Registration Dossier

Administrative data

Description of key information

Acute toxicity: Oral LD50 (rat, m/f): > 2000 mg/kg bw (OECD 401 and 423, GLP, analogue approach)
Acute toxicity: Dermal LD50 (rat, m/f): > 2000 mg/kg bw (OECD 402, GLP, analogue approach)
Acute toxicity: Inhalation LC50 (rat, m/f): > 5.1 and 5.22 mg/mL (OECD 403 and 436, GLP, analogue approach)

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2, partially due to read-across) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is 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 inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2, partially due to read-across) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is 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

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
17 Sep - 01 Oct 2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-Guideline study with acceptable restrictions (no data on analytical purity available)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted in 1987
Deviations:
yes
Remarks:
no data on analytical purity
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
adopted in 1992
Deviations:
yes
Remarks:
no data on analytical purity
GLP compliance:
yes
Remarks:
Department of health of the government of the United Kingdom, UK
Test type:
standard acute method
Species:
rat
Strain:
other: Sprague-Dawley CD (Crl: CD IGS® BR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Ltd, Margate, Kent, UK
- Age at study initiation: 12 weeks
- Weight at study initiation: 221 – 248 (male) and 202 – 216 (female)
- Housing: 5 animals of the same sex per cage in suspended solid-floor polypropylene cages furnished with woodflakes (except during the 24-h exposure period where the animals were housed individually)
- Diet: certified Rat and Mouse diet (Code 5LF2) (supplied by International Product Supplies Limited, Wellingborough, Northants, UK), ad libitum
- Water: mains water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C):19-25
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: clipped skin of back and flanks
- % coverage: 10%
- Type of wrap if used: The treated skin was covered with of surgical gauze which was covered, held in place with self-adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed with cotton wool moistened with distilled water.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.11 mL/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed for mortality or evident signs of toxicity ½, 1, 2, and 4 hours after dosing and subsequently once daily for 14 days. After removal of the dressing and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored according to the Draize score method. Individual body weights were recorded prior to application of the test material on Day 0 and on Days 7 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, and grosspathology.
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:
No clinical signs of toxicology were observed up to the end of the 14-day observation period.
Body weight:
Body weight gains of all doses were within the normal ranges in males and females during the whole study period.

Gross pathology:
Necropsy examination revealed no substance-related findings.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details).
Taken together, the information from these independent sources is consistent and provides sufficient weight of evidence for hazard assessment leading to an endpoint conclusion in accordance with Annex XI, 1.2, of Regulation (EC) No 1907/2006. Therefore, the available information as a whole is 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.

Additional information

Justification for grouping of substances and read-across

There are no data available for the acute toxicity of Fatty acids, tall-oil, triesters with trimethylolpropane (CAS 94581-09-6). In order 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, read-across from structurally related substances was conducted. 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 put 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 grouping of substances and 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 regular pattern as a result of structural similarity, the substance listed below are selected as reference substances for hazard assessment.

Overview of acute toxicity

CAS

Acute toxicity oral

Acute toxicity inhalation

Acute toxicity dermal

94581-09-6

Target substance

RA: CAS Formerly 85005-23-8

RA: CAS 403507-18-6

RA: CAS Formerly 85186-89-6

RA: CAS 68424-31-7

RA: CAS 68855-18-5

RA: CAS 403507-18-6

85005-23-8

LD50 > 2000 mg/kg bw

--

--

85186-89-6

LD50 > 2000 mg/kg bw

--

--

403507-18-6

LD50 > 2000 mg/kg bw

--

LD50 > 2000 mg/kg bw

68424-31-7

LD50 > 2000 mg/kg bw

LC50 > 5.1 mg/L (analytical concentration)

--

68855-18-5

LD50 > 2000 mg/kg bw

LC50 > 5.22 mg/L

(analytical concentration)

--

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Fatty acids, tall-oil, triesters with trimethylolpropane (CAS 94581-09-6). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Acute toxicity: oral

CAS 403507-18-6

An acute oral toxicity study with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) was performed comparable to OECD Guideline 423 (Acute Toxic Class Method, limit test) and under GLP conditions (Sanders, 2002). The test substance was administered by gavage to three Sprague-Dawley CD (Crl: CD IGS® BR) male and female rats at 2000 mg/kg bw. Animals were subjected to daily observations and weekly determination of body weight. Gross pathology examination was performed after terminal sacrifice (Day 15). No treatment related abnormalities with regard to clinical signs, body weights and necropsy were observed. The oral LD50 value in rats was found to exceed 2000 mg/kg bw.

Formerly CAS 85005-23-8

An acute oral toxicity study was conducted with Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (Formerly CAS 85005-23-8) according to OECD Guideline 423 (Acute Toxic Class Method). Upon treatment of male and female Wistar rats with 2000 mg/kg bw of the test substance no mortality or any adverse effect was observed during the 14-day observation period. The animals had normal weight gain until the end of the observation period (Busschers, 1997). The LD50 value was therefore determined to be > 2000 mg/kg bw.

Formerly CAS 85186-89-6

An acute oral toxicity study (limit test) with Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane (CAS 85186-89-6) was performed according to OECD Guideline 401 and GLP (Kuszewski, 1996). The test substance was administered by gavage at a concentration of 2000 mg/kg bw to groups of five male and female Hsd/Cpb:WU rats. The animals were observed for 14 days following administration. No mortalities occurred during the study period. No clinical signs of toxicity, only slight changes in body weights for some animals and no differences at macroscopic examination were reported. The acute oral LD50 was found to be greater than 2000 mg/kg bw.

 

Acute toxicity: inhalation

CAS 68424-31-7

An acute inhalation toxicity study was performed with Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7) comparable to OECD Guideline 403. 5 male and female Alpk:APfSD rats were exposed for 4 hours to 5.1 mg/L test substance aerosol by nose only inhalation (Parr-Dobrzanski, 1994). The test substance caused no mortality, body weight changes or abnormalities in necropsy during the 15 day study period. Some clinical signs were noticed, which consisted of hunched position, chromodacryorrhea, piloerection, staining around nose and wet fur. These signs however occurred during or just after exposure and were clearly consistent with the use of restraint for exposure. The LC50 was therefore found to be greater than 5.1 mg/L.

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) under GLP conditions. Three RccHanTM:WIST rats per sex were exposed for 4 hours to 5.22 mg/L (mean achieved concentration) test substance aerosol by nose only inhalation (Griffiths, 2012). The test concentration was chosen based on the outcome of a preliminary test with two rats at a dose of 2.14 mg/L. In the main study, the animals were subjected to daily observations for clinical signs, and twice daily for morbidity and mortality. Body weights were determined prior to treatment and afterwards on test Days 1, 3, 7, and 14. After terminal sacrifice the animals were submitted to full external and internal observation. Detailed macroscopic examination of the respiratory tract was performed to determine signs of irritancy or local toxicity. No mortality occurred throughout the study period. Signs of hunched posture and pilo-erection were commonly seen in animals for short period on removal from the chamber following 4-h inhalation studies. 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 and also hunched posture as well as occasional instances of pilo-erection. 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 which not gained 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 inhalation LC50 value in rats was determined >5.22 mg/L.

Acute toxicity: dermal

CAS 403507-18-6

An acute dermal toxicity (limit test) was performed on Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) according to OECD Guideline 402 and GLP (Sanders, 2004). 5 male and female Sprague-Dawley CD (Crl: CD IGS® BR) rats each were exposed to 2000 mg test substance /kg bw for 24 hours on the back skin under semiocclusive conditions. The observation period was 14 days. No mortality, clinical signs of systemic toxicity and changes in body weight were noted in any animal during the study period. Necropsy at study termination revealed no abnormalities. Thus, the acute dermal LD50 in rats for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane was found to exceed 2000 mg/kg bw.

Conclusion for acute toxicity

In summary, for acute oral toxicity, studies from Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6), Fatty acids, C16-18 (even numbered) and C18-unsatd., branched and linear, di and triesters with trimethylolpropane (Formerly CAS 85005-23-8) and Fatty acids, C8-10(even), C14-18(even) and C16-18(even)-unsatd., triesters with trimethylolpropane (Formerly CAS 85186-89-6) are available and resulted in oral LD50 values > 2000 mg/kg bw.

For acute inhalation toxicity, studies with Pentaerythritol tetraesters of n-decanoic, n-heptanoic, n-octanoic and n-valeric acids (CAS 68424-31-7), and Heptanoic acid, ester with 2,2-dimethyl-1,3-propanediol (CAS 68855-18-5) resulted in no mortality when tested with concentrations 5.10 and 5.22 mg/mL respectively.

An acute dermal toxicity studies conducted with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) showed no treatment related effects at the limit dose of the current valid guideline. Therefore, the dermal LD50 is considered to be greater than 2000 mg/kg bw respectively.

Thus, the available data indicate a very low level of acute toxicity for the source substances and thus no hazard for acute oral, inhalative and dermal toxicity was identified.


Justification for selection of acute toxicity – oral endpoint
Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – inhalation endpoint
Hazard assessment is conducted by means of read-across from structural analogues. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of acute toxicity – dermal endpoint
Hazard assessment is conducted by means of read-across from structural analogue. The available study are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on the information received for read-across from structurally similar substances, the available data on acute oral, inhalation and dermal toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.