4,8-Dimethyl-2,5,7,10-tetraoxaundecane

Endpoint summary

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:

From 4 February 2021 to 16 March 2021

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: Lambiotte & Cie - 2101081010R
- Purity, including information on contaminants, isomers, etc.: 99.96%

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: Young adult animals (approximately 8-10 weeks old)
- Weight at study initiation: 145 to 192 g
- Fasting period before study: no
- Housing: group housed (up to 3 animals of the same sex and same dosing group together) in polycarbonate cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.
- Method of randomisation in assigning animals to test and control groups: Animals were assigned to the study at the discretion of the coordinating biotechnician, with all animals within ± 20% of the sex mean body weights. Animals in poor health or at extremes of body weight range were not assigned to the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 21°C
- Humidity (%): 40 to 59%
- Air changes (per hr): Ten or greater air changes per hour with 100% fresh air (no air recirculation) were maintained in the animal rooms.
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle was maintained

IN-LIFE DATES: From: 15 February 2021 To: 16 March 2021

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The test item, 4,8-Dimethyl-2,5,7,10-tetraoxaundecane, was administered as received. Amber glassware was used for the preparations of formulations.

The dose volume for each animal was based on the body weight measurement prior to dosing. Dose volume (mL/kg body weight) was calculated as follows: Dose level (g/kg) / spec.gravity or density (g/mL) * purity correction factor.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The starting dose level should be the one that is likely to produce mortality in at least some of the animals and was selected based on available toxicity data of the test item.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were weighed individually on Day 1 (pre-dose), 8 and 15. A fasted weight was recorded on the day of dosing. Post-dose observations were performed at periodic intervals on the day of dosing (at least three times) and once daily thereafter.
- Necropsy of survivors performed: yes

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred.

Clinical signs:

irregular respiration

lethargy (hypoactivity)

observations of tremors

other: hunched posture, erected fur, partly closed eyes

Body weight:

other body weight observations

Remarks:

The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.

Gross pathology:

Enlargement of the heart was found in two animals at macroscopic post-mortem examination.
Macroscopic post-mortem examination of the other animals did not reveal any abnormalities

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The oral LD50 value of 4,8-Dimethyl-2,5,7,10-tetraoxaundecane in Sprague Dawley rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 5000 mg/kg body weight.
Based on the results and taking into account the severe clinical signs seen, according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments), 4,8-Dimethyl-2,5,7,10-tetraoxaundecane should be classified as: may be harmful if swallowed (Category 5) for acute toxicity by the oral route.
According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), 4,8-Dimethyl-2,5,7,10-tetraoxaundecane does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Executive summary:

The objective of this study was to assess the toxicity of the test item when administered in a single dose to female rats at one or more defined dosages. Furthermore, the results of the study allowed the test item to be ranked according to most classification systems, currently in use. This study should provide a rational basis for risk assessment in man.
The study was carried out in compliance with the guidelines described in:
• OECD No.423 (2001) "Acute Oral Toxicity, Acute Toxic Class Method".
• EC No 440/2008, part B: "Acute Oral Toxicity, Acute Toxic Class Method".
• EPA, OPPTS 870.1100 (2002), "Acute Oral Toxicity".
• JMAFF Guidelines (2000), including the most recent revisions.
4,8-Dimethyl-2,5,7,10-tetraoxaundecane was administered by oral gavage to two consecutive groups of three female Sprague Dawley rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).
No mortality occurred.
Shallow breathing, hunched posture, erected fur, partly closed eyes, and decreased activity were noted for all animals between Days 1 and 4. In addition, some of the animals also showed slight tremors and/or prostrate posture on Day 1 and one animal also showed abnormal breathing sounds on Day 1.
The body weight gain shown by the animals over the study period was considered to be similar to that expected for normal untreated animals of the same age and strain.
Enlargement of the heart was found in two animals at macroscopic post-mortem examination.
Macroscopic post-mortem examination of the other animals did not reveal any abnormalities.
The oral LD50 value of 4,8-Dimethyl-2,5,7,10-tetraoxaundecane in Sprague Dawley rats was established to exceed 2000 mg/kg body weight.
According to the OECD 423 test guideline, the LD50 cut-off value was considered to be 5000 mg/kg body weight.
Based on these results:
• According to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments), 4,8-Dimethyl-2,5,7,10-tetraoxaundecane should be classified as: may be harmful if swallowed (Category 5) for acute toxicity by the oral route.
• According to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), 4,8-Dimethyl-2,5,7,10-tetraoxaundecane does not have to be classified and has no obligatory labelling requirement for oral toxicity.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

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:

05 November 2020 to 09 December 2020

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity: Fixed Dose Procedure)

Version / remarks:

09 October 2017

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: Lambiotte & Cie
- Purity, including information on contaminants, isomers, etc.: 99.90%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature (15-25°C) in darkness, under nitrogen atmosphere
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: The test item was administered as supplied and no vehicle was used
- Stability in the medium, i.e. sensitivity of the test material to hydrolysis and/or photolysis: Determination of the homogeneity, stability and purity of the test item not undertaken as part of this study.


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing (e.g. warming, grinding): no
- Preliminary purification step (if any): no

Species:

rat

Strain:

Wistar

Remarks:

RccHan™:WIST albino rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Rationale for alternative/additional species to rat: Rats are the preferred species of choice as they are historically used for safety evaluation studies and are specified in the appropriate test guidelines. As there were no data to indicate males were likely to be more sensitive to the test item, the testing was performed in females only.
- Source: Envigo RMS (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: approximately eight to twelve weeks of age prior to dosing (Day 1)
- Weight at study initiation: 187 to 207 g
- Fasting period before study: no
- Housing: housed in groups of one or two rats
- Diet: ad libitum; Teklad 2014C Diet
- Water: ad libitum; Potable water taken from the public supply
- Acclimation period: at least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 24C
- Humidity (%): 40 to 70%
- Air changes (per hr): animal room was kept at positive pressure with respect to the outside by its own supply of filtered fresh air, which was passed to atmosphere and not re-circulated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 05 November 2020 To: 09 December 2020

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 10%
- Type of wrap if used: porous gauze

REMOVAL OF TEST SUBSTANCE
- Washing (if done): washed with warm water (30 to 40°C)
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.1 ml/kg
- Constant volume or concentration used: 2 ml/kg for the first animal and 2.1 ml/kg for the 3 other animals

Duration of exposure:

24 hours

Doses:

- 2000 mg/kg bw

No. of animals per sex per dose:

4

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Cages of rats were checked at least twice daily for any mortalities; The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15
- Necropsy of survivors performed: yes
- Clinical signs including body weight: 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). Additional observations were performed as necessary when evident toxicity was observed. The nature and severity, where appropriate, of any clinical signs and the time were recorded at each observation.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 200 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths in the study.

Clinical signs:

other:

Body weight:

other body weight observations

Remarks:

There was a low body weight gain for female number 92, from Day 1 to Day 8, however, this animal achieved a satisfactory body weight gain between Day 8 and Day 15. A low body weight gain was noted for one female (number 93) from Day 8 to Day 15. All other animals were considered to have achieved satisfactory body weight gains throughout the study.

Gross pathology:

Macroscopic examination at study termination on Day 15 revealed pallor of the liver in two females (number 92 and 93) in the main study. No abnormalities were revealed in any other animal at the macroscopic examination at this time.

Other findings:

A bandage reaction was observed from Day 8 until the end of the study for animal number 91, dosed in the sighting study at a dose level of 1906 mg/kg. There were no other dermal reactions throughout the study.

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

The acute median lethal dermal dose (LD50) to rats of 4,8-Dimethyl-2,5,7,10-tetraoxaundecane was demonstrated to be greater than 2000 mg/kg body weight.
4,8-Dimethyl-2,5,7,10-tetraoxaundecane is included in Category 5/Unclassified, according to the Globally Harmonised System (GHS).

Executive summary:

The purpose of this study was to assess the toxic potential of 4,8-Dimethyl-2,5,7,10-tetraoxaundecane, an industrial chemical, following a single dermal dose in the rat.
Female rats received a single dermal dose of the test item at the following dose levels:
Sighting investigation: 1906 mg/kg body weight
Main study: Based on the results of the sighting investigations a further three females were dosed at 2000 mg/kg body weight.
During the study, clinical conditions, dermal reactions, body weight and macropathology investigations were undertaken.
Results
There were no deaths in the study.
Urine staining in the lower ventral area was observed for two females in the main study dosed at 2000 mg/kg. This sign was first noted on Day 2 and recovery of this sign was complete by Day 3. No clinical signs were observed in the sighting study female dosed at 1906 or other main study animal dosed at 2000 mg/kg.
A bandage reaction was observed from Day 8 until the end of the study for animal number 91, dosed in the sighting study at a dose level of 1906 mg/kg. There were no other dermal reactions throughout the study.
There was a low body weight gain for female number 92, from Day 1 to Day 8, however, this animal achieved a satisfactory body weight gain between Day 8 and Day 15. A low body weight gain was noted for one female (number 93) from Day 8 to Day 15. All other animals were considered to have achieved satisfactory body weight gains throughout the study.
Macroscopic examination at study termination on Day 15 revealed pallor of the liver in two females (number 92 and 93) in the main study. No abnormalities were revealed in any other animal at the macroscopic examination at this time
Conclusion
The acute median lethal dermal dose (LD50) to rats of 4,8-Dimethyl-2,5,7,10-tetraoxaundecane was demonstrated to be greater than 2000 mg/kg body weight.
4,8-Dimethyl-2,5,7,10-tetraoxaundecane is included in Category 5/Unclassified, according to the Globally Harmonised System (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw