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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
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 endopoint do not affect the quality of relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
1992
GLP compliance:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
not specified
Duration of treatment / exposure:
Male: 44 days including 14 days before mating.
Female: form 14 days before mating to day 3 of lactation.
Premating exposure period: 14 days (male and female)
Frequency of treatment:
7 days/week
Remarks:
Doses / Concentrations:
750 mg/kg
Basis:
no data
Remarks:
Doses / Concentrations:
150 mg/kg
Basis:
no data
Remarks:
Doses / Concentrations:
30 mg/kg
Basis:
no data
Remarks:
Doses / Concentrations:
0 mg/kg
Basis:
no data
No. of animals per sex per dose:
12 animals/sex/group
Control animals:
yes, concurrent vehicle
Clinical signs:
no effects observed
Description (incidence and severity):
The results in clinical observations did not reveal any effects atributable to the administration of test substance and there were no mortality in all groups.
Mortality:
no mortality observed
Description (incidence):
The results in clinical observations did not reveal any effects atributable to the administration of test substance and there were no mortality in all groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Depression of body weight gain observed in both males and female rats receiving 750 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption of male rats receiving 750 mg/kg/day was less than those of control until day 7 and thereafter, increases in food consumption were observed in them from day 28.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Description (incidence and severity):
As a result of hematology, there were no essential effects of test substance.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Blood examination: increases in the BUN and GPT were observed in male rats (150 mg/kg/day and 750 mg/kg/day), and increases in total protein, albumin, creatinine and total bilirubin and decrease of glucose were observed in male rats (750 mg/kg/day)
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increases in liver weights were observed in both male and female rats receiving 750 mg/kg/day, moreover increases in kidneys weights were observed in male rats receiving 150 mg/kg/day or more groups.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Increase in incidence of brown coloured livers or enlargement of the livers were observed in male rats receiving 750 mg/kg/day
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
swelling of liver cells observed in livers of male rats receiving 750 mg/kg/day
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: see 'Remark'
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Increase in liver weights at 750 mg/kg/day
Dose descriptor:
dose level:
Effect level:
750 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Dose descriptor:
dose level:
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Dose descriptor:
NOEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Dose descriptor:
LOEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Critical effects observed:
not specified
Conclusions:
The results described above led to a conclusion that effects of repeated dose toxicity study were considered to appear at 150 mg/kg/day or more in male rats and at 750 mg/kg/day in female rats (MHW, Japan, 1993b). The NOAEL for repeated dose toxicity in rats is considered 30 mg/kg/day in males and 150 mg/kg/day in female rats.
Executive summary:

1,4 -diethylbenzene was tested in 28 day repeated dose oral toxicity study in rats according to OECD Guideline 422 at doses of 30, 150, 500 and 750 mg/kg bw/day.  The effects observed in male rats have been increased BUN and GPT at 150 & 750 mg/kg; increases in total protein albumin, creatinine and total bilirubin, decrease in glucose at doses of 750 mg/kg/day and increase in kidney weight at 150 and 750 mg/kg/day; brown coloured livers and swelling of liver cells at 750 mg/kg bw. In male and female rats the effects observed were increase in liver weights at 750 mg/kg/day .

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study is a GLP compliant and has Klimisch score 1.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose oral toxicity information is derived from a 28 day oral toxicity study conducted in rats. The effects observed in male rats have been increased BUN and GPT at 150 and 750 mg/kg; increases in total protein albumin, creatinine and total bilirubin, decrease in glucose at doses of 750 mg/kg/day and increase in kidney weight at 150 and 750 mg/kg/day; brown coloured livers and swelling of liver cells at 750 mg/kg bw. In male and female rats the effects observed were increase in liver weights at 750 mg/kg/day .

This study allows to identify two NOAELs which have been set up to be 30 mg/kg bw/day for males and 150 mg/kg bw/day for females. 

The observed effects at the observed concentrations are considered not to support classification for specific target organ toxicity following repeated 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).

Using a validated (Q)SAR model, a NOAEL of 288 mg/kg bw/day for long-term oral exposure has been predicted.

For derivation of DNEL the lowest available NOAEL has been chosen.

According to the CSA performed and the risk characterisation values obtained no further testing is proposed for 1,4-diethylbenzene.

 

No test substance related systemic toxicity has been reported for dermal toxicity. 1,4-diethylbenzene is classified as skin irritant Cat. 2, and it is expected that the effects observed would be all related to the inflammation at the site of application caused by the irritating properties of the substance. Although the irritation can cause damage to the skin and favour the uptake of 1,4-diethylbenzene, it is not expected that it occurs (see toxicokinetics expert assessment).

 

No test substance related systemic toxicity has been reported for inhalation toxicity. The acute inhalation toxicity test didn't show indication of elevated rate of uptake of 1,4-diethylbenzene. This substance has a low vapour pressure so that normal processing and use conditions will not generate inhalation exposure.

 

Exposure to 1,4-diethylbenzene may occur only at 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. Repeated exposure via the inhalation or dermal routes is therefore not expected to pose an issue for human health. Repeated oral exposure is not expected at the workplace.

 

 


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available. The study is a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

Based on the results of repeated oral exposure, the observed effects at the observed concentrations are considered not to support classification for specific target organ toxicity following repeated 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).