Bis(2,2,6,6-tetramethyl-4-piperidyl) sebacate

Endpoint summary

Description of key information

The following LD 50 values were derived:

oral LD50 in rats: 3700 mg/kg bw

dermal LD50 in rats: > 3170 mg/kg bw (rat)

inhalation LC50 in rats: 0.5 mg/l (rat)

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 1972

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

no

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: CFY

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: not indicated
- Age: not indicated
- Number: 5/sex/group
- Weight at study initiation: 97-112 g
- Controls: 5/sex (vehicle)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on oral exposure:

- Vehicle: 0.5% CMC
- Volume administered or concentration: =<16.7 mL/kg bw
The test material was prepared as a 30% suspension. Rats dosed with the vehicle alone (16. 7ml/kg) served as controls.

Doses:

0, 2500, 3200, 4000 and 5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of weighing: once per week
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 700 mg/kg bw

Mortality:

- Males: 0/5, 2/5, 2/5, 3/5 and 5/5 at 0, 2500, 3200, 4000 and 5000 mg/kg bw
- Females: 0/5, 0/5, 0/5, 2/5 and 4/5 at 0, 2500, 3200, 4000 and 5000 mg/kg bw
- Time of death: between 42 hours and 4 days after dosing

Clinical signs:

other: Salivation, diarrhoea and diuresis. Animals recovered within 2 days

Gross pathology:

Pale patches on liver lobes of animals that died.

Other findings:

SEX-SPECIFIC DIFFERENCES: None

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 was established at 3700 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

3 700 mg/kg bw

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

Study period:

7 days

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

7 days observation instead of 14 days

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Tif. RAI

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age: 8-9 weeks old
Weight: 180-220 g
The males and females were segregated and kept in Macrolon cages, type 4, (9 animals to a cage) during an observation period of 7 days in a room maintained at a constant temperature of 22 ± 1 °C and a relative humidity of approximately 50 %.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: ethanol

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: modified version of an apparatus described by Niessen et al. (Arch. Toxicol. 20, 44-60 (1963))
- Method of holding animals in test chamber: in PVC tubes positioned radially around the exposure chamber
- System of generating particulates/aerosols: A 20 % dilution in ethanol was sprayed into the exposure chamber by means of a pressure nozzle. The liquid was injected by a motor-driven syringe at a rate of 6, 12 and 30 ml/hr into a stream of compressed air (2 atm.) flowing through a spray nozzle at a rate of 10 lit./min. The aerosol mist thus produced was discharged into the exposure chamber. The animals were exposed to the test substance when the aerosol was evenly dispersed throughout the chamber (15 minutes).
- Method of particle size determination:

TEST ATMOSPHERE
- Brief description of analytical method used: The individual concentrations of the test substance and the particle-size distribution in the aerosol were determined gravimetrically. The aerosol was sampled on Membrane Filters, pore size 0.2 µm hourly after the beginning of the test.
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): ethanol

Analytical verification of test atmosphere concentrations:

yes

Remarks:

hourly

Duration of exposure:

4 h

Concentrations:

measured concentrations: 232 ± 46, 394 ± 72 and 887 ± 138 mg/m³

No. of animals per sex per dose:

9

Control animals:

yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

500 mg/m³ air

Exp. duration:

4 h

Mortality:

No animals died after exposure to 232 mg/m³. One animal per sex died within the first 4-hour while exposed to 394 mg/m³. All animals died within the first 4-hour while exposed to 887 mg/m³.

Clinical signs:

other: After 4-hour exposure all rats showed dyspnoea, salivation, trismus, tremor and sedation with a dose-dependent intensity. The surviving animals recovered within 24 hours. Animals treatment with ethanol alone did not show any effect.

Body weight:

No data

Gross pathology:

Dead animals: slight pulmonary edema
Killed animals: no substance related gross organ changes.

Mean particle size distribution (cascade impactor):

232 mg/m³: 29%: > 7 µm; 14%: 3 -7 µm; 14%: 1 -3 µm; 43%: < 1 µm

394 mg/m³: 10% > 7 µm; 27%: 3 -7 µm; 36%: 1 -3 µm; 27%: 1 µm

887 mg/m³: 17% > 7 µm; 21%: 3 -7 µm; 28%: 1 -3 µm; 34%: 1 µm

Conclusions:

The LC50 was established to be 500 mg/m³ (0.5 mg/l). Based on a split-entry apporach, classification is not required.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

500 mg/m³ air

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:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

- Size of the treatment area not indicated - Low number of animals (3/sex instead of 5) - No information on body weight gain

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

The formulation is 50% test substance in 2% CMC (aqueous susp. assumed, but not specifically stated in the report)

Species:

rat

Strain:

other: Tif. RAI

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Ciba-Geigy breeding unit
- Age at study initiation: not indicated
- Weight at study initiation: 180-200 g
- Housing: individually in Macrolon cages (type 2)
- Diet: ad libitum rat food - NAFAG, Gossau SG
- Water: ad libitum
- Acclimation period: minimum of 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1
- Humidity (%): 55 ± 5
- Air changes (per hr): not indicated
- Photoperiod (hrs dark / hrs light): 10/14

Type of coverage:

occlusive

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

2%

Details on dermal exposure:

TEST SITE
- Area of exposure: back
- % coverage: not indicated (shaved area 60 cm²)
- Type of wrap if used: occlusive dressing which was fastened around the trunk with an adhesive elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with lukewarm water
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): not indicated
- Concentration (if solution): 50% formulation

Duration of exposure:

24 hours

Doses:

2150 and 3170 mg/kg bw
no higher concentrations were possible

No. of animals per sex per dose:

3

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 3 170 mg/kg bw

Mortality:

- Number of deaths at each dose: no deaths occurred
- Time of death: not applicable

Clinical signs:

other: Dyspnoea, exophthalmus, ruffled fur and hunched posture. Animals recovered within 13 days.

Gross pathology:

No test substance related gross changes.

Other findings:

SEX-SPECIFIC DIFFERENCES: None

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 was determined to be higher than 3170 mg/kg bw

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 170 mg/kg bw

Additional information

Acute oral toxicity

In an acute oral toxicity study, groups of 5 male and 5 female rats were given a single oral dose of the test substance prepared as a 30% suspension in 0.5% aqueous carboxy methyl cellulose at the following dose levels: 0, 2500, 3200, 4000 and 5000 mg/kg bw. Deaths occurred from 2500 mg/kg and up in males and at 4000 mg/kg and higher in females. Salivation, diarrhoea and diuresis were recorded, animals recovered within 2 days. Under the chosen test conditions, the oral LD50 was calculated at 3700 mg/kg bw.

Acute inhalation toxicity

The test article was tested for acute inhalation toxicity by the exposure of albino rats to an aerosol. Nine male and female animals were exposed to 232, 394 and 887 mg/m³ followed by an observation period of 7 days. No animals died after exposure to 232 mg/m³. One animal per sex died within the first 4-hour while exposed to 394 mg/m³. All animals died within the first 4-hour while exposed to 887 mg/m³. After 4-hour exposure all rats showed dyspnoea, salivation, trismus, tremor and sedation with a dose-dependent intensity. The surviving animals recovered within 24 hours. Animals treatment with ethanol alone did not show any effect. In conclusion, the LC50 determined in rats of both sexes, exposed to the substance for four hours is approximately 500 mg/m³ air.

Acute dermal toxicity

In an acute dermal toxicity study groups of 3 male and 3 female rats were exposed to the test material at concentrations of 2150 and 3170 mg/kg body weight followed by an observation period of 14 days. No higher doses were possible. The substance was evenly dispersed on the skin with a syringe and was covered with an occlusive dressing for 24 hours. Within 24 hours after treatment the rats in all dosage groups showed dyspnoea, exophthalmus, curved position and ruffled fur. No local skin irritation was seen. The animals recovered from systemic symptoms within 13 days. No deaths occurred. The acute dermal LD50 in rats of both sexes observed over a period of 14 days is therefore greater than 3170 mg/kg.

Justification for classification or non-classification

There are conclusive but not sufficient data for classification of the test item with regard to acute toxicity.

The test item is not classified for this endpoint in accordance to Directive 67/548/EEC or the CLP Regulation (EC) No 1272/2008 as well as GHS regulations.

Inhalation Acute toxicity

Specifically for acute inhalation toxicity, the split entry approach does apply. In a Heubach Test, a sample of the test material was mechanically stressed in a rotating drum (dust generation device), and both the dust already contained in this sample and the dust generated due to abrasion were removed from the dust generation device by an air current. The proportion of dust separated and considered as dust with the ability to become airborne was fed into a seven-stage cascade impactor connected to the dust generation device. Particle size classification was conducted by subsequent weighing of the respective dust masses deposited on the individual cascade stages reflecting certain particle size ranges.

 

Result:

Total dustiness (ratio of the mass of removed dust to the total sample mass initially weighed in)	13.06 [mg/g]
Inhalable fraction (≤ 100 µm aerodynamic diameter)	7.55 [mg/g]
Thoracic fraction (≤ ca. 10 µm aerodynamic diameter)	0.62 [mg/g]
Respirable fraction (≤ ca. 4 µm aerodynamic diameter)	0.03 [mg/g]

 

Split Entry-Approach (Pauluhn, 2008)

The Guidance on the Application of Regulation (EC) No 1272/2008 acknowledges (e.g. chapter 3.1.2.3.2) that special consideration is required if a substance is tested in a form (i.e. specific particle size distribution) that is different from the forms in which the substance is placed on the market and in which it can reasonably be expected to be used. According to Pauluhn (Experimental and Toxicologic Pathology 60, 2008, 111-124) there is an option for a modified Classification and Labelling (C&L), called “split-entry concept”. While the current test principles for acute inhalation uses a predetermined particle size in the breathing zone of exposed animals in order to allow a robust relative ranking of the acute lethal toxic potency of different substances, split entry takes into account for an assessment of potential human hazards the actual percentage of the critical percentage of particles present in the product as commercialized and used (thoracic fraction).

For the test item, a Heubach dust generation measurement (shown above) showed that the thoracic fraction of the product used is 0.62 mg/g after abrasion.

ATE split-entry = 100/Cth x ATE

with

CTh = concentration of an ingredient corrected for its thoracic fraction (%)

ATE = Acute Toxicity Estimate

ATE split-entry = 100/0.062 x 500 mg/m³ = 806451 mg/m³ = 806.5 mg/l

Accordingly, no classification by inhalation is indicated based on the criteria defined in Table 3.1.2. of the GHS – Part 3 document.