Registration Dossier

Administrative data

Description of key information

NOAEL systemic= 300 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available study comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6 of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The long-chain aliphatic ester (LCAE) category covers mono-esters of a fatty acid and a fatty alcohol. The category contains both mono-constituent and UVCB substances. The fatty acid carbon chain lengths range is C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear chains) esterified with fatty alcohols with chain lengths from C8 - C22 (even and uneven numbered, including saturated, unsaturated, branched and linear) in varying proportions to mono-esters.

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 and environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group, by interpolation to the target substances in the group (read-across approach), applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements for adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

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.

 

Overview of repeated dose toxicity

CAS

Repeated dose toxicity oral

Annex VIII

Repeated dose toxicity oral

Annex IX

91031-48-0 (b)

Experimental result:

NOAEL ≥1000 mg/kg bw/day

(28-day study)

--

868839-23-0

--

Experimental result:

NOAEL ≥1000 mg/kg bw/day

(90-day study)

3687-46-5

Experimental result:

NOAEL ≥1000 mg/kg bw/day

(28-day study)

--

59231-34-4 (a)

RA: CAS 3687-46-5, 95912-86-0, 93803-87-3

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

(OECD 422)

RA: CAS 868823-02-0

36078-10-1

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

95912-86-0

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

(28-day study)

RA: CAS 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

95912-87-1

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

91031-91-3

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

85116-88-7

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

3234-85-3

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

 

22393-85-7

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 study ongoing)

RA: CAS 868823-02-0

101227-09-2

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

72576-80-8

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

3687-45-4

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 study)

RA: CAS 868823-02-0

17673-56-2

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

96690-38-9

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3, 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

93803-87-3

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

(28-day study)

RA: CAS 59231-34-4

RA: CAS 22393-85-7, 17671-27-1 (OECD 422 studies ongoing)

RA: CAS 868823-02-0

17671-27-1

RA: CAS 3687-46-5, 95912-86-0,

93803-87-3

Experimental result:

NOAEL ≥ 1000 mg/kg bw/day

 (14-day dose-range finding study)

OECD 422 study ongoing

RA: CAS 868823-02-0

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

(b) Substances that are either already registered under REACh, or not subject to the REACh Phase-in registration deadline of 31 May 2013, are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

(c) Surrogate substances are chemicals of structurally similar fatty acid esters. Available data on these substances are used for assessment of (eco-)toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

Discussion

Repeated dose toxicity, oral, subacute

CAS 3687-46-5

A 28-day oral repeated dose toxicity study was performed according to a protocol similar to OECD 407, using decyl oleate (CAS 3687-46-5) (Potokar, 1987). No detailed clinical observations or neurobehavioural tests were performed. 10 Wistar rats/sex/dose were administered 0, 100, 500 and 1000 mg/kg bw/day by gavage, 5 days/week, over a period of 28 days. A satellite group with 5 rats/sex/dose was included for the control and highest dose level. There was no mortality and no treatment-related clinical signs were observed during the study period. No toxicologically relevant effects were noted on body weight, body weight gain, food consumption and water consumption. The ophthalmoscopic examination did not show treatment-related effects on the eyes.

Significant decreases in haemoglobin levels were observed in all dose groups. As the changes were not dose-related and no other relevant effects were seen in histopathological parameters, this is not considered to be a toxicologically relevant effect. The inorganic phosphorus level was increased with statistical significance in all male dose groups and in the low- and mid-dose female groups. The effect was not dose-related in the males and not observed at the highest dose level in females, therefore it is not considered to be toxicologically relevant. The urinary parameter values were comparable between the control group and the treatment groups. In females administered the highest dose, the absolute kidney weight was increased. The relative weight was not affected and the change was seen only in one sex, leading to the conclusion that this effect does not have toxicological relevance. The relative heart weight in males in the mid- and high-dose groups was reduced slightly, but with statistical significance, while the absolute heart weight was increased in the mid-dose group. The male high-dose group was not affected and no related effects were noted in the histopathological examination. Therefore, this effect is not considered to have toxicological relevance. No treatment-related gross pathologic effects were observed in organs or tissues. The mucosa of the forestomach in control and treatment groups showed degenerative changes or signs of inflammation; 1/10 males and 3/10 females in the control group, plus 2/10 females in the high-dose group had hyperplasia. 7/10 males and 7/10 females in the control group, and 5/10 males and 7/10 females in the high-dose group showed focal eosinophilic infiltration of the forestomach. These effects were possibly caused by the repeated use of a stomach tube for the dosing by gavage. As humans do not have a forestomach, this effect is not relevant to human exposure. No other treatment-related effects were observed on organs or tissues during the histopathological examination. No treatment-related changes were noted in the salivary gland, lungs, pancreas or stomach in the satellite animals.

Based on the lack of toxicologically relevant effects up to and including the highest dose level, the NOAEL is considered to be ≥ 1000 mg/kg bw/day.

 

CAS 36078-10-1

In a publication by Sato and Tsuchiya (1977), the occurrence of seborrhoea (abnormally increased secretion and discharge of sebum) following the repeated intake of waxes in rats was examined. Male Wistar rats were administered 10 and 15% of lauryl oleate (CAS 36078-10-1) in the diet (approximately 140 and 300 mg/kg bw/day, based on average weight and food intake), for 30 consecutive days. There was no mortality during the study period. The animals gained weight during the study period and no seborrhoea was observed.

 

CAS 22393-85-7

In a publication by Sato and Tsuchiya (1977), the occurrence of seborrhoea (abnormally increased secretion and discharge of sebum) following the repeated intake of waxes in rats was examined. Male Wistar rats were administered 10 and 15% tetradecyl oleate (CAS 22393-85-7) in the diet (approximately 200 and 300 mg/kg bw/day, based on average weight and food intake), for 30 consecutive days. There was no mortality during the study period. The animals in the 10% group gained weight during the study period, while no results were reported for the 15% group. No seborrhoea was observed. Because only limited information was available for a very limited number of parameters, the study was considered to be insufficient for assessment. 

 

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) is currently being performed using tetradecyl oleate. 10 rats/dose/day will be administered 0, 100, 300 and 1000 mg /kg bw/day of the test substance for 28 day (males) and up to 54 days (females).

The results of the main study will be included and evaluated when available.

 

CAS 95912-86-0

A 28-day oral repeated dose toxicity study was performed according to a protocol similar to OECD 407, using Fatty acids, C8-10, C12-18 alkyl esters (CAS 95912-86-0) (Pitterman, 1993). 10 Wistar rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day by gavage, 5 days/week, over a period of 28 days. In addition, satellite groups of 5 rats/sex/dose were administered 0 and 1000 mg/kg bw/day for 28 days, followed by an observation period of 33 days. There was no treatment-related mortality, however, one female in the low-dose group died when a blood sample was drawn during anaesthesia. No treatment-related clinical signs were observed in the main and satellite groups. No significant effects on body weight or food and water consumption were noted in main or satellite groups. The ophthalmological examination did not show any treatment-related changes to the eyes of the animals.

The males in the high-dose dose main group had a significant increase in the level of leucocytes with segmented nuclei. As this effect was only observed in one sex and there were no other haematological or histopathological effects, this is not considered to be a treatment-related effect. In males in the high-dose main group the ALT-level was significantly increased. This increase in a liver enzyme may be caused by an increase in the liver metabolism due to the test substance. However, no other effects were seen on clinical chemistry parameters or in the histopathology results. Therefore, the effects are considered not to be of toxicological relevance. A slight decrease was observed in the relative and absolute heart weight of males in the low-dose main group and in the relative heart weight in males in the mid-dose main group. As no effect was observed in the highest dose groups, this is not seen as a treatment-related effect. 4/10 males and 2/10 females in the high-dose main group had oedema in the forestomach; the females also had ulceration. No similar effects were seen in the low- and mid-dose groups. These findings were probably related to the gavage treatment. As none of the animals in the satellite group had effects on the forestomach, this is considered to be a reversible effect. Because humans do not have a forestomach this effect is not relevant to human exposure. The NOAEL is considered to be ≥ 1000 mg/kg bw/day.

 

CAS 93803-87-3

A 28-day oral repeated dose toxicity study was performed according to OECD 407, using octyldodecyl isooctadecanoate (CAS 93803-87-3) (De Hoog, 1998). 5 Wistar rats/sex/dose were administered 0, 50, 200 and 1000 mg/kg bw/day by gavage, for 28 consecutive days. There was no mortality and no toxicologically relevant clinical signs were observed during the study period. No significant differences in body weight, body weight gain and food consumption between the control group and treatment groups were noted. In females of the high-dose group, a statistically significant increase in relative leucocyte level (approx. 8%) and decrease in relative neutrophil level (approx. 8%) was noted, compared with the control group values. These values are related to each other as a percentage of the total lymphocyte concentration, and a variation in one will necessarily affect one or several other specific lymphocyte values. As the changes are minimal, no effects were seen in males and no other haematological effects were noted, this result is considered not have toxicological relevance. In males of the high-dose group, the level of calcium and chloride was significantly increased. These increases were around 5% compared with the control group levels and no similar effects were observed in the female groups. Therefore, they are not considered to have toxicological relevance. No treatment-related effects on neurobehavioural parameters were observed. There were no significant differences in absolute or relative organ weight in the treatment groups, compared to the control group. No treatment-related gross pathologic effects were observed in organs or tissues. No substance-related effects were observed on organs or tissues during the histopathological examination. Based on the lack of toxicologically relevant effects up to and including the highest dose level, the NOAEL is considered to be ≥ 1000 mg/kg bw/day.

 

CAS 59231-34-4

A 14-day dose range-finding study was performed with isodecyl oleate (CAS 59231-34-4) similar to the criteria outlined in OECD 422 in order to find appropriate dose levels for a subsequent combined repeated dose toxicity and reproduction/developmental toxicity screening study (Leuschner, 2012). In this study, 5 rats per sex and dose were administered the test substance once daily at 100, 300 and 1000 mg/kg bw/day via oral gavage. No mortality occurred and no clinical signs were observed during the study period. The body weight and food consumption was comparable between the control and treatment groups. At necropsy, no substance-related findings were noted. Based on the results of this study, the subacute NOAEL for male and female rats was considered to be ≥ 1000 mg/kg bw/day.

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422 under GLP conditions) was performed (Hansen, 2013). 10 rats/dose/day were administered 0, 100, 300 and 1000 mg/kg bw/day isodecyl oleate once daily for 28 day (males) and up to 54 days (females) via gavage. The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 36 for the male rats and on lactation day 4 or shortly thereafter for the female rats. No test item-related premature death was noted. No test item-related signs of toxicity were noted during the observational and neurological screenings. A test item-related decrease in body weight was noted for the female animals of the high dose group (1000 mg /kg bw/day) on lactation day 4. A test item-related decrease in food consumption was noted for the female animals of the high dose group (1000 mg /kg bw/day) during the lactation period. No test item-related changes were noted for the haematological parameters and the parameters of clinical chemistry. Macroscopic inspection at autopsy revealed no test item related changes. The histopathological examination revealed no test item-related changes. No other effect was observed in any further group or any parameter. The effects observed at 1000 mg/kg bw/d in the females were considered adverse and leading to maternal toxicity; thus, the NOAEL for systemic toxicity was determined to be 300 mg/kg bw/day in this study.

 

CAS 17671-27-1

In a 14-day dose range-finding study in rats, appropriate dose levels of docosyl docosanoate were determined for subsequent repeated dose studies according to OECD 422 and OECD 407 (Reig, 2012). Three animals per sex and dose received the test substance in vehicle (1% methylcellulose +1% Tween® 80 in aqueous solution) once daily for 7 days/week at 100, 500 and 1000 mg/kg bw/day for a period of 14 days. A similar constituted group of animals was administered the vehicle only and served as control. During the study, no mortalities and no relevant clinical signs of toxicity were observed. Salivation was occasionally noted in 1 male and 1 female treated with 1000 mg/kg bw/day, but this effect was not considered to be of adverse nature. Food consumption was comparable between treated and control animals. A dose-dependent, but non-adverse, lower water consumption was recorded in males from all treatment groups and in females treated with 1000 mg/kg bw/day. Body weight gain in all treatment groups was similar or slightly higher compared to control group. In females of all treatment groups, lower haemoglobin, haematocrit and erythrocyte values were observed at haematological examination. However, this effect was only statistically significant compared to controls at 1000 mg/kg bw/day and appeared in the absence of any corresponding adverse effect. No changes in haematological parameters compared to control were observed in treated males. Clinical chemistry analysis revealed higher values of creatinine in both sexes and at all dose levels. Furthermore, decreases in alkaline phosphatase in males and decreases in aspartate amino transferase values in females were observed. However, the differences in clinical chemistry parameters were not statistically significant compared to control. Alterations in absolute and/or relative organ weights of thymus, testes and thyroid were recorded at the end of the treatment period. At all dose levels, decreases in thyroid weight in females and increases in testes weight in males were observed. Furthermore, a decrease in thymus weight was observed in both genders of all treatment groups. However, in the absence of abnormal findings at gross pathology, these effects were not considered to be toxicologically relevant. Macroscopic examination did not reveal any treatment-related findings in any other organs or tissues. All lesions (reddish mandibular lymph nodes, reddish foci in thymus and dilation of uterine horns) noted in individual females treated with 500 and 1000 mg/kg bw/day were within the normal range of background alterations observed in rats of this strain and age and under the experimental conditions used in this study, and thus not related to treatment with the test substance. Based on the results of this study, the NOAEL for rats was considered to be 1000 mg/kg bw/day.

A combined repeated dose toxicity and reproduction/developmental toxicity screening study (according to OECD 422) is currently being performed using docosyl docosanoate. 10 rats/dose/day are administered 0, 100, 500 and 1000 mg /kg bw/day of the test substance for 28 day (males) and up to 54 days (females).

The results of the main study will be included and evaluated when available.

 

Repeated dose toxicity, oral, subchronic

CAS 868839-23-0

A 90-day repeated dose toxicity study was performed in rats according to OECD 408, using propylheptyl octanoate (CAS 868839-23-0) (Leuschner, 2006). 10 Wistar rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day of the test substance in soybean oil by gavage, for 90 consecutive days.

1/10 females in each of the low-, mid- and high dose groups, respectively, died during the laboratory examinations on the last treatment day after blood withdrawal. These deaths are considered to be caused by the ether narcosis and are therefore not treatment-related. No treatment-related clinical signs were observed. No treatment-related effects were noted on body weight, body weight gain, food consumption and water consumption. The ophthalmoscopic examination did not shown treatment-related effects on the eyes. No treatment-related effects were observed during the neurobehavioral and observational tests. There were no statistically significant differences in the haematology parameters between the control group and the treatment groups. The albumin and blood urea nitrogen levels were significantly increased in the males in the high-dose group. As no effects were noted on these parameters in the females of the high-dose group, and in the absence of related histopathological findings, these effects are not considered to be toxicologically relevant. A statistically significant decrease in urinary pH value was noted in males in the mid-dose group and in males and females in the high-dose groups. This is considered to be a treatment-related, but not toxicologically relevant, effect as no other effects on urinary parameters or kidney histopathology were noted. The absolute and relative liver weight in high-dose males and females was significantly increased. This is probably an adaptive response to the increased metabolic load due to ingestion of the test substance. As no related effects were noted on liver enzyme levels or liver histopathology, this is not considered to be a toxicologically relevant effect. There were no statistically significant differences in the mean length of the oestrus cycles and the number of complete cycles between the females in the control group and the treatment groups. In males, there were no statistically significant differences between the control group and the treatment groups in the mean number and percentage of ultrasound-resistant spermatids, number of motile spermatozoa in the cauda epididymis, and in the percentage of spermatids with malformations. No treatment-related gross pathological or histopathological effects were observed in organs or tissues.

Based on the lack of toxicologically relevant effects up to and including the highest dose level, the NOAEL is considered to be ≥ 1000 mg/kg bw/day.

 

Overall conclusion for repeated dose toxicity

The 3 available 28-day repeated dose toxicity studies with the category members and surrogate substances all indicate that no treatment-related effects occur up to and including the highest dose level of 1000 mg/kg bw/day (De Hoog, 1998; Pitterman, 1993; Potokar, 1987). Combined repeated dose toxicity and reproduction/developmental toxicity screening studies are currently being performed with the category members tetradecyl oleate (CAS 22393-85-7 and docosyl docosanoate (CAS 17671-27-1). The 14-day dose range-finding studies using isodecyl oleate and docosyl docosanoate showed no effects up to and including the highest dose level of 1000 mg/kg bw /day. The results of the main studies will be included when they become available and the overall conclusion will be reassessed, if necessary. One OECD 422 study conducted with the test material isodecyl oleate (CAS 59231-34-4) revealed a test item-related decrease in body weight and a decrease in food consumption for the female animals of the high dose group (1000 mg /kg bw/day) (Hansen, 2013). The effects were considered adverse and leading to maternal toxicity; thus, the NOAEL for systemic toxicity was determined to be 300 mg/kg bw/day in this study. The 90-day repeated dose study performed with propylheptyl octanoate (CAS 868839-23-0) showed no toxicologically relevant effects up to and including the highest dose level of 1000 mg/kg bw/day (Leuschner, 2006).

The overall subacute and subchronic NOAEL is therefore considered to be 300 mg/kg bw/day based on the adverse effects observed in the OECD 422 screening study at a dose level of 1000 mg/kg bw/d (Hansen, 2013).

 

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

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 LCAE category, data will be generated from data for reference source 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.