Reaction mass of diisobutyl adipate and diisobutyl glutarate and diisobutyl succinate

Endpoint summary

Description of key information

No acute toxicity was observed.

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:

September 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

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

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

There were no deaths. There were no clinical signs of toxicity, no effects on bodyweight gain nor any abnormalities at necropsy.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

16 426 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

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:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

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 403 (Acute Inhalation Toxicity)

Deviations:

no

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.

Interpretation of results:

GHS criteria not met

Remarks:

Migrated information

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 LC 50 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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records

Reference

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:

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

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

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

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 n° 402 and EU guideline n° 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 LD50 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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Oral:

In the key study, this substance produced no deaths in an acute oral fixed dose toxicity study at the limit dose of 2000 mg/kg bw. In a second study, the LD50 was determined to be 16426 mg/kg bw/day (95% CI >15295, <18189, Slope 15.9). Based on these data this substance is not considered to be acutely toxic via the oral route.

Dermal and Inhalation:

No data are available for the dermal and inhalation acute toxicity of this substance. However the oral route is likely to lead to the highest degree of systemic exposure and the acute oral toxicity data demonstrate this substance is not acutely toxic. It is therefore very unlikely that exposure via dermal or inhalation routes would lead to systemic toxicity capable of producing death at doses relvant for classification. This conclusion is supported by the read across to the methyl esters of the same acids, where acute dermal and inhalation toxicity was minimal (LD50 >2000 mg/kg via dermal and LC50> 11 mg/L via inhalation).

Justification for classification or non-classification

Not classified due to lack of acute toxicity.