Hexamethylene bis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate]

Endpoint summary

Description of key information

In four acute oral toxicity studies LD50 values of greater than 5000 mg/kg bw were determined for several species (hamster, mouse and rat). No mortality was observed in any of the tested species. In an acute inhalation study a LC50 of greater than 1700 mg/m3 air (aerosol, maximum attainable concentration) was determined in rats. A dermal LD50 of greater than 10000 mg/kg bw was determined and no mortality was observed in an acute dermal toxicity study with rabbits.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP and non guideline study. Meets generally accepted scientific standards. No details are given regarding the test substance like purity etc. Information regarding clinical signs or gross necropsy are not presented.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

Only four animals of each sex were used for each dosing group. No details are given regarding clinical signs or gross necropsy.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approx. 12 weeks
- Fasting period before study: yes, overnight
- Diet: ad libitum
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 50%

Doses:

1250, 2500, 5000 mg/kg bw (screening test)
5000 mg/kg bw (main study)

No. of animals per sex per dose:

1 (screening test)
4 (main study)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: no

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths were observed up to the highest tested dose.

Clinical signs:

other: No data

Gross pathology:

No data

Interpretation of results:

practically nontoxic

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP study. Scientifically acceptable study report equivalent to OECD guideline 403. Specific data regarding the test substance are missing.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

Animals were only observed for 8 days.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: RAI

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in house breed
- Age at study initiation: 7 - 8 weeks old
- Weight at study initiation: 180 - 185 g
- Housing: groups of 9 animals in macrolon cages (Type 4)
- Diet: ad libitum,
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1
- Humidity (%): ca. 50

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: according to Niessen et al. (Arch. Toxicol. 20, 44-60 (1963))
- Method of holding animals in test chamber: separate PVC tubes
- Rate of air: 10 L/min
- System of generating particulates/aerosols: a pressure nozzle was used.
- Method of particle size determination: The particle-size distribution in the aerosol was determined gravimetrically on Selectron-Filters, pore size 0.2 µm (Schleicher and Schuell, 8714 Feldbach, Switzerland) every hour with the aid of a "Cascade Impactor" (CT. Casella and Co. Ltd., London N.l, England)

TEST ATMOSPHERE
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle: Ethanol
- Concentration of test material in vehicle: 20%

TEST ATMOSPHERE
- Particle size distribution: 2% >7 µm; 39% 3-7 µm; 51% 1-3 µm; 14% <1 µm

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

1688±195 mg/m3

No. of animals per sex per dose:

9

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 8 days
- Frequency of observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 1.7 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality was observed.

Clinical signs:

other: After the 4-hour exposure the rats showed lateral position and apathy. Rats that were only treated with the vehicle did not show any toxic symptoms.

Body weight:

Not determined.

Gross pathology:

No gross internal lesions were observed.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information

Conclusions:

The LC50 of the test item determined after an observation period of 7 days in rats of both sexes, exposed to the substance for four hours is greater than 1700 mg/m^3, air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

1 700 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:

Dec. 1969 - Jan. 1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP study. Scientifically acceptable report with few methodological defiencies. Only two dose levels with 4 animals each were tested.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

Only two dose levels were tested. Only 4 animals were used at each dose level. Half of the animals were abraded.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in house breed
- Weight at study initiation: 2 - 3 kg
- Housing: individually
- Diet: ad libitum, Altromin K (ALTROMIN GmbH, Lage/Lippe))
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2
- Humidity (%): 60±3
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Vehicle:

not specified

Details on dermal exposure:

TEST SITE
- Area of exposure: back was shaved and half of the animals were abraded.
- Type of wrap if used: rubber sleeve

TEST MATERIAL
- Concentration: 50% suspension

Duration of exposure:

Refer to observation period. Skin sites were not washed after 24 hours with the semiocclusive dressing.

Doses:

2500, 10000 mg/kg bw

No. of animals per sex per dose:

4

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations and weekly weighings
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed.

Clinical signs:

other: No clinical signs were observed.

Gross pathology:

No gross internal lesions were observed during necropsy.

Interpretation of results:

practically nontoxic

Remarks:

Migrated information

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

10 000 mg/kg bw

Additional information

Acute oral toxicity

In the first acute oral toxicity study, groups of male and female Wistar rats (4/sex) were given a single oral dose of the test substance in corn oil per gavage at a dose level of 5000 mg/kg bw (Shell, 1978). Animals were then observed for 14 days. No mortality was observed in any of the dosing groups. A LD50 of greater than 5000 mg/kg bw was determined.

In the second acute oral toxicity study similar to OECD guideline 401, groups of male and female Tif:MAGf mice (5/sex) were given a single oral dose of the test substance in polyethylene glycol per gavage at dose levels of 4640, 6000 and 7750 mg/kg bw (Ciba-Geigy, 1978). Animals were then observed for 14 days. Within 2 hours after treatment the rats in all dosage groups showed sedation, dyspnoea, curved position and ruffled fur. Additionally in the highest dosage group ventral position was also observed. All animals recovered within 8 to 14 days. No mortality was observed and no gross internal lesions were observed during necropsy in any of the animals. A LD50 of greater than 7750 mg/kg bw was determined.

In the third acute oral toxicity study similar to OECD guideline 401, groups of male and female Chinese hamsters (5/sex) were given a single oral dose of the test substance in polyethylene glycol per gavage at dose levels of 4640, 6000 and 7750 mg/kg bw (Ciba-Geigy, 1978). Animals were then observed for 14 days. All animals gained weight throughout the study period. Slight sedation, dyspnoe and a curved body posture was observed in all dosing groups. All animals had recovered within 11 to 13 days. No mortality was observed and no gross internal lesions were observed during necropsy in any of the animals.A LD50 of greater than 7750 mg/kg bw was determined.

In the fouth acute oral toxicity study, groups of male and female rats (5/sex) were given a single oral dose of the test substance per gavage at dose levels up to 5000 mg/kg bw (BASF, 1969). Animals were then observed for 8 days. Due to the short summary of the study, information regarding clinical signs, mortality und gross necropsy is missing. Only a LD50 value of above 5000 mg/kg bw was determined.

 

 

Acute inhalation toxicity

In an acute inhalation study equivalent to OECD guideline 403, groups (9/sex) of RAI rats were exposed nose only to the test substance in ethanol (aerosol) for 4 hours at a maximum attainable concentration of 1700 mg/m³ (IBT, 1973). Animals were then observed for 8 days. After the 4-hour exposure the rats showed lateral position and apathy. Rats that were only treated with the vehicle did not show any toxic symptoms. All animals had recovered within 24 hours. No mortality and no gross internal lesions during necropsy were observed. A LC50 of greater than 1700 mg/m³ air was determined.

Acute dermal toxicity

In an acute dermal toxicity study equivalent to OECD guideline 402, groups of young adult New Zealand White rabbits (2/sex) were dermally exposed to a 50% suspension of the test substance for 24 hours at dose levels of 2500 and 10000 mg/kg bw. The skin of half of the animals was abraded before exposure. The animals were then observed for 8 days. No clinical signs were observed and the body weight gain was normal for all animals throughout the study period. No mortality and no gross internal lesions during necropsy were observed. Therefore a LD50 of above 10000 mg/kg bw was determined for both intact and abraded skin.

 

In a second acute dermal toxicity study, groups of 12 weeks old male and female Wistar rats (4/sex) were dermally exposed to the test substance in corn oil at a limit dose of 1000 mg/kg bw. Animals were then observed for 14 days. No mortality or any toxic signs were observed. No retardation of body weight gain was seen throughout the study period. A LD50 of greater than 1000 mg/kg bw was determined.

 

Conclusions

No deaths occurred when rats were exposed orally at doses above 5000 mg/kg bw, dermally at doses above 10000 mg/kg bw and by inhalation at doses of above 1700 mg/m³ air. Furthermore no severe clinical signs were observed during the studies. Although not necessary according to column 2 of REACH Annex VIII, part 8.5, the test substance proved its low acute toxicity in all three types of application.

Justification for selection of acute toxicity – oral endpoint
Worst case LD50 value with the most common animal species.

Justification for selection of acute toxicity – inhalation endpoint
Scientifically acceptable study report equivalent to OECD guideline 403.

Justification for selection of acute toxicity – dermal endpoint
Scientifically acceptable study report.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. As a result the substance does not need to be classified and labelled for acute toxicity (oral, dermal and inhalation) under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EC.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not eed to be classified and labelled for acute toxicity (oral dermal and inhalation) under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation EC No 605/2014.