3,6,9-trioxaundecamethylene bis(2-ethylhexanoate)

Endpoint summary

Description of key information

In an acute oral toxicity study in male and female Sprague-Dawley rats, no deaths were noted and only minimal clinical changes were observed during the observation period. These clinical changes generally resolved by 3 to 5 days of observation. There were no adverse necropsy findings. The acute oral LD 50 value was found to be greater than 5.0 g/kg.

In an acute dermal toxicity study in male and female New Zealand White rabbits, no deaths were noted during the observation period. There were no necrospsy findings. The acute dermal LD 50 value was found to be greater than 20 g/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Remarks:

Acute toxicity of TegMeR 804 in rats - limit test

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 18, 1992, to December 3, 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

A study conducted under Good Laboratory Practice Standards (40 CFR) and conforming with internationally recognized protocols and in particular satisfying criteria of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and OECD Guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

other: The protocol satisfies the criteria established by the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

Deviations:

no

Principles of method if other than guideline:

Young adult, Sprague Dawley derived rats (male and femald) weighing between 232 and 342 grams at the start of the study were used. The undiluted test material was administered to five male and five female rats at a dose level of 5.0 g/kg.

GLP compliance:

yes (incl. QA statement)

Remarks:

All aspects of this study, as defined in the Protocol and the Project Instruction Sheet, were conducted in accordance with Good Laboratory Practice Standards (40 CFR).

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

The test material was a clear, golden-yellow liquid and was stored at room temperature throughout the study in two clear, glass jars.

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Young, adult male and female Sprague-Dawley derived albino rats were used. Animals weighed between 232 and 342 grams at the start of the study. The animals were purchased from a U.S.D.A. approved supplier.

All animals were acclimated to the laboratory for at least four days before use. Animals were housed in groups of five (5) in wire mesh suspension cages and were supplied PURINA LABORATORY RODENT CHOW (or other comparable diet) and tap water ad libitum except for the withholding of food overnight prior to dosing. The animals were maintained in 12-hour light/12-hour dark cycles.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Each animal received the test material by gavage at a dose level of 5.0 g/kg bwt. The material was administered undiluted. Individual doses were calculated using post-fast body weights.

Doses:

All animals received a single dose of 5.0 gm/kg bwt

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

All animals were observed for gross signs of systemic toxicity and mortality several times during the day of dosing, and at least twice daily thereafter for a total of 14 days.

Body weights were measured for each animal on the day of dosing, on day 7 of the observation period, and at the time of necropsy either at the end of 14 days or following the death of any animal.

At the end of the 14-day observation period, each surviving rat was sacrificed and a gross necropsy performed.

Statistics:

Individual and mean body weights with standard deviations were determined.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

There was no mortality in the study.

Clinical signs:

Normal behavior was observed in all animals. Fecal staining was seen in 1 or 2 animals during the first 3 to 5 days of the observation period. Oily hair coat was observed in some or all of the animals during this same time period.

Body weight:

Body weights were not affected by the dosing.

Gross pathology:

There was no gross pathology noted.

Table 1: Body Weight Data in Male and Female Rats Treated Orally with Undiluted Test Material

Animal Number	Sex	Day 0	Day 7	Day 14	Body Weight Change (grams) Day 0 -14
1	M	340	410	441	101
2	M	294	330	361	67
3	M	320	362	380	60
4	M	342	395	419	77
5	M	305	361	383	78
Mean		320	372	397	77
Standard Deviation		21	31	32	18
6	F	256	294	304	48
7	F	232	258	269	37
8	F	237	269	277	40
9	F	263	291	305	42
10	F	271	311	314	42
Mean		252	285	294	42
Standard Deviation		17	21	20	4

Interpretation of results:

other: Category IV - Greater than 5,000 mg/kg

Remarks:

Hazard potential as specified in 40 CFR 156.10

Conclusions:

The test material is relatively non-toxic to rats.

Executive summary:

The acute oral toxicity of the test material was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines

No deaths were noted during the observation period.

Minimal clinical changes were noted involving fecal staining and oily hair coat. These generally resolved by 3 to 5 days of observation.

There were no necropsy findings

The acute oral LD 50 value was found to be greater than 5.0 g/kg in male and female Sprague Dawley rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Quality of whole database:

The key result is based on a guideline study conducted in rats. Supporting data from stucturally similar ester materials further supports the low acute oral toxicity of the test substance.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Remarks:

Acute toxicity of TegMeR 804 in rabbits

Type of information:

experimental study

Adequacy of study:

key study

Study period:

November 18, 1992, to December 15, 1992

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Justification for type of information:

A study conducted under Good Laboratory Practice Standards (40 CFR) and conforming with internationally recognized protocols and in particular satisfying criteria of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and OECD Guidelines.

Qualifier:

equivalent or similar to guideline

Guideline:

other: The protocol satisfies the criteria established by the Federal Insecticide, Fungicide, and Ro denticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

Deviations:

no

Principles of method if other than guideline:

Young adult, male and female New Zealand White rabbits weighing between 2064 grams to 2467 grams at the start of the study were used. The test material was administered as received at a limit dose of 20 g/kg bw.

GLP compliance:

yes (incl. QA statement)

Remarks:

All aspects of this study, as defined in the Protocol and the Project Instruction Sheet, were conducted in accordance with Good Laboratory Practice Standards (40 CFR).

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

The test material was a clear, golden-yellow liquid and was stored at room temperature throughout the study in two clear, glass jars.

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

Young adult male and female New Zealand White rabbits were used. Animals weighed between 2064 and 2467 grams at the start of the study. The animals were purchased from a U.S.D.A. approved supplier.

All animals were acclimated to the laboratory for at least four days before use. Animals were housed singly in wire mesh suspension cages and were supplied PURINA LABORATORY RABBIT CHOW (or other comparable diet) and tap water ad libitum except for the withholding of food overnight prior to dosing. The animals were maintained in 12-hour light/12-hour dark cycles.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Shortly prior to dosing, the hair of each rabbit was closely clipped from the ventral surface of the trunk using an electric clipper so as to expose approximately 10% of the body surface area.

Animals were weighed shortly before test material exposure in order to calculate doses. The test material was applied to sleeves of rubber dental dam. Each sleeve was wrapped around the trunk of the respective animal and secured with staples. An outer layer of gauze was then wrapped around the trunk of each aniaml and secured with tape. Each rabbit was then fitted with a colar to prohibit removal of the wrapping.

At the end of a 24-hour exposure period, the wrapping was removed and any unabsorbed test material remaining on the skin was removed by gently sponging using a moistened towel. The presence or absence of any residual test material was documented.

Duration of exposure:

24 hours

Doses:

All animals received a single dermal application of 20 gm/kg bwt.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

All animals were observed for signs of toxicity and behavioral changes once, or more frequently if clinical signs were present, on the day of treatment. All surviving rabbits were then maintained for 14 days following completion of the exposure period. An examination for gross signs of toxicity were carried out once daily with additioinal checks for viability during the day. Skin reactions and other evidence of injury including erythema, edema, atonia, desquamaation, necrosis, coriaceousness and fissuring were noted if present.

Body weights were measured for each animal on the day of dosing, on day 7 of the observation period, and at the time of necropsy either at the end of 14 days or following the death of any animal.

At the end of the 14-day observation period, each surviving rat was sacrificed and a gross necropsy performed.

Statistics:

Individual and mean body weights with standard deviations were determined.

Key result

Sex:

male/female

Dose descriptor:

other: A limit dose was administered

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

There was no mortality in the study.

Clinical signs:

Mild to marked erythema and edema were observed in all animals and generally decreasing in severity at the end of the 14-day observation period. Mild to marked desqamation was observed in all animals generally in the last 4 or 5 days of the 14-day observation period and persisting until study termination. Hunched posture was observed in nearly all animals and generally on the day of dosing. Slight to moderate depression and shallow breathing were observed in some animals during the observation period. Normal behavior was reported for all animals by the end of the 14-day observation period.

Body weight:

Body weights were not affected by the dosing.

Gross pathology:

There was no gross pathology noted.

Table 1: Body Weight Data in Male and Female Rabbits Treated Dermally with Undiluted Test Material at a Dose Level of 20 g/kg

Animal Number	Sex	Day 0	Day 7	Day 14	Body Weight Change (grams) Day 0 -14
1	M	2084	2206 (1)	2331	267
2	M	2335	2363 (1)	2471	136
3	M	2301	2260 (1)	2343	42
4	M	2326	1621	2454	128
5	M	2258	1548	2364	106
Mean		2257	2000	2393	136
Standard Deviation		112	384	65	82
6	F	2346	2437 (1)	2457	111
7	F	2336	2555 (1)	2524	188
8	F	2408	2609 (1)	2806	398
9	F	2233	2236 (1)	2259	26
10	F	2238	2230 (1)	2361	113
Mean		2312	2413	2479	167
Standard Deviation		75	176	209	141

(1) Day 7 body weights taken with collars on.

Interpretation of results:

other: Category IV - Greater than 20,000 mg/kg Hazard potential as specified in 40 CFR 156.10

Conclusions:

The test material is relatively non-toxic to rabbits.

Executive summary:

The acute dermal toxicity of the test material was evaluated in compliance with the conditions specified in the regulation for the enforcement of the Federal Insecticide, Fungicide, and Rodenticide Act (40 CFR), the Toxic Substances Control Act (40 CFR), and the OECD Guidelines.

No deaths were noted during the observation period.

There were no necrospsy findings.

The acute dermal LD 50 value was found to be greater than 20 g/kg in male and female New Zealand White rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

20 000 mg/kg bw

Quality of whole database:

The key result is based on a guideline study conducted in rabbits.

Additional information

The test substance is a member of a category of aliphatic esters submitted by The American Chemistry Council's (ACC) Aliphatic Esters Panel (Panel) under the High Production Volume (HPV) Chemical Challenge Program (ACC, 2003). Information from a Screening Information Data Set (SIDS) developed in that program serves as supplementary or weight-of-evidence information in the current dossier. The glycol esters chosen to supply additional information are very closely related in molecular structure They exhibit similar behavior with respect to physicochemical , environmental fate. Category ester compounds with similar structures and functionalities were of low acute oral toxicity in rats. In the first of three studies conducted in rats, heptanoic acid, oxybis(2,1 -ethanediyloxy-2,1 -ethanediyl)ester (CAS 70729 -68 -9) displayed little or no toxicity in male or female Wistar rats up to a limit gavage dose of 2000 mg/kg bw. No mortality was reported in this study. Limited clinical signs included slight piloerection and sporadic findings. Similarly, CAS 70729 -68 -9 displayed little or no acute toxicity when administered by gavage to male rats at a limit dose of 25 g/kg bw. There was only one mortality. Clinical signs included hyperemia, lethargy and prostration. In a third study with CAS 70729 -68 -9, the acute oral LD50 of the test substance in females rats after gavage administration was > 24 g/kg bw and < 25 g/kg bw. All deaths occurred within 2 days of dosing. At this elevated dose level, clinical observations included flat body posture, moribundness, labored breathing, stained/wet perineal area, lacrimation, stained face, weakness, ataxia, lethargy, prostration, salivation and chromodacryorrhea. Information from a secondary source reports LD50 values in rats of 12.5 g/kg bw and 31.4 g/kg bw for the test material 2,2'-ethylenedioxydiethyl bis(2 -ethylhexanoate) (CAS 94 -28 -0). Heptanoic acid, ester with 2,2,4 -trimethyl-1,3 -pentanediol (CAS 71839 -38 -8) displayed an acute oral LD50 of > 2000 mg/kg in male and female rats. Decanoic acid, mixed diesters with octanoic acid and triethylene glycol (CAS 68583 -52 -8) displayed no adverse clinical signs when tested in rats at a limit dose of 5000 mg/kg bw.  All rats were reported as normal at all observation points.

Justification for classification or non-classification

Based on the results of acute oral and dermal toxicity testing in rats, the test substance would not be classified for acute toxicity according to the European Regulation (EC) No. 1272/2008 on classification and labelling of chemicals.