Registration Dossier

Administrative data

Description of key information

Acute oral LD50: >2000 mg/kg bw; OECD 423; Bull, A. (2012)

Acute dermal LD50: >2000 mg/kg bw; OECD 402; Bull, A. (2012)

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:
26 July 2011 - 02 March 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Study was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
17 December 2001
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
Commission Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Version / remarks:
2002
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF, Test Data for Registration of Agriculture Chemicals, Acute Oral Toxicity (2-1-1), 12 Nousan No. 8147, Agriculture Protection Bureau
Version / remarks:
24 November 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: N/A
- Specific activity: N/A
- Locations of the label: N/A
- Expiration date of radiochemical substance: N/A

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark and under nitrogen.
- Stability under test conditions: Asumed stable.
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was formulated at a concentration of 200 mg/mL in corn oil. Assumed stable.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: N/A.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: N/A
- Preliminary purification step (if any): N/A
- Final dilution of a dissolved solid, stock liquid or gel: N/A
- Final preparation of a solid: N/A

FORM AS APPLIED IN THE TEST (if different from that of starting material): Applied as liquid formulant.

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable): N/A

OTHER SPECIFICS: No
Species:
rat
Strain:
other: Crl:CD'SD'
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 217-240 g
- Fasting period before study: Yes, overnight and 4 hours prior to dosing
- Housing: Animals were housed inside a barriered rodent facility. The facility was designed and operated to minimise the entry of external biological and chemical agents and to minimise the transference of such agents between rooms. During the acclimatisation period, each cage of animals was provided with a soft white untreated chew block and plastic shelter for environmental enrichment.
- Diet (e.g. ad libitum): Ad libitum, excpet during fasting.
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: ≥5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 ºC
- Humidity (%): 40-70 %
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12:12 light:dark

IN-LIFE DATES: From: 09 August 2011 To: 25 August 2011
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg body weight
- Justification for choice of vehicle: Test item not soluble in water. Corn oil is an accepted alternative vehicle.
- Lot/batch no. (if required): Not reported
- Purity: Not reported

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg bw

DOSAGE PREPARATION (if unusual): Formulation was stirred prior to and continuously throughout the dosing process.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: 2000 mg/kg is the class method starting point.
Doses:
2000 mg/kg bw (limit test)
No. of animals per sex per dose:
Females: 2 groups of three rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation. The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes and group mean bodyweights were calculated.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight, macroscopic pathology
Statistics:
Not required (no effect)
Preliminary study:
N/A
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
There were no deaths during the study.
Clinical signs:
There were no clinical signs of reaction to treatment throughout the study.
Body weight:
All animals were considered to have achieved satisfactory bodyweight gains throughout the study, the bodyweight gains were lower during the second week.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.
Other findings:
N/A

Table 2      Number of animals dead (and with evident toxicity)

 

Dose

(mg/kg bw)

Mortality

(# dead / total)

Time range of deaths

(hours)

Number with evident toxicity

(# / total)

Male

Female

Combined

Male

Female

Combined

2000

-

0 / 6

0 / 6

n/a

-

0 / 6

0 / 6

 

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, the test article, Tetraesters of pentaerythritol with 2- methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid, was considered to have no significant acute toxic risk in respect of its acute oral toxicity and did not meet the criteria for classification under Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.
Executive summary:

OECD 423 (2012) - In an acute oral toxicity study, a group of fasted, 8-12 week old female, nulliparous Crl:CD’SD’ rats were given a single oral dose of Tetraesters of pentaerythritol with 2-methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid at a single dose rate of 2000 mg/kg bw (limit test) and observed for 14 days.

 

In the absence of mortality during the observation period, the oral LD50 was estimated to be greater than 2000 mg/kg bw.

 

In addition, there were no treatment related clinical signs, necropsy findings or changes in body weight observed in any of the individuals.

 

Tetraesters of pentaerythritol with 2-methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid did not meet the criteria for classification according to Regulation (EC) No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixture.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met. The study was sufficient to conclude on the acute oral toxicity endpoint.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
The substance meets the Annex VIII, Section 8.5.2, Column 2 criteria as the vapour pressure is 2.0E-04 Pa. The use pattern for the substance will not present situations where exposure to aerosols, particles or droplets of an inhalable size is relevant.
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
The substance meets the Annex VIII, Section 8.5.2, Column 2 criteria as the vapour pressure is 2.0E-04 Pa.  The use pattern for the substance will not present situations where exposure to aerosols, particles or droplets of an inhalable size is relevant. Therefore an acute inhalation toxicity test does not need to be conducted.

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:
26 July 2011 - 02 March 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Stuy was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
24 February 1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
Commission Regulation (EC) No 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: JMAFF, Test Data for Registration of Agricultural Chemicals, Acute dermal toxicity (2-1-2), 12 Nousan No 8147, Agricultural Production Bureau
Version / remarks:
24 November 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: N/A
- Specific activity: N/A
- Locations of the label: N/A
- Expiration date of radiochemical substance: N/A

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature in the dark and under nitrogen.
- Stability under test conditions: Asumed stable.
- Solubility and stability of the test substance in the solvent/vehicle: Applied as supplied.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: N/A.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: N/A
- Preliminary purification step (if any): N/A
- Final dilution of a dissolved solid, stock liquid or gel: N/A
- Final preparation of a solid: N/A

FORM AS APPLIED IN THE TEST (if different from that of starting material): Applied as supplied.

TYPE OF BIOCIDE/PESTICIDE FORMULATION (if applicable): N/A

OTHER SPECIFICS: No
Species:
rat
Strain:
other: Crl:CD'SD'
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Chares River UK Ltd.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: Males: 339-365 g; Females: 215-250 g
- Fasting period before study: No
- Housing: The animals were allocated without conscious bias to cages within the treatment group. They were housed individually from Day -1 until Day 3 when they were returned to group housing (in groups of five rats of the same sex). The cages were solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding. Cages, food hoppers, water bottles and bedding were changed at appropriate intervals.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 ºC
- Humidity (%): 40-70 %
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12:12 ligh: dark

IN-LIFE DATES: From: 17 August 2011 To: 31 August 2011
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 50x50 mm
- % coverage: 10 % body area
- Type of wrap if used: Covered with porous gauze held in place with a non-irritating dressing, and further covered by a waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washed with warm water (30 - 40 °C), to remove any residual test substance. The treated area was blotted dry with absorbent paper.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.02 mL/kg (specific gravity of test item = 0.992 g/mL)
- Concentration (if solution): N/A, applied as supplied.
- Constant volume or concentration used: Yes
- For solids, paste formed: N/A

VEHICLE
- Amount(s) applied (volume or weight with unit): N/A, applied as supplied (i.e. liquid)
- Concentration (if solution): N/A
- Lot/batch no. (if required): N/A
- Purity: N/A
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
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 and weighing: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, dermal reactions, body weight, macroscopic pathology
Statistics:
Not required (no effect)
Preliminary study:
N/A
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
not determinable due to absence of adverse toxic effects
Mortality:
There were no deaths.
Clinical signs:
There were no systemic response to treatment in any animal.
Body weight:
There was considered to be no overall adverse effect on bodyweight gain, however, low bodyweight gains / bodyweight stasis was observed for some individuals.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

Table 3       Dermal reactions

 

Dose

(mg/kg)

Sex

Animal no.

E= erythema

O = oedema

Day 2-15

2000

Male

B1

E

0

O

0

B2

E

0

O

0

B3

E

0

O

0

B4

E

0

O

0

B5

E

0

O

0

Female

B6

E

0

O

0

B7

E

0

O

0

B8

E

0

O

0

B9

E

0

O

0

B10

E

0

O

0

Table 4       Individual bodyweight

 

Dose

(mg/kg)

Sex

Animal no.

Bodyweight (g) at Day

Bodyweight changes (g) at Days

1*

8

15

1-8

8-15

2000

Male

B1

339

385

422

46

37

B2

354

390

426

36

36

B3

365

382

416

17

34

B4

364

381

426

17

45

B5

348

377

413

29

36

Mean

354

383

421

-

-

Female

B6

250

257

262

7

5

B7

215

236

251

21

15

B8

247

247

264

0

17

B9

237

247

262

10

15

B10

232

239

251

7

12

Mean

236

245

258

-

-

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in male and female Crl:CD'SD' strain rat.
Executive summary:

OECD 402 (2012) - In an acute dermal toxicity study, a group of 8-12 week old male (5 individuals) and female (5 individuals) (nulliparous) Crl:CD’SD’ rats were exposed to a single dermal application of Tetraesters of pentaerythritol with 2-methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid for 24 hours at a single dose rate of 2000 mg/kg bw (limit test).The test item was applied undiluted to a 50 x 50 mm contact area, equivalent to approximately 10 % of the body surface. After 24-hour exposure, the test site was cleaned with warm water and observations recorded for 14 days.

 

In the absence of mortality during the observation period, the oral LD50 was estimated to be greater than 2000 mg/kg bw.

 

In addition, there were no treatment related clinical signs, necropsy findings or changes in body weight observed in any of the individuals.

 

Tetraesters of pentaerythritol with 2-methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid did not meet the criteria for classification according to Regulation (EC) No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The study was conducted in accordance with International guidelines and in accordance with GLP. All guideline validity criteria were met. The study was sufficient to conclude on the acute dermal toxicity endpoint.

Additional information

Acute Oral Toxicity

OECD 423 (2012) - In an acute oral toxicity study, a group of fasted, 8-12 week old female, nulliparous Crl:CD’SD’ rats were given a single oral dose of Tetraesters of pentaerythritol with 2-methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid at a single dose rate of 2000 mg/kg bw (limit test) and observed for 14 days.

 

In the absence of mortality during the observation period, the oral LD50 was estimated to be greater than 2000 mg/kg bw.

 

In addition, there were no treatment related clinical signs, necropsy findings or changes in body weight observed in any of the individuals.

Acute Inhalation Toxicity

Study waiver - The substance meets the Annex VIII, Section 8.5.2, Column 2 criteria as the vapour pressure is 2.0E-04 Pa.  The use pattern for the substance will not present situations where exposure to aerosols, particles or droplets of an inhalable size is relevant. Therefore an acute inhalation toxicity test does not need to be conducted.

 

Acute Dermal Toxicity

OECD 402 (2012) - In an acute dermal toxicity study, a group of 8-12 week old male (5 individuals) and female (5 individuals) (nulliparous) Crl:CD’SD’ rats were exposed to a single dermal application of Tetraesters of pentaerythritol with 2- methylpropanoic acid and 3,5,5-trimethyl-hexanoic acid for 24 hours at a single dose rate of 2000 mg/kg bw (limit test).The test item was applied undiluted to a 50 x 50 mm contact area, equivalent to approximately 10 % of the body surface. After 24-hour exposure, the test site was cleaned with warm water and observations recorded for 14 days.

 

In the absence of mortality during the observation period, the oral LD50was estimated to be greater than 2000 mg/kg bw.

In addition, there were no treatment related clinical signs, necropsy findings or changes in body weight observed in any of the individuals.

Justification for classification or non-classification

The substance does not meet the criteria for classification in accordance with Regulation (EC) No 1272/2008 (CLP).