of the test substance is greater than 5.17 mg/l in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5.13 µg/m³ air

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:

1 July 2018 - 2 August 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

2017

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

d.d. 03 Aug 2018

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Females, nulliparous and non-pregnant: yes
- Age at study initiation: ~9 weeks old
- Weight at study initiation: Between 204 g and 241 g
- Fasting period before study: No
- Housing: Individual and group caging
- Cage type: Type II. polypropylene/polycarbonate
- Bedding: Lignocel 3/4-S Hygienic Animal Bedding (produced by J. Rettenmaier & Söhne GmbH+Co.KG, Germany) was available to animals during the study. The quality of the bedding was guaranteed by the supplier. Details of bedding quality are archived with the raw data.
- Nesting: Nest building material Arbocel Crinklets natural (produced by J. Rettenmaier & Söhne GmbH+Co.KG, Germany) was available to animals during the study. The quality of the nest building material was guaranteed by the supplier. Details of nest building material quality are archived with the raw data.
- Enrichment: Rodents were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Diet: Animals received ssniff® SM R/M "Autoclavable complete diet for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest, Germany, ad libitum
- Water: tap water from the municipal supply, ad libitum
- Acclimation period: 12 or 14 days
- Microbiological status: SPF at arrival

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.1–25.3
- Humidity (%): 40–79
- Air changes (per hr): 15-20 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.

IN-LIFE DATES: From: 17 JUL 2018 To: 02 AUG 2018

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: 10% of total body surface
- Type of wrap if used: Sterile gauze pads were placed on the skin of rats to cover the test item. Entire truk of the animal was wrapped with semi occlusive plastic wrap for 24 hours.

REMOVAL OF TEST SUBSTANCE
- Washing: water at body temperature
- Time after start of exposure: 24 hours

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

Pre-study: 1 female at 2000 mg/kg bw
Main study: 2 females at 2000 mg/kg bw

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations were performed at periodic intervals on the day of dosing and once daily thereafter; body weights were recorded on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

No mortality occured.

Clinical signs:

other: There were no systemic clinical signs noted in any animal throughout the study. No adverse local dermal signs were observed after treatment with the test item or during the 14 days observation period.

Gross pathology:

There was no evidence of any gross macroscopic changes at a dose level of 2000 mg/kg bw.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

In an acute dermal toxicity study according to OECD TG 402 and in accordance with GLP principles the LD50 of the test item Di-n-hexyl ether was found to be greater than 2000 mg/kg body weight in female Crl:WI rats.
According to the GHS criteria, Di-n-hexyl ether can be ranked as "Category 5 or Unclassified" for acute dermal exposure.

Executive summary:

An acute dermal toxicity study was performed with the test item Di-n-hexyl ether in three female Wistar rats, in compliance with OECD Guideline No. 402.

The test item was applied as a single dermal 24-hour exposure of 2000 mg/kg followed by a 14-day observation period.

Test item did not cause mortality and no systemic clinical signs were noted in any animal throughout the study. No adverse local dermal signs were observed after treatment with the test item or during the 14 days observation period. There was no treatment related effects on body weight or body weight gain during the observation period. Body weights were within the range commonly recorded for this strain and age and there was no evidence of any macroscopic changes.

The acute dermal median lethal dose (LD50) of the test item Di-n-hexyl ether was found to be greater than 2000 mg/kg body weight in female Crl:WI rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Additional information

Acute toxicity studies with dihexyl ether show no mortality nor clinical signs in rats for both oral and dermal route with at 2000 mg/kg

In an acute inhalation toxicity study of dihexyl ether no mortalites nor clinical effects were observed at test concentrations of 5.17 mg/l.

Justification for classification or non-classification

Based on the available data the substance does not need to be classified according to GHS (Regulation (EU) 1272/2008).