Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Oral: Key study: Read-across from experimental results on the substance 6-tert-Butyl-2,4-xylenol: Test according to OECD guideline 422. GLP study.

Repeated dose oral:

NOAEL= 6 mg/kg/day (male)    

NOAEL= 30 mg/kg/day (female)

Oral: Data waiving: In accordance with column 2 of REACH Annex IX, a subchronic toxicity study (90-days) does not need to be conducted since a reliable short-term toxicity study is available showing severe toxicity effects according to the criteria for classifying the substance, for which the observed NOAEL, with the application of an appropriate uncertainty factor, allows the extrapolation towards the NOAEL-90 days for the same route of exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
(combined repeated dose and reproduction / developmental screening)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
The substance CAS No. 1879-09-0 is one of the main components of the reaction mass of 2-tertbutyl-4,6-dimethylphenol and 4-tert-butyl-2,5-dimethylphenol and it is present in a concentration of more than 70%. Therefore, the results obtained with the substance CAS No. 1879-09-0 can be used for the read-across approach.
See attached the reporting format.
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
6 mg/kg bw/day (actual dose received)
Based on:
other: Read-across from an analogue
Sex:
male
Basis for effect level:
other: Read-across from an analogue for which effects in clinical chemistry, liver and kidney weights and histopathological examination were observed.
Remarks on result:
other: read-across from an analogue for which NOEL = 6 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
other: Read-across from an analogue
Sex:
female
Basis for effect level:
other: Read-across from an analogue for which effects in liver and kidney weights and histopathological examination were observed.
Remarks on result:
other: read-across from an analogue for which NOEL = 30 mg/kg bw/day
Critical effects observed:
not specified
Conclusions:
Based on read-across approach from experimental data on analogue substance 6-tert-butyl-2,4-xylenol (CAS 1879-09-0), NOAELs for repeat dose toxicity of the reaction mass of 2-tert-butyl-4,6-dimethylphenol and 4-tert-butyl-2,5-dimethylphenol are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females.



Executive summary:

In a experimental study the NOELs of 6-tert-butyl-2,4-xylenol were found to be 6 mg/kg/day in males and 30 mg/kg/day in females. Based on these results, the read-across approach was applied and the NOAELs of the reaction mass of 2-tert-butyl-4,6- dimethylphenol and 4-tert-butyl-2,5-dimethylphenol are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females.

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:
comparable to guideline study
Remarks:
Meets the requirements of GLP. There are no deviations from the recommended guideline.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
Males: 45 days including 14 days before mating
Females: from 14 days before mating to day 3 of lactation
Frequency of treatment:
Daily
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
(vehicle)
Dose / conc.:
6 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Males,12; females, 12/group
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
ORGAN WEIGHTS: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
There were no clinical abnormal signs attributable to the administration of the test substance. However, two female animals given 150 mg/kg died at the end of gestation period (one of them during the delivery).
Mortality:
mortality observed, treatment-related
Description (incidence):
Two female animals given 150 mg/kg died at the end of gestation period (one of them during the delivery).
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight gain of females given 150 mg/kg was lower than that of the controls during the gestation period. However, body weights of males did not demonstrate any effects attributable to the administration of test substance.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption of both males and females did not demonstrate any effects attributable to the administration of test substance.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematological examination revealed decreases in hematocrit, hemoglobin and red blood cells, increases in reticulocytes and a slight tendency for anemia in males given 150 mg/kg. Blood clinical examination revealed decreases in GOT and increases in gamma-GTP in the 30 and 150 mg/kg males.
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver and kidney weights showed increases or a tendency for increase in males given 30 mg/kg or more and females given 150 mg/kg. At necropsy enlargement of the liver in males given 30 and 150 mg/kg, and of the liver and kidneys in females given 150 mg/kg was noted.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathological examination revealed swelling of centrilobular hepatocytes in males given 150 mg/kg and swelling and necrosis of centrilobular hepatocytes, and single cell necrosis in females given 150 mg/kg. The dead females and females with pups which all died showed increased incidences of parakeratosis of the tongue, esophageal swelling and necrosis of centrilobular hepatocytes, as well as a variety of degenerative charges, single cell necrosis and mitosis in the liver. Degeneration and protein cast in the proximal tubules and PAS positive granules deposited in the renal papilla, were observed in the kidneys of females given 150 mg/kg.
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Key result
Dose descriptor:
NOEL
Effect level:
6 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Changes in clinical chemistry, liver and kidney weights, histopathological examination.
Key result
Dose descriptor:
NOEL
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Changes in liver and kidney weights and histopathological examination.
Critical effects observed:
not specified
Conclusions:
NOELs for repeat dose toxicity are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females.



Executive summary:

The substance 6-tert-Butyl-2,4-xylenol was studied in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 6, 30 and 150 mg/kg/day. With regard to repeat dose toxicity, two female rats given 150 mg/kg died at the end of the gestation period (one of them during delivery). Body weight gain of females given 150 mg/kg was lower than that of the control during the gestation period. Hematological examination showed decreases of hematocrit, hemoglobin and red blood cells, and increases of reticulocytes and a slight tendency for anemia in male rats given 150 mg/kg. Blood chemical examination revealed decreases in levels of GOT and increases in γ-GTP in males given 30 and 150 mg/kg. Liver and kidney weights showed increases or a tendency for increase in the male rats given 30 mg/kg or more and in the females given 150 mg/kg. As gross findings, enlargement of the liver was observed in males given 30 and 150 mg/kg, and enlargement of the liver and kidneys was observed in females given 150 mg/kg. Histopathological examination revealed swelling of liver cells in the centrilobular zone in males and females of the 150 mg/kg group, and degeneration of liver cells, necrosis of centrilobular hepatocytes and single cell necrosis in the females of the same group. NOELs for repeat dose toxicity are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females of the group.

 

Endpoint:
sub-chronic toxicity: oral
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
a sub-chronic toxicity study (90 days) does not need to be conducted because a reliable short-term toxicity study (28 days) is available showing severe toxicity effects according to the relevant criteria for classifying the substance, for which the observed NOAEL-28 days, with the application of an appropriate uncertainty factor, allows the extrapolation towards the NOAEL-90 days for the same route of exposure
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
In accordance with column 2 of REACH Annex IX, a subchronic toxicity study (90-days) does not need to be conducted since a reliable short-term toxicity study is available showing severe toxicity effects according to the criteria for classifying the substance, for which the observed NOAEL, with the application of an appropriate uncertainty factor, allows the extrapolation towards the NOAEL-90 days for the same route of exposure.
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
6 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 1. This study was carried out in accordance with internationally valid GLP principles.

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

Oral: Key study: In a experimental study the NOELs of 6-tert-butyl-2,4-xylenol were found to be 6 mg/kg/day in males and 30 mg/kg/day in females. Based on these results, the read-across approach was applied and the NOAELs of the reaction mass of 2-tert-butyl-4,6- dimethylphenol and 4-tert-butyl-2,5-dimethylphenol are considered to be 6 mg/kg/day in males and 30 mg/kg/day in females.

Oral: Data waiving: In accordance with column 2 of REACH Annex IX, a subchronic toxicity study (90-days) does not need to be conducted since a reliable short-term toxicity study is available showing severe toxicity effects according to the criteria for classifying the substance, for which the observed NOAEL, with the application of an appropriate uncertainty factor, allows the extrapolation

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

Only one study available.

Justification for classification or non-classification

Based on the available data, the substance is classified as STOT Rep. Exp. Category 2.