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Administrative data

Description of key information

Oral: An acute oral toxicity study of 1,2,4,5,7,8-Hexoxonane, 3,6,9-trimethyl-, 3,6,9-tris(Ethyl and Propyl) derivatives is available (key study, 2015).  The LD50 exceeds 2000 mg/kg. Two acute oral toxicity studies and an acute dermal toxicity study of CAS# 24748-23-0 (one of the major constituents of the test substance) also had the LD50 values exceeding 2000 mg/kg, providing supportive data to the test item. Due to low vapor pressure of the test substance, inhalation is not expected to be the major route of exposure.

Inhalation: Due to low vapor pressure of the test item, inhalation is not expected to be the major route of exposure.

Dermal: No acute dermal toxicity data are available for the test item. However, based on the Weight-Of-Evidence approach (described in the discussion section), the LD50 is estimated to be > 2000 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:
Experimental starting date: 11 November 2014 Experimental completion date: 02 December 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
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), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 10 December 2002
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non-pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ±20% of the mean body weight of the initially dosed group.

The animals were housed in groups of three in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study, PP R 001 (CAS#1613243 54 1) was used as supplied. The specific gravity was determined and used to calculate the appropriate dose volume for the required dose level.

Procedure
Using available information on the toxicity of PP R 001 (CAS#1613243 54 1), 2000 mg/kg was chosen as the starting dose.

Groups of fasted animals were treated as follows:

Dose Level Number of Rats
(mg/kg) Specific Gravity Dose Volume Female
(mL/kg)
2000 0.882 2.27 3
2000 0.882 2.27 3

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each group to confirm the survival of the previously dosed animals.

Doses:
2000 mg/kg
No. of animals per sex per dose:
2 groups, each of 3 females
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for fourteen days.

Individual body weights were recorded prior to dosing and seven and fourteen days after treatment.

At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Evaluation of Data
Data evaluations included the relationship, if any, between the exposure of the animal to PP R 001 (CAS#1613243-54-1) and the incidence and severity of all abnormalities including behavioral and clinical observations, gross lesions, body weight changes, mortality and any other toxicological effects.
Statistics:
None reported
Preliminary study:
Using available information on the toxicity of PP R 001 (CAS#1613243 54 1), 2000 mg/kg was chosen as the starting dose.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
No abnormalities were noted at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of PP R 001 (CAS#1613243 54 1) in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

PP R 001 (CAS#1613243 54 1) does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.
Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of PP‑R‑001 (CAS#1613243‑54‑1) in the Wistar strain rat.

 Guidelines / Regulations

This study was designed to be compatible with the procedures indicated by the following internationally accepted guidelines and recommendations:

 ·     OECD Guideline for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

·     Method B1 tris Acute Toxicity (Oral) of Commission Regulation (EC) No. 440/2008·     US EPA, OCSPP (OPPTS 870.1100, 2002)

·     Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), Testing Guidelines for Toxicology Studies, 12 NohSan No. 8147, amended 10 December 2002

 

Methods

A group of three fasted femaleWistar (RccHan™:WIST) strain ratswas treated with PP‑R‑001 (CAS#1613243‑54‑1) at a dose level of 2000 mg/kg body weight. This was followed by a further group of three fasted females at the same dose level. Dosing was performed sequentially.

 

The test item was administered orally undiluted. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

 

Results

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Body Weight. All animals showed expected gains in body weight.

Necropsy. No abnormalities were noted at necropsy.

 

Conclusion

The acute oral median lethal dose (LD50) of PP‑R‑001 (CAS#1613243‑54‑1) in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

 

CAS#1613243‑54‑1 does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
Reliable without restrictions.

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

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April - May 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted study according to GLP
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Animals and Animal Husbandry
Five male and five female Sprague-Dawley CD (Crl : CD ® BR) strain rats
supplied by Charles River (UK) Ltd, Margate, Kent were used. At the start of
the study the males weighed 206 to 228g, and the females 209 to 233g, and
were approximately eight to twelve weeks old. After a minimum
acclimatisation period of five days the animals were selected at random and
given a number unique within the study by indelible ink-marking on the tail
and a number written on a cage card.

The animals were housed in suspended polypropylene cages furnished with
woodflakes. The animals were housed individually during the 24-hour
exposure period and in groups of five, by sex, for the remainder of the study.
Free access to mains drinking water and food (Rat and Mouse Expanded Diet
No.1, Special Diets Services Limited, Witham, Essex, UK) was allowed
throughout the study.

The animal room was maintained at a temperature of 19 to 24 degrees C and relative
humidity of 47 to 54%. The rate of air exchange was approximately fifteen
changes per hour and the lighting was controlled by a time switch to give
twelve hours continuous light and twelve hours darkness.
Type of coverage:
semiocclusive
Vehicle:
other: None, test material was administered as supplied
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:
For the purpose of the study the test material was used as supplied. The
specific gravity was determined and used to calculate the appropriate dose
volume for the required dose level.

On the day before treatment the back and flanks of each animal were clipped
free of hair using veterinary clippers.

DOSE LEVEL(mg/kg): 2000
SPECIFIC GRAVITY: 0.882
DOSE VOLUME (ml/kg): 2.27

The calculated volume of the test material, as received, was applied uniformly
to an area of shom skin (approximating to 10% of the total body surface area)
using a graduated syringe. A piece of surgical gauze was placed over the
treatment area and semi-occluded with a piece of self-adhesive bandage. The
bandage was further secured with a piece of BlENDERM wrapped around each
end. The animals were caged individually for the 24-hour exposure period.
Shortly after dosing the dressings were examined to ensure that they were
securely in place.
The animals were observed for deaths or overt signs of toxicity l/2, 1,2 and
4 hours after dosing and subsequently once daily for fourteen days.
After the 24-hour contact period the bandage was carefully removed and the
treated skin and surrounding hair wiped with cotton wool moistened with
distilled water to remove any residual test material. The animals were returned
to group housing for the remainder of the study period.
After removal of the dressings and subsequently once daily for fourteen days,
the test sites were examined for evidence of primary irritation and scored
according to the following scale from Draize J H (1977) "Dermal and Eye
Toxicity Tests" In: Principles and Procedures for Evaluating the Toxicity of
Household Substances, National Academy of Sciences, Washington DC p.31:
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Clinical signs:
Signs of toxicity related to dose levels: no signs of systemic toxicity were noted during the study.
Gross pathology:
Effects on organs: no abnormalities noted at necropsy.
Other findings:
Signs of toxicity (local): no effects of skin irritation or any other local effects were noted during the study.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute dermal median lethal dose (LD50 of the test material, in the Sprague-Dawley CD strain rat was found to be greater than 2000 mg/kg
bodyweight.
Executive summary:

A study was performed to assess the acute dermal toxicity of the test material in the Sprague-Dawley CD strain rat. The method used followed that described in the OECD Guidelines for Testing of Chemicals No. 402 "Acute Dermal Toxicity" (adopted 24 February 1987) and Method B3 of Commission Directive 92/69/EEC (which constitutes Annex V of Council Directive 67/548/EEC).

A group of ten animals (five males and five females) was given a single 24-hour, semioccluded dermal application to intact skin at a dose level of 2000 mg/kg bodyweight. The animals were observed for fourteen days after the day of treatment and were then killed for gross pathological examination. There were no deaths. No signs of systemic toxicity or skin irritation were noted during the study. All animals showed expected gain in bodyweight during the study. No abnormalities were noted at necropsy.

The acute dermal median lethal dose (LDso) of the test material (which is one of the major component of CAS 1613243 -54 -1) in the SpragueDawley CD strain rat was found to be greater than 2000 mg/kg bodyweight.

Endpoint:
acute toxicity: dermal
Type of information:
other: expert statement
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: expert statement
Interpretation of results:
practically nontoxic
Remarks:
Criteria used for interpretation of results: expert judgment
Conclusions:
The LD50 for acute dermal toxicity of the test substance is deemed to be > 2000 mg/kg.
Executive summary:

In general, numerous organic peroxides have been tested in acute dermal toxicity tests (41 organic peroxides covering all chemical subgroups/families of oragnic peroxides, excluding hydroperoxides). Experimental data of all of these organic peroxides, (except hydroperoxides), show no toxic effects at dermal application up to the tested concentration limit of 2000 mg/kg bw and show for this reason an acute dermal toxicity of >2000 mg/kg bw. Therefore, a weight of evidence approach is scientifically applicable for chemically comparable organic peroxides and allows one to conclude also a dermal LD50 > 2000 mg/kg bw for the untested organic peroxide. Additional testing for such organic peroxides is therefore not required and would not be in line with animal welfare legislation.

More specifically, CAS# 1613243 -54 -1 is neither a corrosive nor a skin irritant as per invitro test results from OECD 431 and OECD 439 tests, repectively. Also, as no systemic acute toxicity was observed in the acute oral toxicity study, toxicity following dermal absorption is also not expected. Furthermore, it is likely that the peak absorption (generally responsible for acute toxicity) is higher following oral route than following dermal route, the latter could result in lower peak concentrations. In general, following intestinal absorption, a large fraction is already metabolized by the liver before systemic distribution. On the other hand, the skin also has metabolizing capacity, and the process of dermal uptake is probably slower than via intestinal route. Finally, the LD50 of acute dermal toxicity for CAS#24748 -23 -0, one of the major constituents of the test substance was >2000 mg/kg.

Based on these reasoning, the LD50 for acute dermal toxicity of the test substance is deemed to be > 2000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The study was conducted on CAS# 24748-23-0, a major constituent of the test item and the data were found to be reliable without restrictions.

Additional information

Dermal:

Both CAS# 1613243 -54 -1 and CAS# 24748 -23 -0 are somewhat similar in that they both contain trimeric peroxide in approximately 60% petroleum based solvent. The difference between CAS 24748-23-0 and CAS 1613243-54-1 is that the former contains methyl/ethyl based trimeric peroxide, whereas the latter basically contains the same methyl/ethyl based trimeric peroxide and an equal amount (16%) of methyl/ethyl based trimeric peroxide in which one ethyl is replaced by one propyl group. Additionally, CAS 1613243-54-1 contains another methyl/ethyl based trimeric peroxide (5%) with two propyl substitutions and another methyl/ethyl based trimeric peroxide (1%) with three propyl substitutions.

 

By simple reasoning it can be deduced that the substitution of one (or more) ethyl group(s) with a propyl group makes the molecule slightly larger. Also, other properties can be expected to show some changes. The Table below provides an overview of the direction of these changes. With the increasing alkyl length from ethyl to propyl:

(1) Octanol/water partitioning is expected to increase, as well as the boiling point and melting point, with a related lowering of vapor pressure, (2) Related intestinal uptake (HIA) was already maximal, and the expected increase of uptake is therefore of no significance, and (3) Dermal absorption could increase with increased propyl substitution.

 

However, dermal exposure of CAS# 24748-23-0 did not result in acute toxicity and did not show signs of systemic toxicity. Theoretically, the dermal absorption of CAS# 1613243-54-1 may be slightly higher for the propyl substituted fractions, which is related to the higher Pow. However, as the Pow for the constituents of the test item is already very large (>90%) and water solubility limited, the accuracy of the predicted faster dermal uptake (based on simple formula with linear relation to Kow without upper border) can be questionable.

CAS# 1613243 -54 -1 is neither a corrosive nor a skin irritant. As no systemic acute toxicity was observed following the near-complete oral absorption, toxicity following dermal absorption is also not expected for the test item even if relatively more is being absorbed via skin. Furthermore, it is likely that the peak absorption (generally responsible for acute toxicity) is higher following oral route than following dermal route, the latter could result in lower peak concentrations. In general, following intestinal absorption, a large fraction is already metabolized by the liver before systemic distribution. On the other hand, the skin also has metabolizing capacity, and the process of dermal uptake is probably slower than via intestinal route.

Based on the above weight-of-evidence, the LD50 for acute dermal toxicity of the test substance is deemed to be > 2000 mg/kg.

Molecular Profiling and Estimated Properties of CAS# 1613243-54-1

 

 

1,2,4,5,7,8-Hexoxonane, 3,6,9-triethyl-3,6,9-trimethyl-

3,6-diethyl-3,6,9-trimethyl-9-propyl-1,2,4,5,7,8-hexoxonane

3-ethyl-3,6,9-trimethyl-6,9-dipropyl-1,2,4,5,7,8-hexononane

3,6,9-trimethyl-3,6,9-tripropyl-1,2,4,5,7,8-hexoxonane

 

(methylethylketone peroxide trimer)

1 ethyl replaced by propyl

2 ethyl replaced by propyl

3 ethyl replaced by propyl

 

CCC1(C)OOC(C)(CC)OOC(C)(CC)OO1

CCCC1(C)OOC(C)(CC)OOC(C)(CC)OO1

CCCC1(C)OOC(C)(CC)OOC(C)(CCC)OO1

CCCC1(C)OOC(C)(CCC)OOC(C)(CCC)OO1

 

           (CAS# 24748-23-0)

 

 

  (CAS# 63364-41-0)

Content in test substance (CAS#1613243-54-1)

Ca.16%

Ca.16%

Ca.5%

Ca.1%

Molecular weight

264,3154

278,3419

292,3685

306,3951

LogP (Marvin Sketch 6.1.6)

4.09

4.53

4.97

5.42

Log Kow (Epiweb 4.1)

6.10

6.59

7.09

7.58

Boiling point

(Epiweb 4.1)

309.85 °C

323.47

336.18

348.08

Melting point

(Epiweb 4.1)

93.27 °C

102.05

110.43

118.46

Vapor Pressure (Epiweb 4.1)

0.0634 Pa

0.0256 Pa

0.0109 Pa

0.00481 Pa

Water solubility:
(WSKOW v1.42)

WATERNT v1.01)

 

0.1208 mg/L

0.095007 mg/L

 

0.03827 mg/L

0.029053 mg/L

 

0.0121 mg/L

0.0088619 mg/L

 

0.003815 mg/L

0.0026969 mg/L

Kp (est): Dermwin v2.02 (Epiweb 4.1)

0.586 cm/hr

1.04 cm/hr

1.83 cm/hr

3.24 cm/hr

HIA

91.6%

91.9%

92.2%

92.5%

 

Molecular formula, molecular weight, and logP were all calculated using ChemAxon MarvinSketch (v.6.1.6).

Melting point, boiling point, vapour pressure, water solubility and logPow were estimated by EPI Suite (v4.1).

- dermal: EpiSuite v. 4.1; (water:0.0005 cm/hr): log Kp = -2.80 + 0.66 log Kow - 0.0056 MW

- intestinal: HIA: QSAR toolbox (version 3.2) (Human Intestinal Absorption)

Justification for selection of acute toxicity – oral endpoint

A well conducted GLP study.

Justification for selection of acute toxicity – dermal endpoint

Weight-of-evidence approach.

Justification for classification or non-classification

The acute oral median lethal dose (LD50) of CAS#1613243 54 1 in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight and showed no signs of systemic toxicity.

Due to low vapor pressure of the test item, inhalation is not expected to be the major route of exposure.

For CAS# 24748 -23 -0, the LD50 in rat was greater than 2000 mg/kg body weight and no adverse effects were observed in the acute dermal toxicity study. Based on the Weight-Of-Evidence approach, the acute dermal LD50 of CAS#1613243 54 1 was deemed to be similar to that of the acute oral

toxicity. No adverse effects were observed

The data are conclusive and the test substance is not classified for the acute toxicity endpoint.