Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
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

Toxicity to reproduction

Annex VIII

Developmental toxicity/teratogenicicty

95912-89-3 (a)

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138-60-6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

91001-61-5

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138-60-6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

EC 921-836-0

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138-60-6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

11138-60-6 (b)

--

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

67762 -53 -2

--

Experimental result:

NOAEL (m/f): <800 mg/kg bw/day

105-99-7

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

Experimental result:

NOAEL (m/f): 300 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 toxicity to reproduction 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

An oral gavage reproduction/developmental toxicity screening test with Dibutyl adipate (CAS 105-99-7) was performed in Sprague-Dawley rats according to OECD guideline 421 and under conditions of GLP (Nagao, 1996). Dilutions of the test substance in corn oil were administered once daily to groups of 13 animals per sex at dose levels of 100, 300 and 1000 mg/kg bw/day via gavage. A similar constituted group received the vehicle and acted as control. Females were exposed for a total period of 42-53 days, including 14 days before mating and until Day 3 of lactation, whereas males were treated 14 days before mating and 28 days thereafter. After administration, clinical signs involved a dose-dependent increase in salivation in animals of both sexes. However, the increase in salivation was not regarded as neurological effect, but caused by stimulation by the administration of the test substance. A slight, but non-significant suppression of body weight gain was observed in males at 1000 mg/kg bw/day. The relative organ weight of kidney was statistically significantly increased in both sexes at 1000 mg/kg bw/day. In addition, an increase in the relative weight of spleen in males treated with 100 and 1000 mg/kg bw/day was observed, while the only change in spleen weight noted in females involved the increase in absolute weight at 100 mg/kg bw/day. No effects on reproductive function (sperm parameters and oestrus cyclicity) and performance (copulation, fertility, gestation, implantation and delivery index) were observed after treatment compared to controls in any of the parental animals. Testis weight, epididymis weight, and histology of these organs did not reveal any substance-related effects in males. Effects on offspring included a statistically significant decrease in the pub viability on Day 4 of lactation at the 1000 mg/kg bw/day dose group compared to controls. At the same dose, a slight decrease in pub weight was observed on Day 0 and Day 4 of lactation without reaching statistical significance.

Based on the results of this study, the NOAEL for reproductive toxicity in parental animals was established at >=1000 mg/kg bw/day, while the NOAEL for systemic toxicity in parental and F1 animals was set at 300 mg/kg bw/day.

 

CAS 403507-18-6

No reproductive toxicity study is available with Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6). Nevertheless, information on toxicity to reproductive organs was evaluated from a repeated dose toxicity study. 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. No abnormalities were observed in the reproductive organs as ovaries, uterus, testes, and seminal vesicles. 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

No reproductive toxicity study is available with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2). Nevertheless, information on toxicity to reproductive organs was evaluated from 2 repeated dose toxicity studies after inhalation and dermal exposure.

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. No substance-related adverse effects were observed for body weight, body weight gain, mortality, clinical biochemistry and haematological parameters. No abnormalities were observed in the reproductive organs as ovaries, uterus, testes, and seminal vesicles. In addition, no treatment-related effects were noted in sperm morphology or in sperm and spermatid counts. 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. No effects on reproductive organs have been reported. No effects on sperm morphology were detected. 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 reproductive toxicity are expected. On the one hand category members have a very low potential for absorption and thus bioavailability of all mixed polyol polyesters with adipic acid independently of the fatty acid chain length is supposed to be low. On the other hand surrogate substances that represent the whole spectrum of the main structural chemical building blocks of the category members do not possess a reproductive hazard after repeated exposure. Dibutyl adipate (CAS 105-99-7) had no effects on reproductive function in a screening test in rats after gavage. Furthermore, in 90-day studies using Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane (CAS 403507-18-6) (oral route) and Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2) (dermal and inhalation route) no effects on the reproductive organs were reported.


Short description of key information:
WoE based on available data from surrogate substances:
CAS 105-99-7: NOAEL (fertility) >=1000 mg/kg bw/day
CAS 403507-18-6, CAS 67762-53-52: no indications for adverse effects on reproductive parameters in several repeated dose toxicity studies

Effects on developmental toxicity

Description of key information
WoE, based on available data from surrogate substances:
CAS 105-99-7: NOAEL = 300 mg/kg bw/day
CAS 11138-60-6: NOAEL >/= 1000 mg/kg bw/d
CAS 67762-53-2: NOAEL < 800 mg/kg bw/d
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no adverse effect observed
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

Toxicity to reproduction

Annex VIII

Developmental toxicity/teratogenicicty

95912-89-3 (a)

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138-60-6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

91001-61-5

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138-60-6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

EC 921-836-0

W

WoE:

RA: CAS 105-99-7

WoE:

RA: CAS 11138 -60 -6

RA: CAS 67762 -53 -2

RA: CAS 105 -99 -7

11138-60-6 (b)

--

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

67762 -53 -2

--

Experimental result:

NOAEL (m/f): <800 mg/kg bw/day

105-99-7

Experimental result:

NOAEL (m/f): ≥1000 mg/kg bw/day

Experimental result:

NOAEL (m/f): 300 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 developmental 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 11138-60-6

Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (CAS 11138-60-6) was tested in a prenatal developmental toxicity study comparable to OECD Guideline 414 (Azuka and Daston, 2004). The test substance was percutaneously applied to Sprague-Dawley rats for 6 h/day under occlusive conditions. 25 animals per sex per dose were treated with 200, 600 or 2000 mg/kg bw/day in corn oil on Days 6-15 of gestation. Control animals (25 per sex per dose) received the vehicle. The middle and the high dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or food consumption. There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Therefore, a NOAEL of 2000 mg/kg bw/day was derived for prenatal development and for systemic maternal toxicity. Due to the irritation effects on skin, the local maternal NOAEL was found to be 200 mg/kg bw/day.

CAS 67762-53-2

The developmental toxicity of Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was investigated comparable to OECD Guideline 414 (prenatal developmental toxicity study) (Feusten, 1988). Groups of 15 presumed pregnant female Sprague-Dawley rats received daily dermal doses of the test substance at concentrations of 800 and 2000 mg/kg bw/day during gestational days 0 to 19. Control animals remained untreated. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 2000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities revealed no differences to controls and thus no indication for teratogenic effects. The only effect found was a dose-dependently increased number of fetuses with levocardia, although no hearth malformations have been detected. Furthermore levocardia was observed in vehicle control foetuses (Smith et al. 1988) and in the control foetuses conducted in the test laboratory. Since levocardia was observed in both treated groups, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats Fatty acids, C5-9, tetraesters with pentaerythritol was found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

CAS 105-99-7

An oral gavage reproduction/developmental toxicity screening test with Dibutyl adipate (CAS 105-99-7) was performed in Sprague-Dawley rats according to OECD guideline 421 and under conditions of GLP (Nagao, 1996). Dilutions of the test substance in corn oil were administered once daily to groups of 13 animals per sex at dose levels of 100, 300 and 1000 mg/kg bw/day via gavage. A similar constituted group received the vehicle and acted as control. Females were exposed for a total period of 42-53 days, including 14 days before mating and until Day 3 of lactation, whereas males were treated 14 days before mating and 28 days thereafter. After administration, clinical signs involved a dose-dependent increase in salivation in animals of both sexes. However, the increase in salivation was not regarded as neurological effect, but caused by stimulation by the administration of the test substance. A slight, but non-significant suppression of body weight gain was observed in males at 1000 mg/kg bw/day. The relative organ weight of kidney was statistically significantly increased in both sexes at 1000 mg/kg bw/day. In addition, an increase in the relative weight of spleen in males treated with 100 and 1000 mg/kg bw/day was observed, while the only change in spleen weight noted in females involved the increase in absolute weight at 100 mg/kg bw/day. No effects on reproductive function (sperm parameters and oestrus cyclicity) and performance (copulation, fertility, gestation, implantation and delivery index) were observed after treatment compared to controls in any of the parental animals. Testis weight, epididymis weight, and histology of these organs did not reveal any substance-related effects in males. Effects on offspring included a statistically significant decrease in the pub viability on Day 4 of lactation at the 1000 mg/kg bw/day dose group compared to controls. At the same dose, a slight decrease in pup weight was observed on Day 0 and Day 4 of lactation without reaching statistical significance. No morphological findings were reported in pups on day 4 of lactation, except one spontaneous visceral malformation (agenesis of midgut) in the 100 mg/kg bw/day group.

Based on the results of this study, the NOAEL for reproductive toxicity in parental animals was established at >=1000 mg/kg bw/day, while the NOAEL for systemic toxicity in parental and F1 animals was set at 300 mg/kg bw/day. No developmental effects were reported.

 

In conclusion, based on a weight of evidence approach, no effects of category members on developmental toxicity are expected. On the one hand category members have a very low potential for absorption and thus bioavailability of all mixed polyol polyesters with adipic acid independently of the fatty acid chain length is supposed to be very low. On the other hand surrogate substances representing the whole spectrum of the main structural chemical building blocks of the category members are not considered to possess a developmental toxicity hazard at toxicologically relevant doses.

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 toxicity to reproduction/developmental 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.