Registration Dossier

Administrative data

Description of key information

LD50 oral = 815 mg/kg bw (95% C.I.: 643-1049 mg/kg)
LD50 dermal = 1331 mg/kg bw (95% C.I.: 954-1863 mg/kg)

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:
End of the study: 02/04/1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
yes
Test type:
other: Acute Oral Toxicity
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, 69210 L'Arbresle. France.
- Age at study initiation: 6 weeks old
- Weight at study initiation: 185 +/- 7g for the males, 149 +/- 7 g for the females
- Fasting period before study: 18 hours, they were then given food 4 hours after treatment.
- Housing: The animals were housed in groups of 4 to 7 animals of the same sex in polycarbonate cages (48x27x20 cm) during the acclimatization period and groups of 5 animals of the same sex during the study.
- Food consumption (e.g. ad libitum): ad libitum
- Water consumption (e.g. ad libitum): ad libitum
- Acclimation period: 5 days during which they were observed daily.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 50 +/- 20% relative humidity
- Air changes (per hr): the air was non-recycled and filtered by absolute filters.
- Photoperiod (hrs dark / hrs light): 12hr/12hr

In-life dates: From 12/12/1991 to 13/02/1992


Route of administration:
oral: gavage
Vehicle:
other: paraffin oil
Details on oral exposure:
VEHICLE
A different vehicle (water for injections) was used for the preliminary assay.
- Batch n°: 1336 for water for injections (preliminary assay) and batch n°: 6852 for paraffin oil (main assay)

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg



Doses:
preliminary assay: 2000 mg/kg bw
main assay: 490, 680, 880, 1200 mg/kg bw (males) and 680, 880 mg/kg bw (females)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
DETAILS ON STUDY DESIGN
- Duration of observation period following administration: 14 days
- Frequency of observations: the animals were observed frequently after administration of the test substance and at least once a day for clinical signs and at least twice a day for mortality.
- Frequency of weighing: Animals were weighed just before administration of the test substance and then on days 5, 8 and 15.
- Necropsy of survivors performed: yes on day 15
- Other examinations performed: macroscopic examination at necropsy (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organ with obvious abnormalities)
Statistics:
no data
Sex:
male/female
Dose descriptor:
LD50
Effect level:
815 mg/kg bw
95% CL:
643 - 1 049
Mortality:
Mortality was observed within the 24 hours of administration of the test substance. No sex-related differences were noted.
At the dose level of 2000 mg/kg, all animals found dead.
The mortality in males was 0%, 20%, 60% and 100% at the dose levels of 490, 680, 880 and 1200 mg/kg respectively. The mortality in females was 0% and 60% at the dose levels of 680 and 880 mg/kg respectively.
Clinical signs:
Following administration of the test substance, a severe decrease in spontaneous activity accompanied by piloerection and dypsnea were seen at all dose levels. Other clinical signs noted in a few animals were hypersalivation and coma. Clinical signs were reversible between days 8 and 14.
Body weight:
Decreased body weight gain, sometimes resulting in slight to severe body weight loss, was observed between days 1 and 5 at all dose levels. Body weight gain returned to normal thereafter.
Gross pathology:
At necropsy of the animals found dead during the study, signs of ulceration of the stomach were observed at all dose levels. The macroscopic examination revealed no abnormalities in the animals sacrified at the end of the study.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
TBC 100% ECAILLES is considered as harmful if swallowed.

EU GHS Classification:
Acute oral toxicity Cat. 4 (H302)
Executive summary:

In an acute oral toxicity study (CIT study, 7674 TAR, 1992), groups of 6 weeks old fasted Sprague-Dawley rats (5/sex) were given a single oral dose of 4 -tert-butylpyrocatechol (100% Ecailles) in paraffin oil at doses of 490, 680, 880 and 1200 mg/kg bw for males and at doses of 680 and 880 mg/kg bw for females. Animals were observed for 14 days.

Oral LD50 Males = 815 mg/kg bw (95% C.I.: 643 - 1049 mg/kg)

4 -tert-butylpyrocatechol is harmful based on the LD50 in males.

The mortality in males was 0%, 20%, 60%, 100%, and 100% at the dose levels of 490, 680, 880, 1200 and 2000 mg/kg respectively. The mortality in the females was 0%, 60% and 100% at 680, 880 and 2000 mg/kg respectively. The necropsy of animals found dead showed signs of ulceration of the stomach at all dose levels. The macroscopic observation revealed no abnormalities in the animals sacrified at the end of the study. The observed decrease in body weight gain, sometimes resulting in body weight loss, in few surviving animals returned to normal after day 5. It can be stated that, according to the results, the LD50 in the females was similar to that of males.

This acute oral study is classified as acceptable. It does satisfy the guideline requirement for an acute oral study (OECD 401) in the rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
815 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
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
Type of information:
experimental study
Adequacy of study:
key study
Study period:
end of study: 31 March 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, 69210 L'Arbresle. France.
- Age at study initiation: 8 weeks old
- Weight at study initiation: 263 +/- 5g for the males, 212 +/- 7 g for the females
- Fasting period before study: no fasted
- Housing: The animals were housed in groups of 4 to 7 animals of the same sex per cage (sterilizable polycarbonate cages (48x27x20 cm)) during the acclimatization period and individually (sterilizable polycarbonate cages (35.5x23.5x19.3 cm)) during the study.
- Food consumption (e.g. ad libitum): ad libitum
- Water consumption (e.g. ad libitum): ad libitum
- Acclimation period: 5 days during which they were observed daily.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 +/- 3°C
- Humidity: 50 +/- 20% relative humidity
- Air changes: the air was non-recycled and filtered by absolute filters.
- Photoperiod: 12hr of light / 12hr of dark

In-life dates: From 10 December 1991 to 11 February 1992
Type of coverage:
semiocclusive
Vehicle:
other: paraffin oil
Details on dermal exposure:
TEST SITE
- Area of exposure: 5x6 cm for the females and 5x7 cm for the males
- % coverage: 10
- Type of wrap if used: hydrophilic gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing: after removal of the dresses, any residual test item was wiped out with a gauze moistened with water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount applied (volume): 5 mL/kg
- Doses: 500, 750, 1120, 1690 and 2000 mg/kg bw for the males and 750, 1120 and 2000 mg/kg bw for the females

VEHICLE:
A different vehicle (water for injections) was used for the preliminary assay.
preliminary assay: water for injections batch n° 1336
main assay: paraffin oil batch n° 6852

Duration of exposure:
24 hours
Doses:
preliminary assay: 2000 mg/kg bw
main assay: 500, 750, 1120 and 1690 mg/kg bw (males) and 750 and 1120 mg/kg bw (females)
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: the animals were observed frequently after administration of the test substance and then at least once a day.
- Frequency of weighing: animals were weighed just before administration of the test substance and then on days 5, 8 and 15.
- Necropsy of survivors performed: yes on day 15
- Other examinations performed: macroscopic examination at necropsy (digestive tract, herat, kidneys, liver, lungs, pancreas, spleen and any other organ with obvious abnormalities)
Statistics:
no
Sex:
male
Dose descriptor:
LD50
Effect level:
1 331 mg/kg bw
95% CL:
954 - 1 863
Mortality:
Mortality was observed within 48 hours of administration of the test substance. No sex-related differences were noted.
At the dose level of 2000 mg/kg, all animals found dead.
The mortality in males was 0%, 0%, 60% and 40% at the dose levels of 500, 750, 1120 and 1690 mg/kg respectively. The mortality in females was 40% and 60% at the dose levels of 750 and 1120 mg/kg respectively.
Clinical signs:
During the first few hours following application of the test substance, hypokinesia, sedation and dyspnea were noted in all treated animals. Clinical signs had reversed by day 3 at 500 mg/kg, by day 5 at 750 mg/kg and by day 7 at 1120 and 1690 mg/kg.
After the removal of the dressing and for at least one week, signs of severe cutaneous reactions were observed at all dose levels.
Body weight:
Between days 1 and 5, slight or severe loss of body weight was recorded in a few animals at 750 and 1120 mg/kg, respectively. Body weight gain was not influenced by the treatment in the other surviving animals.
Gross pathology:
At necropsy, signs of cutaneous necrosis were observed in all animals found dead during the study. The macroscopic examination revealed no abnormalities in the animals killed at the end of the study.
Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
TBC 100% ECAILLES is considered as harmful in contact with skin.
The toxicity of the test substance in the females was similar to that in the males. In order to comply with new ethic and scientific recommandations concerning the LD50, a more precise determination was not necessary in the females.

EU GHS classification:
Acute dermal toxicity Category 4 (H312)
Executive summary:

In an acute dermal toxicity study (CIT study 7675 TAR, 1992), groups of 8 weeks old non-fasted Sprague-Dawley rats (5/sex) were dermally exposed to 4 -tert-butylpyrocatechol (100% Ecailles) for 24 hours on approximately 10% of the body surface at doses of 500, 750, 1120, 1690 and 2000  mg/kg bw for males and at doses of 750, 1120 and 2000 mg/kg bw for females.  Animals then were observed for 14 days.

Dermal LD50 Males = 1331 mg/kg bw (95% C.I.: 954 - 1863 mg/kg bw)

4 -tert-butylpyrocatechol is harmful based on the LD50 in males. The toxicity of the test substance in the females was similar to that of the males.

The mortality in males was 0%, 0%, 60%, 40% and 100% at the dose levels of 500, 750, 1120, 1690 and 2000 mg/kg respectivley. The mortality in females was 40%, 60% and 100% at the dose levels of 750, 1120 and 2000 mg/kg respectively.

During the first few hours following application of the test substance, hypokinesia, sedation and dyspnea were noted in all treated animals. Clinical signs was reversed between day 3 and 7.

After the removal of the dressing and for at least one week, signs of severe cutaneous reactions were observed for all dose levels.

This acute dermal study is classified as acceptable. It does satisfy the guideline requirement for an acute dermal study (OECD 402) in the rat.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 331 mg/kg bw

Additional information

Oral route:

Three studies are available, one was selected as a key study, of reliability 1 according to Klimisch cotation criteria (CIT, 1992) and the two others were selected as supporting studies, of reliability 2 (Hazleton, 1986 and Sax, 1996).

In the key study, the oral LD50 in male and female rats was 815 mg/kg bw, warranting classification. The Hazleton supporting study provided similar oral LD50 values (817 - 821 mg/kg bw). The other LD50 value, taken from a reference handbook, was the least consistent (2820 mg/kg), and would have warranted no classification by itself, but no details were available as to the materials and methods used which could account for such a discrepancy.

In the key study several doses had been tested with sufficient number of animals per group (5/sex) to evaluate the toxic effects of the substance following acute exposure. A LOAEL could be determined at the lowest dose tested, 490 mg/kg, no mortality was observed at this dose, and the clinical signs after administration of the test substance were severe decrease in spontaneous activity accompanied by piloerection and dyspnea. These clinical signs were reversible between days 8 and 14.

4 -tert-butylpyrocatechol is therefore classified as Xn; R22: harmful if swallowed, according to the criteria of Annex VI Directive 67/548/EEC or acute oral tox. cat. 4, H302: harmful if swallowed, according to the UN/EU GHS, based on the main values obtained for oral LD50.

Inhalation route:

No data is available for this route of administration.

Dermal route:

Four studies are available for dermal route, two are considered as unreliable (reliability 3) (Sax, 1996 and Mellon, 1952) and two are considered as reliable (CIT, 1992 with reliability 1 and Hazleton, 1986 with reliability 2). CIT, 1992 study (reliability 1) has been selected as a key study and Hazleton, 1986 (reliability 2) has been selected as supporting study.

In the key study, the dermal LD50 was 1331 mg/kg bw, warranting classification. In the Hazleton study, the dermal LD50 was higher than 2003 mg/kg bw, which would warrant no classification. The difference between vehicles used (85% TBC in water used in this study instead of flakes in paraffin oil in the key study) may account for this discrepancy.

In the key study sufficent doses had been tested in groups of 5 animals/sex/dose to determine a dose-response. The lowest dose tested was 500 mg/kg which was considered as a LOAEL. The clinical signs observed after dermal application were hypokinesia, sedation and dyspnea (reversible within 3 days), plus a severe cutaneous reaction.

The two other studies (Sax, 1996 and Mellon, 1952) were performed on rabbits but were considered as unreliable since a lot of information is missing: condition of the test, information on the test substance. Mellon, 1952 study does not follow any guideline and the patch used was occlusive.

4 -tert-butylpyrocatechol is therefore classified as Xn; R21: harmful in contact with skin, according to the criteria of Annex VI Directive 67/548/EEC or acute dermal tox. cat. 4, H312: harmful in contact with skin, according to the UN/EU GHS, based on the LD50 value obtained in the key study.


Justification for selection of acute toxicity – oral endpoint
The study was a GLP-compliant OECD guideline study.

Justification for selection of acute toxicity – inhalation endpoint
Likely route of human exposure is more in favor of acute dermal toxicity study than inhalation one.

Justification for selection of acute toxicity – dermal endpoint
The study was a GLP-compliant OECD guideline study.

Justification for classification or non-classification

Based on EU classification criteria and on the experimental data, 4 -tert-butylpyrocatechol is classified as harmful if swallowed and as harmful in contact with skin, when we consider the pure substance (100% flakes). And, 4 -TBC is classified as harmful if swallowed for the hydrate form (85% 4 -TBC in water).