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Administrative data

Description of key information

Recent and well-conducted guideline studies in rats indicate no significant toxicity up to limiting doses of 2000 mg/kg bw either by the oral or dermal routes of exposure.

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:
April - June 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
CYANOX® 1790 Antioxidant
IUPAC nomenclature - Tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate
Synonym - [tris(4-t-butyl-3-hydroxy-2,6-dimethyl-benzyl)-s-triazine-2,4,6-(1H,3H,5H) trione]
Lot WP1031901
Appearance - White powder, odorless
CAS No. 40601-76-1
Molecular Formula - C42H57N3O6
Molecular Weight - 699.92 g/mole
Purity > 99%
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals (approx. 8-9 weeks old)
- Weight at study initiation: +/- 20% of the sex mean
- Fasting period before study: yes, overnight
- Housing: individually housed in Makrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet: free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany)
- Water: free access to tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 6 - 26 April
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% in water
Details on oral exposure:
GAVAGE METHOD: plastic feeding tubes.

VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. No correction was made for purity of the test substance.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6 females (2 groups of 3 females in a stepwise manner)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy performed: yes, all animals
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Hunched posture was noted in all animals on days 1 and/or 11.
Body weight:
No effect on body weight gain was observed.
Gross pathology:
No toxicologically relevant abnormalities were found at macroscopic post mortem examination of the animals.
One animal showed pelvic dilation in both kidneys. This finding is occasionally seen among rats of this age and strain and was therefore considered not related to treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
The oral LD50 value of CYANOX® 1790 Antioxidant in Wistar rats was established to exceed 2000 mg/kg body weight.
Based on these results, CYANOX® 1790 Antioxidant does not have to be classified and has no obligatory labelling requirement for acute oral toxicity.
Executive summary:

In a GLP compliant acute oral toxicity study, performed according to OECD guideline 423, the test item was administered to two groups of 3 female Sprague Dawley rats ata single dose level of 2000 mg/kg bw.

No mortalities or clinical signs were noted.

In conclusion, the LD50 ofthe test itemisdeterminedto be> 2000 mg/kg body weight by oral route in the rat.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Acute toxicity: via inhalation route

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:
April - October 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No. 8147, April 2011; including the most recent partial revisions
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
CYANOX® 1790 Antioxidant
IUPAC nomenclature - Tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate
Synonym - [tris(4-t-butyl-3-hydroxy-2,6-dimethyl-benzyl)-s-triazine-2,4,6-(1H,3H,5H) trione]
Lot WP1031901
Appearance - White powder, odorless
CAS No. 40601-76-1
Molecular Formula - C42H57N3O6
Molecular Weight - 699.92 g/mole
Purity > 99%
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals (approx. 11 weeks old)
- Weight at study initiation: +/- 20% of the sex mean
- Housing: individually housed in Makrolon cages containing sterilized sawdust as bedding material and paper as cage-enrichment
- Diet: free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany)
- Water: free access to tap water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-24
- Humidity (%): 40-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 12 - 26 April
Type of coverage:
occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
1% in water
Details on dermal exposure:
One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.
The formulation was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D), successively covered with aluminum foil and Coban elastic bandage. A piece of Micropore tape was additionally used for fixation of the bandages in females only.
Frequency: Single dosage, on Day 1.
Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
VEHICLE
- Justification for choice of vehicle: The vehicle was selected based on trial formulations performed at NOTOX and on test substance data supplied by the sponsor.

Dose level (volume): 2000 mg/kg bw (10 ml/kg bw)

DOSAGE PREPARATION:
The formulation (w/w) was prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level. No correction was made for purity of the test substance.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: days 1 (pre-administration), 8 and 15
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The time of onset, degree and duration were recorded and the symptoms graded according to fixed scales.
- Necropsy performed: yes, all animals
Statistics:
No statistics needed.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred.
Clinical signs:
Chromodacryorrhoea was noted in four males and two females on Days 1 and/or 2. One male showed flat posture on Day 1. White staining of the treated skin was seen in all animals on Day 2. One female showed scales on the treated skin between Days 4 and 11.
Body weight:
No effect on body weight gain was noted.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The dermal LD50 value of CYANOX® 1790 Antioxidant in Wistar rats was established to exceed 2000 mg/kg body weight.
Based on these results, CYANOX® 1790 Antioxidant does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity.
Executive summary:

An acute dermal toxicity test with male and female rats was performed under GLP principles. The rats were exposed occlusively for 24 hours to 2000 mg/kg bw and observed for 14 days after removal of the test substance. No mortality, clinical signs or particular findings at necropsy were observed.

Based on these results, the LD50 of the test substance was found to be > 2000 mg/ kg bw and therefore the test substance is not classified.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Acute Oral Toxicity

In an earlier non-guideline study, 10 male Wistar rats were treated with a single dose of 10 g/kg bw and observed for signs of toxicity for 14 days. The were no adverse effects reported in this study. The LD50 was reported as > 10,000 mg/kg bw. In a recent study conducted according to OECD Guideline 423, 6 female Wistar rats were treated up to a limit dose of 2000 mg/kg bw and observed for signs of toxicity for 14 days. There was no mortality or other toxicologically relevent abnormalities reported in this study. The LD50 was reported as > 2000 mg/kg bw.

Acute Dermal Toxiciy

In an earlier non-guideline study, 5 male albino rabbits were administered 5000 mg/kg bw dermally under semi-occlusive wrap and animals were then observed for signs of toxicity for 14 days. There was no mortality, signs of intoxication or irritation. No clinical signs were noted. The LD 50 was reported as > 5000 mg/kg bw. In a recent guideline study, groups of 5 male and female Wistar rats were administered 2000 mg/kg bw dermally under occlusive wrap. The exposure duration was 24 h after which the animals were observed for signs of toxicity for 14 days. There was no mortality and no abnormalities found at macroscopic examination at study termination. The LD 50 was reported as > 2000 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
A recent study conducted according to OECD Guideline 423 (Acute Toxicity Class Method).

Justification for selection of acute toxicity – dermal endpoint
A recent study conducted according to OECD Guideline 402 (Acute Dermal Toxicity).

Justification for classification or non-classification

In well-conducted oral and dermal acute toxicity studies in experimental animals, there was no significant toxicity noted. Thus, no classification for acute toxicity is warranted. Also, no classification for STOT (single) is warranted.