COASOL 290 PLUS

Endpoint summary

Description of key information

The following studies are available:

- 4 acute oral toxicity studies in the rat, 2 studies using the reaction mass of diisobutyl esters of adipic acid, glutaric acid and succinic acid; 1 using the methyl esters of this mixture and 2 studies using dibutyl adipate.

- 2 acute inhalations studies: one using the reaction mass of methyl esters and another using di-n-butyl adipate

- 2 dermal studies: one using the reaction mass of methyl esters and the second using di-n-butyl adipate.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

September 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The members of the category are all alcohol esters of dicarboxylic acids. All category members are manufactured by reacting an alcohol (methanol, butanol or isobutanol) with single dicarboxylic acids, succinic, glutaric or adipic acids or mixtures of these acids. The ester bonds are effectively metabolised by the body releasing the component alcohols and acids. The difference between members involves 3 parameters: 1) the alcohol used to esterify the acids, 2) the length of the acid molecule (4C, 5C or 6C) and 3) the presence of individual esters or mixtures thereof.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
The toxicity profile of the members (ecotoxicity and human health toxicity and the environmental fate) is consistent. All have low acute toxicity potential, are not sensitising, are mildly irritating to eyes and upper respiratory tract (where vapour pressure allows exposure), are not genotoxic or clastogenic (in vivo) and have minimal systemic toxicity. Data are available predominantly for the methyl esters (individual and mixture), dibutyl adipate and diisobutyl esters (mixture). Within the category, read across is used to cover the higher tier human health toxicity studies predominantly.

See attached document with the justification for the category/read-across approach.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Specific details on test material used for the study:

COASOL: DBE-IB

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd.
- Age at study initiation: 8 - 12 weeks
- Fasting period before study: yes
- Housing: The animals were housed in groups of up to four in suspended solid-floor polypropylene cages furnished with woodflakes
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25°C
- Humidity (%): 30- 70 %
- Air changes (per hr): 15 changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

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 its fasted bodyweight at the time of dosing.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5 females. Only females were used as they are typically more sensitive, and are the preferred choice when it is unknown if there is a sex difference in toxicity

Control animals:

no

Details on study design:

1 animal dosed first, then in the absence of toxicity at the dose of 2000 mg/kg bw/day 4 additional animals were dosed with 2000 mg/kg bw/day. Clinical observations were made at 0.5, 1, 2, and 4 hours following dosing and then once daily for the remaining 14 days. Individual bodyweights were recorded at day 0 and day 7. At the end of observation period animals were euthenized by cervical dislocation and subject to gross necropsy consisting of external examination and opening of the abdominal and thoracic cavities. Any macroscopic abnormalities were noted.

Statistics:

not applicable

Preliminary study:

not applicable

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

There were no deaths

Clinical signs:

other: There were no clinical signs of toxicity

Gross pathology:

No abnormalities identified at necropsy

Other findings:

none

None

Interpretation of results:

not classified

Conclusions:

There were no deaths at the limit dose of 2000 mg/kg bw. Therefore this substance does not require classification for acute oral toxicity.

Executive summary:

An acute oral toxicity study in female rats was conducted according to OECD TG 420 and in accordance with the Principles of Good Laboratory Practice (GLP). One female animal dosed first, then in the absence of toxicity at the dose of 2000 mg/kg bw/day four additional animals were dosed with 2000 mg/kg bw/day. Clinical observations were made at 0.5, 1, 2, and 4 hours following dosing and then once daily for the remaining 14 days. Individual bodyweights were recorded at day 0 and day 7. At the end of observation period animals were euthenized by cervical dislocation and subject to gross necropsy consisting of external examination and opening of the abdominal and thoracic cavities. Any macroscopic abnormalities were noted. There were no deaths and no clinical signs of toxicity, based on which the the substance does not require classification for acute oral toxicity.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

2006-09-05 to 2006-11-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

The animals were nulliparous and non-pregnant. After an acclimatisation 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 bodyweights fell within an interval of ± 20% of the mean initial bodyweight of the first treated 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 was allowed throughout the study. The diet, drinking water and bedding were routinely analysed 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. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. 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.

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 4.96 ml/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: based on available historical data/information

Doses:

5000 mg/kg

No. of animals per sex per dose:

3 female animals

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: 30 min, 1h, 2h, 4h, then daily up to 14 days
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights

Statistics:

not applicable

Preliminary study:

not applicable

Sex:

female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: Hunched posture and pilo-erection were noted in one animal two days after dosing and in one animal three days after dosing. Animals appeared normal three or four days after dosing.

Gross pathology:

No abnormalities were noted at time of necropsy.

Other findings:

none

None

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute oral median lethal dose (LD50) of the test material in the female Sprague-Dawley CD strain rat was estimated to be greater than 5000 mg/kg bodyweight. Therefore DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Executive summary:

DBE has been tested in an acute oral toxicity study using female Sprague Dawley rats, according to OECD guideline n° 423 and EU guideline no. B.1 tris in compliance with Good Laboratory Practice. The test item was administered without vehicle once by oral route (gavage) to a group of three fasted female rats at a dose level of 5000 mg/kg. Clinical signs, mortality and body weight gain were checked for a period of up to 14 days after the single administration of DBE. All animals were subjected to necropsy. No mortality was recorded during the study. Body weight gain of the treated animals was not affected by treatment. At necropsy, no abnormalities were observed in any animal. As the LD 50 is higher than 5000 mg/kg, DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: CRL:CD

Sex:

male

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

13000, 14500, 16000, 20000 mg/kg bw

No. of animals per sex per dose:

10 males per dose

Control animals:

no

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

16 426 mg/kg bw

Based on:

test mat.

95% CL:

> 15 295 - < 18 189

Remarks on result:

other: Slope: 15.9

Clinical signs:

other:

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute oral toxicity in male rats was very low with the LD50 >16,000 mg/kg bw.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1951

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Qualifier:

no guideline available

Principles of method if other than guideline:

Male albino rats were administered the test substance (20% dispersion) at levels of 7.95 g/kg, 15.8 g/kg and 31.6 g/kg observed for mortality and clinical signs of toxicity

GLP compliance:

no

Remarks:

study conducted prior to GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 90-120 grams
- Fasting period before study: no

Route of administration:

oral: gavage

Vehicle:

other: 1% Tergitol 7

Details on oral exposure:

Male albino rats were administered the test substance (20% dispersion) at levels of 7.95 g/kg, 15.8 g/kg and 31.6 g/kg observed for mortality and clinical signs of toxicity

Doses:

7.95 g/kg, 15.8 g/kg and 31.6 g/kg

No. of animals per sex per dose:

5 male rats/dose

Control animals:

no

Details on study design:

Male albino rats were administered the test substance (20% dispersion) at levels of 7.95 g/kg, 15.8 g/kg and 31.6 g/kg observed for mortality and clinical signs of toxicity for 14 days

Statistics:

Thompson's method of estimating the median-effective dose (LD50) was used.

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

112 600 mg/kg bw

Based on:

test mat.

Remarks on result:

other: The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 11.26 gm/kg.

Mortality:

100 per cent mortality was noted in the 15.8 and 31.6 g/kg group.

Clinical signs:

other: Animals of the 15.8 and 31.6 g/kg group appeared prostrated and narcotized within 4 hours pots adminsitration

Gross pathology:

Autopsy of the animals found dead from the 15.8 and 31.6 g/kg dose group revealed congested liver and kidney and gastrointestinal irritation

Other findings:

none

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 11.26 gm/kg

Executive summary:

Male rats (non-fasted) were administered n-butyl adipate as a 20% dispersion in 1% Tergitol 7 doses of 7.95 g/kg, 15.8 and 31.6 g/kg and observed for 14 days. Thompson's method of estimating the median-effective dose (LD50) was used. No clinical signs were noted. All the rats from the 15.8 and 31.6 g/kg dose group died approximately 1 day after administration. Autopsy of the animals found dead from the 15.8 and 31.6 g/kg dose group revealed congested liver and kidney and gastrointestinal irritation. The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 11.26 gm/kg.

Reference 5

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1951

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Qualifier:

no guideline available

Principles of method if other than guideline:

Male albino rats were administered the test substance (20% dispersion) at levels of 7.95 g/kg and twice this dose (15.9 g/kg) and observed for mortality and clinical signs of toxicity

GLP compliance:

no

Remarks:

study conducted prior to GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sherman

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: in-house raised
- Age at study initiation: 5-6 weeks
- Weight at study initiation: 90-120 grams
- Fasting period before study: no
- Diet (e.g. ad libitum): Rockland rat diet

Route of administration:

oral: gavage

Vehicle:

other: 1% Tergitol 7

Details on oral exposure:

Male Sherman strain rats (non-fasted) were administered a 20% dispersion in 1% Tergitol 7 doses of 7.95 g/kg and another group adminsitered twice the dose (15.9 g/kg).

Doses:

7.95 g/kg and twice this dose (15.9 g/kg)

No. of animals per sex per dose:

no information available

Control animals:

not specified

Details on study design:

Male Sherman strain rats (non-fasted) were administered a 20% dispersion in 1% Tergitol 7 doses of 7.95 g/kg and another group adminsitered twice the dose (15.9 g/kg) and observed for 14 days

Statistics:

Thompson's method of estimating the median-effective dose (LD50) was used.

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

129 300 mg/kg bw

Based on:

test mat.

95% CL:

9 850 - 169 700

Remarks on result:

other: The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 12.93 (9.85 to 16.97) gm./kg.

Mortality:

The majority of the rats died within 24 hours and some instances (1-2 rats) of sporadic mortality was noted between 36-48 hours

Clinical signs:

other: No signs noted

Gross pathology:

Autopsy findings indicated severe damage to the gastrointestinal tract.

Other findings:

none

None

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 12.93 (9.85 to 16.97) gm./kg.

Executive summary:

Male Sherman strain rats (non-fasted) were administered n-butyl adipate as a 20% dispersion in 1% Tergitol 7 doses of 7.95 g/kg and another group adminsitered twice the dose (15.9 g/kg) and observed for 14 days. Thompson's method of estimating the median-effective dose (LD50) was used. No clinical signs were noted. The majority of the rats died within 24 hours and some instances (1-2 rats) of sporadic mortality was noted between 36-48 hours. Autopsy findings indicated severe damage to the gastrointestinal tract. The R.F. LD50 of n-butyl adipate for male albino rats fed a 20% dispersion in 1% Tergitol 7 by stomach tube in a single doee was 12.93 (9.85 to 16.97) gm./kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

April 16 to May 18, 1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The members of the category are all alcohol esters of dicarboxylic acids. All category members are manufactured by reacting an alcohol (methanol, butanol or isobutanol) with single dicarboxylic acids, succinic, glutaric or adipic acids or mixtures of these acids. The ester bonds are effectively metabolised by the body releasing the component alcohols and acids. The difference between members involves 3 parameters: 1) the alcohol used to esterify the acids, 2) the length of the acid molecule (4C, 5C or 6C) and 3) the presence of individual esters or mixtures thereof.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
The toxicity profile of the members (ecotoxicity and human health toxicity and the environmental fate) is consistent. All have low acute toxicity potential, are not sensitising, are mildly irritating to eyes and upper respiratory tract (where vapour pressure allows exposure), are not genotoxic or clastogenic (in vivo) and have minimal systemic toxicity. Data are available predominantly for the methyl esters (individual and mixture), dibutyl adipate and diisobutyl esters (mixture). Within the category, read across is used to cover the higher tier human health toxicity studies predominantly.

See attached document with the justification for the category/read-across approach.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

no

Remarks:

but with quality assurance documentation

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Young adult male and female Crl:CD BR rats were received from Charles River Breeding Laboratories. Rats were quarantined for approximately 1 week prior to testing and were weighed and observed 3 times during the quarantine period. During the quarantine period rats were housed singly in 5” x 11" x 7" suspended, stainless steel, wire mesh cages. After exposure, rats were housed (sexes separate) either 1 or 2 per cage in 8” x 14" x 8”cages. Prior to exposure, rats’ tails and cage cards were color-coded so that individual rats could be identified after exposure. For rats housed in pairs, the rat with the lower number was identified by a slash in the right ear.

On the day of exposure, rats were approximately 7-8 weeks old; male rats weighed 238-281 g and female rats weighed 174-222 g. Except during exposure, Purina Certified Rodent Chow and water were available ad libidum. Animal rooms were maintained on a timer-controlled, 12 hour/12 hour light/dark cycle.

Environmental conditions of the animal rooms were targeted for a temperature of 23°+ 2°C and relative humidity of 50 % + 10 %. Excursions outside these ranges were judged to have been of insufficient magnitude and/or duration to have adversely affected the validity of the study.

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Details on inhalation exposure:

For the LC50 determination, groups of 5 male and 5 female rats were individually restrained in stainless steel restrainers with conical nose pieces and exposed nose-only to DBE. Each restrainer was inserted into a 38-L cylindrical exposure chamber such that only the nose of each protruded into the chamber. To determine whether the ocular response was diminished by nose-only exposure, an additional group of 4 male rats was placed in a stainless steel and aluminum wire mesh cage within the exposure chamber and exposed whole-body.

Each group of rats was exposed for a single. 4-hour period to an aerosol / vapor mixture of DBE in air. Rats were observed for clinical signs of toxicity (e.g., general physical and clinical disposition. including unusual movements, respiration. etc.) before and during exposure. upon removal from the animal restrainers approximately 30 minutes after the cessation of exposure, and daily thereafter (weekends and holidays excluded unless warranted by the rats' condition). During the exposure. the use of restrainers limited the observations mainly to the presence of nasal or oral discharges. In addition. a sharp rap was periodically delivered to the exposure chamber and rats were observed for a general startle response (rapid movement) during the exposure. This procedure was used primarily as a gross indicator of unconsciousness or death. Rats were weighed prior to exposure, and were weighed daily. weekends and holidays excluded except when warranted by the rats' condition, during the 14-day recovery period.

Atmosphere Generation
DBE was generated by atomization. Test atmospheres of DBE were generated by atomizing the liquid test material using an Airlife, Solo-Sphere Nebulizer. Conditioned, filtered houseline air (approximately 8-16 L/min) was used to generate the aerosol and to carry the aerosol directly into the 38 L cylindrical, glass exposure chamber. Located immediately inside the chamber was a plastic deflection plate (approximately 12.5 cm diameter) which acted as a baffle to promote turbulent flow and facilitate uniform distribution of the aerosol within the chamber. Chamber atmospheres were exhausted through tandem, dry-ice cold traps and an MSA activated charcoal/HEPA filter cartridge prior to discharge into a fume hood

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

3.5, 5.6, 11.0 mg/L DBE;

No. of animals per sex per dose:

5 males;
5 females;

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:starting 30 min after exposure, then daily for 14 days
- Necropsy of survivors performed: no data
- Other examinations performed: opthalmology

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 11 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No rats died following exposure to DBE at atmospheric concentrations as great as 11 mg/L, the highest concentration tested.

Clinical signs:

other: Clinical signs of toxicity observed in some male and female rats during the recovery period included red nasal, ocular or oral discharges, wet, yellow-stained perineum, and hunched posture. All clinical signs were transient and had resolved by study day 4

Body weight:

Rats from all exposure groups exhibited slight to severe body weight losses 1 day after exposure (group average weight losses ranged from approximately 5-11% and 2-9% of initial body weight in male and female rats, respectively). In addition, some transient, slight to moderate weight losses occurred in some male and female rats during the first or second weeks of the recovery period.

Other findings:

Prior to exposure, the eyes of rats from the 11 mg/L group were evaluated and considered ophthalmoscopically normal. After exposure, the eyes of rats from the 3.5 or 11 mg/L groups were considered to be ophthalmoscopically normal; the corneal and pupillary reflexes were normal. At 5.6 mg/L, however, bilateral mild chemosis (edema/swelling) of the bulbar conjunctivae was found in all rats. Although a subepithelial corneal opacity was also noted in 1 rat exposed to 5.6 mg/L, this finding was believed to be due to a preexisting injury and not compound-related.

None

Interpretation of results:

study cannot be used for classification

Conclusions:

Under the conditions of this study, the 4-hour LC50 for DBE exceeds 11 mg/L, the highest concentration tested.

Executive summary:

DBE has been tested in an acute inhalation toxicity study using Crj: CD(SD) rats, according to OECD guideline n° 403 and EU guideline n° B.2 with quality assurance documentation.

5 males and 5 females per dose were exposed to 3.5, 5.6 or 11.0 mg/L DBE for 4 h via inhalation (nose only). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days after the single exposure to DBE. All animals were subjected to necropsy. No rats died following exposure to DBE at atmospheric concentrations as great as 11 mg/L, the highest concentration tested. Rats from all exposure groups exhibited slight to severe body weight losses 1 day after exposure (group average weight losses ranged from approximately 5-11% and 2-9% of initial body weight in male and female rats, respectively). In addition, some transient, slight to moderate weight losses occurred in some male and female rats during the first or second weeks of the recovery period. Clinical signs of toxicity observed in some male and female rats during the recovery period included red nasal, ocular or oral discharges, wet, yellow-stained perineum, and hunched posture. All clinical signs were transient and had resolved by study day 4. Ophthalmoscopic findings in the 5.6 mg/L group were believed to be due to a preexisting injury and not compound related as no comparable findings were seen in the 3.5 or 11 mg/L groups.

 

As the LC50 is higher than 11 mg/L, DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

1951

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Qualifier:

no guideline available

Principles of method if other than guideline:

Groups of animals were exposed to vapours and aerosols of n-butyl adipate and observed for mortality and other signs for 14 days

GLP compliance:

no

Remarks:

study conducted prior to GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Young mature male rats were used for the study

Route of administration:

inhalation

Type of inhalation exposure:

whole body

Vehicle:

not specified

Details on inhalation exposure:

In the first experiment, 6 young mature male rats were exposed to substantially saturated vapor at room temperature for 8 hours. The vapor was generated by passing air at a rate of 2.5 litres/minute through 50 ml of n-butyl adipate contained in a gas washing bottle.
In the second experiment, 6 young mature male rats were exposed for 8 hours to a fog of n-butyl adipate produced by a vaponefrin nebulizer (equivalent to 25 mg/litre of n-butyl adipate)

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

8 h

Concentrations:

substantially saturated vapours and an aerosol equivalent to 25 mg/l of n-butyl adipate

No. of animals per sex per dose:

6 young mature male rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: yes

Statistics:

no information available

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LC0

Effect level:

> 21.86 mg/L air (nominal)

Based on:

other: calculated value - converting substantially saturated vapor generated at room temperature

Exp. duration:

8 h

Remarks on result:

other: refer to conversion below

Mortality:

No mortality was noted in both the exposures

Clinical signs:

other: no signs noted

Body weight:

body weight gains were normal

Gross pathology:

no information available

Other findings:

none

vapor pressure of dibutyl adipate - 2.1 x 10 -2 Pa at 25 degree celsius - OECD TG 104 (source SIDS)

equivalent to 210 Pa - 1.575 mm Hg leading to a saturated vopr concentration of 2072.368421 ppm, molecular weight of 258.35.

According to Patty's handbook - 1 mg/l - 94.8 ppm, therefore 2072.368421 is equivalent to 21.86 mg/l.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Based on the results of the study, no mortality was noted in rats exposed at substantially saturated vapors (calculated 21.86 mg/l) of n-butyl adipate.

Executive summary:

In the first experiment, 6 young mature male rats were exposed to substantially saturated vapor at room temperature for 8 hours. The vapor was generated by passing air at a rate of 2.5 litres/minute through 50 ml of n-butyl adipate contained in a gas washing bottle.

In the second experiment, 6 young mature male rats were exposed for 8 hours to a fog of n-butyl adipate produced by a vaponefrin nebulizer (equivalent to 25 mg/litre of n-butyl adipate). No mortality and signs of toxicity were noted, body weight gains were normal. Based on the results, the calculated LC0 of n-butyl adipate was greater than 21.86 mg/l.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Study period:

January 09 to March 26, 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
The members of the category are all alcohol esters of dicarboxylic acids. All category members are manufactured by reacting an alcohol (methanol, butanol or isobutanol) with single dicarboxylic acids, succinic, glutaric or adipic acids or mixtures of these acids. The ester bonds are effectively metabolised by the body releasing the component alcohols and acids. The difference between members involves 3 parameters: 1) the alcohol used to esterify the acids, 2) the length of the acid molecule (4C, 5C or 6C) and 3) the presence of individual esters or mixtures thereof.

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL
The toxicity profile of the members (ecotoxicity and human health toxicity and the environmental fate) is consistent. All have low acute toxicity potential, are not sensitising, are mildly irritating to eyes and upper respiratory tract (where vapour pressure allows exposure), are not genotoxic or clastogenic (in vivo) and have minimal systemic toxicity. Data are available predominantly for the methyl esters (individual and mixture), dibutyl adipate and diisobutyl esters (mixture). Within the category, read across is used to cover the higher tier human health toxicity studies predominantly.

See attached document with the justification for the category/read-across approach.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, F-76410 Saint Aubin les Elbeuf, France;
- Weight at study initiation: males: 266 ± 2 g, females: 247 ±10 g;
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days;


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 60 ± 20
- Photoperiod (hrs dark / hrs light): 12/12;

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 x 7 cm²; shaved backs and flanks
- % coverage: < 10%;
- Type of wrap if used: gauze


REMOVAL OF TEST SUBSTANCE
- Washing (if done): not specified;
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): not specified;
- Concentration (if solution): 2000 mg/kg bw;

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw;

No. of animals per sex per dose:

5 males;
5 females;

Control animals:

not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations: at least once daily; weighting: at days 1 (pre-administration), 5, 8, and 15
- Necropsy of survivors performed: yes

Preliminary study:

not applicable

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occured.

Clinical signs:

other: No clinical signs of toxicity were detected.

Gross pathology:

No signs of gross pathology have been detected

Other findings:

none

None

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

Under the conditions of the current study, the test article DBE showed no signs of toxicity in female and male rats over a period of 14 days when applied dermally once at 2000 mg/kg bw. The LD50 can therefore be concluded to be greater than 2000 mg/kg bw. Based on this Result DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Executive summary:

DBE has been tested in an acute dermal toxicity study using Crj: CD(SD) rats, according to OECD guideline no. 402 and EU guideline no. B.3 in compliance with Good Laboratory Practice. The test item was applied once under semiocclusive conditions to the shaved backs and flanks of the animals at a dose level of 2000 mg/kg for 24 h (5 males + 5 females per dose, 5 x 7 cm²). Clinical signs, mortality and body weight gain were checked for a period of up to 14 days after the single administration of DBE. All animals were subjected to necropsy. No mortality was recorded in both groups during the study. Body weight gain of the treated animals was not affected by treatment. At necropsy, no abnormalities were observed in any animal. As the LD 50 is higher than 2000 mg/kg, DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

supporting study

Study period:

1950

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

See attached document with the justification for the category/read-across approach.

Principles of method if other than guideline:

similar to OECD TG 402

GLP compliance:

no

Remarks:

study conducted prior to GLP

Test type:

standard acute method

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male

Details on test animals or test system and environmental conditions:

no information available

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

Undiluted n-butyl adipate was held in contact with hair-free trunk of male albino rabbits by means of impervious dams of Vinylite sheeting.

Duration of exposure:

24 hours

Doses:

5, 10 and 20 ml/kg

No. of animals per sex per dose:

5 ml/kg - 3 rabbits,
10 ml/kg - 4 rabbits and
20 ml/kg - 10 rabbits

Control animals:

no

Details on study design:

Undiluted n-butyl adipate was held in contact with hair-free trunk of male albino rabbits by means of impervious dams of Vinylite sheeting.

Statistics:

no information available

Preliminary study:

not applicable

Sex:

male

Dose descriptor:

LD50

Effect level:

> 20 mL/kg bw

Based on:

test mat.

Remarks on result:

other: The estimated R.F. LD50 of undiluted n-butyl adipate is > 20 ml/kg (converted value of 19240 mg/kg, based on relative density of 0.962 g/ml at 25 °C) when tested on male albino rabbits.

Mortality:

At the highest tested level of 20 ml/kg, three out of ten rabbits exposed to undiluted n-butyl adipate succumbed while no mortalities were noted at the lower tested groups of 10 and 5 ml/kg

Clinical signs:

other: no information available

Gross pathology:

no information available

Other findings:

none

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The estimated R.F. LD50 of undiluted n-butyl adipate is > 20 ml/kg (converted value of 19240 mg/kg, based on relative density of 0.962 g/ml at 25 °C) when tested on male albino rabbits.

Executive summary:

In this study, undiluted n-butyl adipate was held in contact with hair-free trunk of male albino rabbits by means of impervious dams of Vinylite sheeting at dose levels of 5, 10 and 20 ml/kg. At the highest tested level of 20 ml/kg, three out of ten rabbits exposed to undiluted n-butyl adipate succumbed while no mortalities were noted at the lower tested groups of 10 and 5 ml/kg. Normal weight gain was observed in most of the surviving animals across the tested groups. The estimated R.F. LD50 of undiluted n-butyl adipate is > 20 ml/kg (converted value of 19240 mg/kg, based on relative density of 0.962 g/ml at 25 °C) when tested on male albino rabbits.

Endpoint conclusion

Value:

mg/kg bw

Additional information

Oral:

There are no acute oral studies available on the reaction mass of dibutyl esters of adipic and glutaric acid. However there are acute oral toxicity studies on the category members used for read across and also on one of the components of the reaction mass (dibutyl adipate). The data available are all very consistent indicating a very low order of acute toxicity values (LD50 >>2000 mg/kg bw). Given the consistency across the category members the LD50 of the reaction mass is expected to be >2000 mg/kg bw.

 

Inhalation:

The vapour pressure of the reaction mass is very low and as such an acute exposure is considered unlikely via the inhalation route. However, the available data on the methyl esters and dibutyl adipate indicate a very low level of acute inhalation toxicity. As such this substance is not expected to be acutely toxic via the inhalation route.

 

Dermal:

In the available data on dibutyl adipate, the acute dermal toxicity was very low (LD50 >5000 mg/kg bw). This is consistent with the available data on the methyl esters where the dermal LD50 was also > 2000 mg/kg bw. Therefore dibutyl esters reaction mass is considered to also have a dermal LD50 of >2000 mg/kg bw.

 

A further comparison of acute toxicity can be found in the category justification attached at section 0 and 13.

Justification for classification or non-classification

Not classified due to lack of acute toxicity.