Registration Dossier

Administrative data

Description of key information

The acute toxicity of 1,4-diethlybenzene has been determined in adequate studies in the rat following oral and inhalation administrations.
1,4 -diethylbenzene is an hydrocarbon. Based on a dynamic viscosity of 3.6 mPa.s at 232K (4.1 mm2/s < 20 mm2/s) the substance can pose a hazard if swallowed and enter airways.

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Results of an study conducted in accordance with generally accepted scientific principles. Possible deficiencies in the reporting of the endpoint do not affect the quality of relevant results.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Doses:
0 or 2000mg/kg
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
not specified
Mortality:
No death was observed in both during the course of the study.
Clinical signs:
As clinical signs, decrease of spontaneous motor activity was observed in both male and female rats and lacrimation was additionnally observed in one female rat.
Body weight:
All animals gained body weight on day 7 and 14 after administration.
Gross pathology:
No remarkable macroscopical changes were observed in both males and females.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Executive summary:

One oral acute toxicity data is available for rat, limit test done according to OECD Guideline 401. Rats were adminitered orally (gavage) 0 and 2000 mg/kg. Clinical signs observed were decrease of spontaneous motor activity (male/female) and lacrimation in one female rat. No deaths occured and no remarkable macroscopic changes were observed in both male/female. With this study a LD50 > 2000 mg/kg was determined.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study is a GLP compliant and has Klimisch score 1.

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
Reliability:
1 (reliable without restriction)
Qualifier:
according to
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Qualifier:
according to
Guideline:
EU Method B.2 (Acute Toxicity (Inhalation))
GLP compliance:
yes (incl. certificate)
Test type:
fixed concentration procedure
Limit test:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
Diet
Commercial diet, ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany; see Appendix 2: Composition of the diet) served as food. Feeding was discontinued approx. 16 hours before administration; only tap water was then available ad libitum.
Periodic analysis of the food for contaminants based on EPA/USA is conducted at least twice a year by LUFA-ITL (see Appendix 2: Limitation for contaminants in the diet).

Housing
Granulated textured wood (Granulat A2, J. Brandenburg, 49424 Goldenstedt, Germany) was used as bedding material for the cages. The cages were changed and cleaned twice a week.
Periodic analysis of the bedding material for contaminants based on EPA/USA is conducted at least once a year by LUFA-ITL (see Appendix 2: Limitation for contaminants in the bedding material).
During the 14-day observation period the animals were kept by sex in groups of 2 and 3 animals in MAKROLON cages (type III plus) at a room temperature of 22°C ± 3°C and a relative humidity of 55% ± 15%. Deviations from the maximum range caused for example during cleaning procedures are dealt with in SOPs.
The rooms were lit (150 lux at approx. 1.50 m room height) and darkened for periods of 12 hours each.

Drinking water
Drinking water in bottles was offered ad libitum.
Drinking water is examined according to the 'Deutsche Trinkwasserverordnung 2001' [German Regulations on drinking water 2001] by the Hamburger Wasserwerke, 20539 Hamburg, Germany, at least four times a year (see Appendix 2: Limitation for contaminants in the drinking water).
In addition, drinking water samples taken at LPT are analysed by LUFA-ITL once a year for means of bacteriological investigations according to the 'Deutsche Trinkwas¬ser-verordnung 2001, Anlage 1' [German Regulations on drinking water 2001, Addendum 1].
Certificates of analysis of diet, drinking water and bedding material are QAU archived.

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
The study was carried out using a dynamic inhalation chamber (air changes/h (≥ 12 times)) with a nose-only exposure of the animals according to KIMMERLE & TEPPER . The apparatus consists of a cylindrical exposure chamber (volume 40 L) which holds the animals in pyrex tubes at the edge of the chamber in a radial position.
The aerosol of the test item was generated using a spray-jet .
The spray-jet was fed with compressed air (5.0 bar) from a compressor and with the test item using an infusion pump .
At the bottom of the exposure chamber, the air was sucked off at a lower rate than created by the dust generator in order to produce a homogenous distribution and a positive pressure in the exposure chamber (inflow 900 L/h, outflow 800 L/h).
A manometer and an air-flow meter were used to control the constant supply of compressed air and the exhaust, respectively. Flow rates were checked hourly and corrected if necessary.
The oxygen content in the inhalation chamber was 21% v/v. It was determined at the beginning and at the end of the exposure with a DRÄGER Oxygen-analysis test set (DRÄGER Tube Oxygen 67 28 081).
The whole exposure system was mounted in an inhalation facility to protect the laboratory staff from possible hazards.
The exhaust air was sucked through gas wash-bottles.
Exposure started by locating the rats into the exposure chamber after equilibration of the chamber concentration for 15 minutes.

Actual mean concentration of 1,4-Diethylbenzene (mg/L air): 5.02

Air flow entrance (L/h): 900
Air flow exit (L/h): 800
Air change (changes per hour): 22.5
Analytical verification of test atmosphere concentrations:
yes
Remarks:
HPLC
Duration of exposure:
4 h
Concentrations:
Limit Test: One concentration of 3 males and 3 females each
Full Test: 3 concentrations of 5 males and 5 females each
No. of animals per sex per dose:
Limit Test: 6 animals (3 males and 3 females)
Control animals:
no
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 5 mg/L air
Based on:
act. ingr.
Exp. duration:
4 h
Mortality:
None of the animals died prematurely.
Clinical signs:
other: Under the present test conditions, a 4-hour exposure to 1,4-Diethylbenzene at the concentration of 5.02 mg/L air revealed slight to severe ataxia, slight to moderate tremor and slight dyspnoea immediately until 60 minutes or 3 hours after end of exposure
Body weight:
All animals gained the expected body weight.
Gross pathology:
No pathological findings were noted at necropsy.

Table 1 Summarized results, Acute inhalation toxicity study of 1,4 -diethylbenzene in rats

 Symptoms/Criteria     5.02 mg 1,4 -diethylbenzene/L air
   males, n=3  females n=3
 clinical signs:    
 ataxia  slight to severe / 0min-3h /3 animals affected    slight to severe / 0min-3h /3 animals affected
 tremor  moderate to severe / 0min-60min/ 3 animals affected    moderate to severe / 0min-60min/ 3 animals affected
 dyspnoea  slight / 0min-3h /3 animals affected   slight / 0min-3h /3 animals affected
 mortality:    
 within 3 h  0 0
 within 24 h  0  0
 within 7 d  0  0
 within 14 d  0  0
 mean body weight (in g):    
 start  256.3  231.7
 after 7 days  290.7 (+13.4% body weight gain compared with start value)  237.7 (+2.6% body weight gain compared with start value)
 after 14 days   338.3 (+32% body weight gain compared with start value)  251.0 (+8.3% body weight gain compared with start value) 
 inhibition of body weight gain  none  none
 necropsy finding  none  none
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the present test conditions, the LC50 value for rats following inhalation of 1,4-Diethylbenzene for 4 hours was determined as follows (actual concentration):

LC50 males and females combined (24 hours and 14 days): exceeding 5.02 mg 1,4-Diethylbenzene/L air for 4 hours (actual concentration).

According to the EC-Commission directive 67/548/EC and its subsequent amendments on the approximation of the laws, regulations and administrative provision relating to the classification, packaging and labelling of dangerous substances and the results obtained under the present test conditions,

1,4-Diethylbenzene requires no labelling as LC50 > 5 mg/L.

Also, according to the EC Regulation 1272/2008 and subsequent regulations, the test material does not require classification for acute inhalation toxicity.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
5 000 mg/m³
Quality of whole database:
The study is a GLP compliant and has Klimisch score 1.

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute oral toxicity:

One oral acute toxicity data is available for rat, limit test done according to OECD Guideline 401. Rats were administered orally (gavage) 0 and 2000 mg/kg. Clinical signs observed were decrease of spontaneous motor activity (male/female) and lacrimation in one female rat. No deaths occurred and no remarkable macroscopic changes were observed in both male/female. With this study a LD50 > 2000 mg/kg was determined.

Acute inhalation toxicity: One inhalation acute toxicity data is available for rats, limit test done according to OECD Guideline 403. Rats were exposed to an atmosphere of 5.02 mg 1,4-diethylbenzene/L air. Clinical signs observed were ataxia, dyspnoea and tremor (male/female). No deaths occured and no remarkable macroscopic changes were observed in both male/female. With this study a LC50 > 5000 mg/m3was determined.

Acute dermal toxicity:

There isn't any test available for acute dermal toxicity.

Dermal exposure to 1,4-diethylbenzene may occur only at the workplace in industrial sites. In this environment, appropriate risk management measures are in place (e.g. closed systems, use of personal protection equipment including impermeable gloves and suitable clothing, along with local exhaust ventilation where appropriate) to reduce contact/exposure. These measures protect against the hazard of 1,4-diethylbenzene to provoque irritation at first contact. The assessment of basic toxicokinetics gives indication that the rate of absorption through the skin is expected to be low. Exposure via dermal route is therefore not expected to pose an issue for human health and no further testing is proposed.


Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for selection of acute toxicity – inhalation endpoint
Only one study available

Justification for classification or non-classification

Acute oral toxicity: Based on the results of acute oral toxicity testing, 1,4 -diethylbenzene is not classified as "Harmful if swallowed" according to the EU DSD classification criteria (EU Directive 67/548/EEC). According to the EU CLP classification criteria (EU Regulation 1272/2008), 1,4 -diethylbenzene is not classified as hazardous. The criteria in CLP Regulation stablishes the limit for classification as Acute Tox Oral Category 4 in 2000 mg/kg, and the value obtained is >2000 mg/kg bw.

Acute inhalation toxicity: According to the EC-Commission directive 67/548/EC and its subsequent amendments on the approximation of the laws, regulations and administrative provision relating to the classification, packaging and labelling of dangerous substances and the results obtained under the present test conditions, 1,4-Diethylbenzene requires no labelling as LC50 > 5000 mg/m3. Also, according to the EC Regulation 1272/2008 and subsequent regulations, the test material does not require classification for acute inhalation toxicity.

1,4 -diethylbenzene is an hydrocarbon. Based on a dynamic viscosity of 3.6 mPa.s at 232K (4.1 mm2/s < 20 mm2/s) the substance is classified as Asp Hazard Category 1.

Acute dermal toxicity: Based on the available information, 1,4-diethylbenzene does not require classification for acute dermal toxicity.

Based on the results of acute exposure, the observed effects at the observed concentrations are considered not to support classification for specific target organ toxicity following single exposure, and 1,4-diethylbenzene does not meet the criteria for classification for this endpoint according to Directive 67/548/EC or CLP (Regulation 1272/2008/EC).