Fatty acids, C8-10, mixed esters with neopentyl glycol and trimethylolpropane

Endpoint summary

Description of key information

Oral (OECD 401): LD50 >2000 mg/kg bw
Inhalation (OECD 436): LC50 >5.22 mg/L (RA from CAS 68855-18-5)
Dermal: Waiving 

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:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (analytical purity not reported)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no analytical purity reported

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Weight at study initiation: 175 g (mean; males), 157 g (mean; females)
- Fasting period before study: animals were fasted 16 hours prior to administration and 3 hours after administration.
- Housing: 5 animals of the same sex per cage in Makrolon type III cages; bedding: soft wood granulate
- Diet: Altromin-Haltungsdiät, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 – 25 °C
- Humidity (%): 45 – 60
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

peanut oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20% g/v
- Amount of vehicle (if gavage): 10 mL/kg

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: not required

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed several times on the day of the application, and twice daily afterwards. Individual body weights were recorded 1 day before the dosing, on the day of the dosing, 48 hours, 7 days and 14 days after the application.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross pathology

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: No clinical signs of toxicity were observed up to the end of the 14-day observation period.

Gross pathology:

males: full bladder in 1/5 animal; haemangioma of the left renal lymph node in 1/5 animals; mild hypoplasia of the right testis in 1/5 animals
females: high grade hydrometra and haemangioma of the left renal lymph node in 1/5 animal.

Interpretation of results:

GHS criteria not met

Conclusions:

CLP: not classified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study, and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 Jun - 26 Jul 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

THE DEPARTMENT OF HEALTH OF THE GOVERNMENT OF THE UNITED KINGDOM

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: RccHanTM:WIST

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Laboratories UK Ltd, Oxon, UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 200-350 g
- Housing: animals were housed in groups of up to 3/sex in solid-floor polypropylene cages with stainless steel lids, furnished with softwood flakes (Datesand Ltd, Cheshire, UK) and provided with environmental enrichment items (wooden chew blocks and cardboard “fun tunnels” (Datesand Ltd, Cheshire, UK)).
- Diet: Harlan 2014C Rodent Diet (Harlan Laboratories UK Ltd, Oxon, UK), ad libitum (with the exception of the exposure period)
- Water: mains drinking water, ad libitum (with the exception of the exposure period)
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical exposure chamber (ADG Developments Ltd, Hitchin, UK)
- Exposure chamber volume: 30 L
- Method of holding animals in test chamber: each rat was individually held in a tapered, polycarbonate restraining tube fitted onto a single tier of the exposure chamber and sealed by means of a rubber ‘O’ ring. Prior to the day of exposure, each rat was acclimatised for approx. 2 h to the tapered polycarbonate restraining tube.
- Source and rate of air: filtered air supplied from an oil-free compressor at 60 L/min
- System of generating particulates/aerosols: glass concentric jet nebuliser (Radleys, Saffron Walden, UK)
- Method of particle size determination: Marple Personal Cascade Impactor (Westech, IS Ltd, Beds., UK), consisting of 6 impactor stages (7.8, 5.8, 3.6, 1.4, 0.74 and 0.34 µm) with stainless steel collection substrates and a back-up glass filter, housed in an aluminium sampler
- Treatment of exhaust air: the extract from the exposure chamber passed through a ‘scrubber’ trap and was connected with a high efficiency filter to a metered exhaust system.
- Temperature, humidity, pressure in air chamber: 19-20 °C, 71-72%, negative

TEST ATMOSPHERE
- Brief description of analytical method used: gravimetric filter analysis was used to determine the actual concentration of the aerosol. The test atmosphere was sampled at regular intervals (approx. every 10-15 min) during the exposure period. A weighed glass fibre filter was placed in a filter holder and temporarily sealed in a vacant port of the exposure chamber. A known quantity of the exposure chamber concentration was drawn through the filter using a vacuum pump. After sampling, the filter was dried in a desiccator under reduced pressure at 19-21 °C for ca. 24 h and weight thereafter.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: see Table 1 and 2 under "Any other information on materials and methods incl. tables"
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.42 µm/2.56 µm

CLASS METHOD
- Rationale for the selection of the starting concentration: a target concentration of 5 mg/L was chosen based on a preliminary sighting study in two rats treated with a mean achieved test atmosphere concentration of 2.14 mg/mL. In this experiment, no significant effects were observed in the animals after an exposure period of 4 h.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

gravimetric

Duration of exposure:

4 h

Concentrations:

5.22 mg/L (mean achieved concentration)
13.5 mg/L (nominal concentration)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals were observed for clinical signs at hourly intervals during exposure, immediately on removal from the restraining tubes at the end of exposure, one hour after termination of exposure and subsequently once daily for over 14 days. Individual body weights were recorded on arrival, prior to treatment and on Days 1, 3, 7 and 14.
- Necropsy of survivors performed: yes, full external and internal observation. Detailed macroscopic examination of the respiratory tract was performed to determine signs of irritancy or local toxicity.
- Other examinations performed: clinical signs, body weight

Statistics:

Mean values and standard deviations of the mean achieved atmosphere concentrations were determined.

Preliminary study:

In a preliminary sighting study, 2 rats treated with a mean achieved test atmosphere concentration of 2.14 mg/mL (target: 2 mg/mL) showed no significant effects after an exposure period of 4 h. Clinical signs during exposure included wet fur and an increased respiratory rate. In addition, hunched posture and pilo-erection were observed directly after exposure and 1 h thereafter. The increase in respiratory rate was still present until Day 3 post-exposure. One day later, all animals were free of any clinical symptoms. No macroscopic findings were observed at necropsy. Thus, a starting concentration of 5 mg/mL was chosen for the main experiment.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.22 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality occurred during the study period.

Clinical signs:

other: Signs of hunched posture and pilo-erection were seen in test animals for a short period after removal from the exposure chamber. Wet fur was recorded during the exposure period and for a short time period thereafter which were considered to be associated

Body weight:

All animals showed the expected body weight gain during the study, except for one female which did not gain weight during the 14-day observation period. In addition, one male exhibited a slight loss in body weight on the first day of exposure.

Gross pathology:

At necropsy, no macroscopic abnormalities were observed in the treated animals.

Interpretation of results:

GHS criteria not met

Conclusions:

CLP: not classified

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Please refer to the Additional Information field in the endpoint study summary

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.22 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Croda, 2012

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable study (Klimisch score 1) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similar functional groups and similar precursors/breakdown products (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are only limited data available for the acute toxicity of Fatty acids, C8-10 (even numbered), diesters with neopentyl glycol and di- and triesters with trimethylolpropane (CAS 97281-24-8). In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

 

Having regard to the general rules for the read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a comparable pattern as a result of structural similarity, the substance Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) is selected as source substance.

 

Acute toxicity: oral

CAS 97281-24-8

A key acute oral toxicity study performed with Fatty acids, C8-10 (even numbered), diesters with neopentyl glycol and di- and triesters with trimethylolpropane (CAS 97281-24-8) equivalent or similar to OECD guideline 401 and in compliance with GLP is available (BASF, 1988a). In this study five fasted Wistar rats of each sex were administered a single dose of 2000 mg/kg bw of the test substance via oral gavage. The animals were observed for 14 days after administration. No mortalities occurred and no signs of systemic toxicity were observed during the study period. The body weight gain shown by the animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. Gross pathology revealed a full bladder (1/5 animals), haemangioma of the left renal lymph node (1/5 animals) and mild hypoplasia of the right testis (1/5 animals) in males, whereas high grade hydrometra and haemangioma of the left renal lymph node was found in one female. The acute oral LD50 value was considered to be greater than 2000 mg/kg bw for male and female rats.

 

Acute toxicity: inhalation

CAS 68855-18-5

An acute inhalation toxicity study was performed with Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) according to OECD guideline 436 (acute toxic class method) and under GLP conditions. Three RccHanTM:WIST rats/sex were exposed for 4 h to 5.22 mg/L (mean achieved concentration) test substance aerosol by nose only inhalation (Croda, 2012b). The test concentration was chosen based on the outcome of a preliminary test with two rats at a dose of 2.14 mg/L. No mortality occurred throughout the study period. Signs of hunched posture and piloerection were commonly seen in animals for a short period after removal from the exposure chamber following exposure. Wet fur was commonly recorded both during and for a short period after exposure. These observations were considered to be associated with the restraint procedure and, in isolation, were not indicative of toxicity. In addition, an increased respiratory rate was noted in all animals. On removal from the chamber and 1 h post-exposure, all animals exhibited increased respiratory rate and ataxia. One day after exposure, all animals still showed increased respiratory rate, hunched posture as well as occasional instances of piloerection. All animals recovered to appear normal from Days 5 to 8 post-exposure. All animals showed the expected body weight gain during the study, except for one female that did not gain weight during the final week of the 14-day observation period. In addition, one male exhibited a slight loss in body weight on the first day of exposure. Necropsy revealed no treatment-related findings. The detailed macroscopic examination of the respiratory tract did not reveal signs of irritancy or local toxicity. The inhalation LC50 value in rats was determined to be >5.22 mg/L.

 

Conclusion for acute toxicity

The reliable data available for the target and source substance indicate a very low level of acute toxicity following the oral and inhalation route, as LD50 and LC50 values were greater than the currently applied limit values. No information on acute dermal toxicity is available for either the target or the source substance. Therefore, as the available data did not identify any hazard for acute toxicity, Fatty acids, C8-10 (even numbered), diesters with neopentyl glycol and di- and triesters with trimethylolpropane (CAS 97281-24-8) is not considered to be hazardous following acute exposure.  

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, C8-10 (even numbered), diesters with neopentyl glycol and di- and triesters with trimethylolpropane (CAS 97281-24-8), data will be generated from information on reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on acute toxicity do not meet the classification criteria according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.