Registration Dossier

Administrative data

Description of key information

WoE based on available data from surrogate substances:
All available subacute and subchronic repeated dose oral toxicity studies resulted in NOAELs of 1000 mg/kg bw/day or greater.
The available subchronic repeated dose inhalation toxicity study results in NOAEC 0.5mg/L.
The available subchronic repeated dose dermal toxicity study results in NOAEL of 2000 mg/kg bw/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Mode of Action Analysis / Human Relevance Framework

Additional information

Justification for grouping of substances and read-across

The category covers fatty acid polyesters of polyols (Trimethylolpropane (TMP) or Pentaerythritol (PE)) mixed with adipic acid. The category contains UVCB substances with fatty acid carbon chain lengths from C8-C18 (even-numbered, including linear saturated and unsaturated chains) building mono-, di-,tri- or higher esters with TMP or PE respectively in variable proportions.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable read across data within the group applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

CAS

Repeated dose toxicity oral

Annex VIII

Repeated dose toxicity oral

Annex IX

Repeated dose toxicity dermal

Annex VIII and IX

Repeated dose toxicity inhalation

Annex VIII and IX

95912-89-3 (a)

W

WoE:

RA: CAS 105-99-7

W

WoE:

RA: CAS 403507-18-6

W

WoE:

RA: CAS 67762-53-2

W

WoE:

RA: CAS 67762-53-2

91001-61-5

W

WoE:

RA: CAS 105-99-7

W

WoE:

RA: CAS 403507-18-6

W

WoE:

RA: CAS 67762-53-2

W

WoE:

RA: CAS 67762-53-2

EC 921-836-0

W

WoE:

RA: CAS 105-99-7

W

WoE:

RA: CAS 403507-18-6

W

WoE:

RA: CAS 67762-53-2

W

WoE:

RA: CAS 67762-53-2

67762-53-2 (b)

--

--

Experimental result:

NOAEL dermal (m/f): ≥2000 mg/kg bw/day

Experimental result:

NOAEC inhalation (m/f):  

0.5 mg/L

403507-18-6

--

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

--

--

105-99-7

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

--

--

--

W = Waiving statement

(a)  Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b)  Surrogate substances (indicated in normal font) are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members. Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by “-“.

Discussion

There are no studies available assessing the repeated dose toxicity of the category members. Therefore a weight of evidence approach was applied which is based on the available data of several surrogate substances, representing the spectrum of the main structural chemical building blocks of the category members.

CAS 105-99-7

The subacute oral toxicity of Dibutyl adipate (CAS 105-99-7) was investigated in a study similar to OECD guideline 407 and in conformity with GLP (Hiratsuka, 1996).

Dilutions of the test substance in olive oil were administered once daily via oral gavage to groups of 6 Crj: CD(SD) rats per sex at doses of 20, 140 and 1000 mg/kg bw for a period of 28 days. A similar constituted group received the vehicle and acted as a control. In addition, satellite groups of 6 animals per sex, each for the control and high dose group, were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. No substance-related mortalities occurred during the whole study period. Clinical signs involved slight salivation in males and females at 1000 mg/kg bw/day during treatment. However, this effect disappeared during the 14-day recovery period. Food consumption was similar between treated and control animals and no changes in body and organ weights were noted during the study. No treatment-related alterations in parameters of haematology, clinical chemistry and urinalysis were observed. At gross and histopathological examination, no abnormal findings were reported in treated animals of the whole study.

Based on the results of this subacute toxicity study, the NOAEL of Dibutyl adipate was considered to be 1000 mg/kg bw/day.

CAS 403507-18-6

A 90-day oral feeding 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 408 and under GLP conditions (McRae, 2004). Groups of 10 male and 10 female Sprague-Dawley rats were exposed to the substance at 5, 50 and 1000 mg/kg bw/day by gavage, 7 days/week for 90 days. Control animals (10 per sex and dose) received the concurrent vehicle, arachis oil. Observations and examinations of the animals included clinical sings, body weight, food consumption, haematology, clinical chemistry, organ weights, neurobehaviour, gross necropsy and histopathology. The daily oral administration of the test substance was tolerated without any adverse effects up to the high dose of 1000 mg/kg bw/day. There were no toxicologically significant effects on body weight, food consumption and clinical condition and mortality up to and including the highest dose level. Some incidental and spontaneous effects during histophathology examinations were observed but those were not due to the test substance administration. Therefore, a 90-day oral NOAEL of 1000 mg/kg bw/day was found for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in male and female rats.

CAS 67762-53-2

A 90-day subchronic inhalation toxicity study was performed with Sprague-Dawley rats with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) comparable to OECD guideline 413 (Dulbey, 1992). 15 males and 15 females per group were whole body exposed to the test substance aerosol for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L. The respective controls (15 animals per sex and dose) inhaled clean air under the same conditions. Animals were observed for clinical sings, body weight, haematology, clinical chemistry, organ weights, gross necropsy and histopathological examinations. 10 additional male animals were included in every group for examination of pulmonary function tests and pulmonary hydroxyproline following exposure. No substance-related adverse effects were observed for body weight, body weight gain, mortality, clinical biochemistry and haematological parameters. The lungs of the high dose animals had a minimal increase in weight which correlated with slightly increased numbers of macrophages in the pulmonary alveoli. Thus, the NOAEC were found to be 0.5 mg/L.

A 90-day dermal toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was performed comparable to OECD Guideline 411 (Cruzan, 1988). Groups of 10 male and female Sprague-Dawley rats were once daily (5 days/week, 24 hours/day) exposed to the substance at 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Animals were observed for clinical signs, body weight, dermal irritation, haematology, clinical chemistry, urinalysis, organ weights, gross necropsy and histopathological examinations.

Overall there were no adverse effects found after dermal application of the test substance for 90 days on the parameters investigated. Treated males gained less body weight than control animals. Since the effect was low and no dose-relation was observed, it was not considered to be due to systemic toxicity. Some serum parameters of the high dose group animals were significant different to the control, but since the differences were small and they did not present any pattern suggestive of effects on a specific organ, they were considered not to be of toxicological relevance. Both treated groups exhibited minimal erythema and flaking of the skin during the dosing phase. At microscopic examination it was identified as very minor epidermal hyperplasia and chronic inflammation of the superficial dermis. Since no effects of systemic toxicity were identified up to the highest dose tested, the 90 day dermal NOAEL was found to be 2000 mg/kg bw/day for Fatty acids, C5-9, tetraesters with pentaerythritol in Sprague-Dawley rats.

In conclusion, no effects of category members on repeated dose toxicity are expected. On the one hand category members have a very low potential for absorption and thus bioavailability of all mixed and branched polyesters with adipic acid independently of the fatty acid chain length is supposed to be very low. On the other hand data from several surrogate substances, representing the whole spectrum of the main structural chemical building blocks of the category members did not provide a hazard after repeated exposure. Dibutyl adipate (CAS 105-99-7) and Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) had no effects in an oral 28- and 90-day study after gavage, respectively. Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) had no effects in a 90-day study via the dermal and inhalation route.

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 group concept is applied to the members of the PFAE, mixed and branched category, available data are used from surrogate substance(s) to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, the available data on repeated dose 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.