3-hydroxypropyl octanoate

Endpoint summary

Description of key information

A repeated dose toxicity study does not need to be conducted according to REACH Annex XI, 1.2, Weight of Evidence (WoE).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Please refer to chapter 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects noted at the highest dose level tested

Key result

Critical effects observed:

no

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

A repeated dose toxicity study does not need to be conducted according to REACH Annex XI, 1.2, Weight of Evidence (WoE).

REACH Annex XI, 1.2. Weight of evidence states as follows:
“There may be sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. (…)
Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available:
— further testing on vertebrate animals for that property shall be omitted (…)”

There are no experimental data on mammalian toxicity available with the test item.

However, comprehensive data from structurally closely related substances is taken into account for assessment of the toxicological properties of the registered substance, according to REACH Annex XI, 1.5 (Read-Across). For respective read-across justification please refer to IUCLID Section 13.

Based on the available data with the read-across source substances, the target substance is considered to be of very low toxicity since no treatment-related adverse systemic effects were obtained in any of the toxicity studies conducted.
A QSAR Toolbox query (2020) with the target substance supports the above considerations. There were no structural alerts in regards to specific target organ toxicity, no categorization according to HESS and the Cramer class was predicted to be low (Class I).

Therefore, a risk assessment does not need to be conducted according to REACH Article 14(4) and DNEL derivation is not required.

Two pre-natal developmental toxicity studies are available with read-across source substances. In both studies no adverse effects could be obtained up to the highest dose tested (i. e. 900 and 1000 mg/kg bw/d, respectively). Therefore, the NOAEL was determined to be the limit dose which is commonly applied for repeated dose toxicity, i. e. 1000 mg/kg bw/d. The treatment period in the pre-natal developmental toxicity study is shorter when compared to a subacute toxicity study (14 days vs. 28 days). However it should be taken into account that pregnant animals were administered being rather more susceptible to xenobiotics. Since no adverse effects were observed at all, it is considered very unlikely that a 14 days longer treatment period would lead to substantial adverse effects.

In addition to the hazard assessment the use profile of the registered substance should be taken in to account. The registered substance is only handled in controlled industrial settings making considerable exposure to humans unlikely. Assessment of toxicokinetic behaviour being based on physicochemical properties of the registered substance and toxicity data of the structural analogue substances concluded that the test items bioavailability will probably be very low, if not negligible. The registered substance is also applied in cosmetic products. Here, human health safety assessment of the final product is ensured under Cosmetics Regulation 1223/2009.

In conclusion and taking into account its low to negligible toxicity, the registered substance raises no concerns in regards to human health risk assessment that would justify a vertebrate repeated dose toxicity study. Neither as a hazard nor in regards to exposure considerations. Thus, conducting a repeated dose toxicity study in vertebrates is not justified. This is in line with REACH Article 25 (1) claiming that animal testing should always be the last resort.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP and Guideline study

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

A repeated dose toxicity study does not need to be conducted according to REACH Annex XI, 1.2, Weight of Evidence (WoE).

REACH Annex XI, 1.2. Weight of evidence states as follows:

“There may be sufficient weight of evidence from several independent sources of information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, while the information from each single source alone is regarded insufficient to support this notion. (…)       

Where sufficient weight of evidence for the presence or absence of a particular dangerous property is available:       

— further testing on vertebrate animals for that property shall be omitted (…)”

There are no experimental data on mammalian toxicity available with the test item.

However, comprehensive data from the source substance Propane-1,3-diol is taken into account for assessment of the toxicological properties of the registered substance together with the assessment of the second source substance Octanoic acid (taken from the disseminated ECHA REACH-Dossier of Octanoic acid), according to REACH Annex XI, 1.5 (Read-Across). These two source substances are the hydrolysis products of the target substance. For the respective read-across justification please refer to IUCLID Section 13.

 

Read across to Propane-1,3-diol

For the source substance Propane-1,3-diol a publication is available describing a subchronic toxicity study with rats (oral administration). The study followed OECD test guideline 408 and was conducted in compliance with GLP. The NOAEL of orally administered propane1,3-diol was determined to be 1000 mg/kg/day (the highest dose tested).

Read across to Octanoic acid

The second source substance, Octanoic acid, was assessed for its oral repeated dose toxicity by means of a read across approach applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Data obtained from oral repeated dose toxicity studies with members of the group of fatty acids were therefore analysed. The following results are obtained from the disseminated ECHA REACH Dossier of Octanoic acid:

Subchronic (84 days, rat): NOAEL oral ≥ 12500 mg/kg bw/day; CAS# 112-80-1, C18:1

Subacute (OECD 422, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS# 112-85-6, C22

Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS# 112-05-0, C9

Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS# 70321-72-1, C8-18 and C18-unsatd, distn. residues

In conclusion, no human hazard for systemic toxicity after repeated oral exposure was identified for the members of the fatty acids category.

As stated in the disseminated Dossier of Octanoic acid, fatty acids are found in all living organisms fulfilling three fundamental roles. Besides their function as part of molecules like phospholipids and glycolipids important for the cell-structure, they are often precursors of signalling molecules such as prostanoids. The third and best understood role of fatty acid is their role as nutritional energy source. Based on their physiological function within the body no toxicity after repeated administration of fatty acids is expected as demonstrated by animal studies with C6 fatty acid (hexanoic acid), C9 fatty acids (nonanoic acid and azelaic acid), C12 fatty acid (lauric acid), C22 fatty acid (docosanoic acid), C18:1 fatty acid (oleic acid), C18:2 conj. fatty acids (conjugated linoleic acid), C18:3 fatty acid (linolenic acid), fatty acids, C8-18 and C18-unsatd, distn. residues and fatty acids, tall oil.

In the disseminated Dossier of Octanoic acid the following summaries of the study data can be found:

Subchronic

A subchronic oral toxicity study was performed with oleic acid (CAS# 112-80-1) in rats (1969). The animals (10/sex/dose) were fed a diet containing 5, 10 and 25% oleic acid equivalent to dose levels of 2500, 5000 and 12500 mg/kg bw/day for 84 days. A control group was administered the plain diet. Two control animals and one female animal from the 10% dosage group died from blood collection trauma. There were no other mortalities or clinical signs of toxicity and no abnormal behavioural reactions were noted. The test animals had slightly higher final body weights than controls, but the differences were not statistically significant. Food consumption among test animals was slightly lower than among the control animals. There were no outstanding differences in haematologic, clinical chemistry or urinalysis parameters among test and control animals. No abnormalities were noted at gross examination. There were no significant differences in organ/body weight ratios except for kidneys, adrenal glands and brain. For these three organs, female test animals showed a higher organ/body weight ratio than control animals. All of these differences could be attributed to the slightly higher body weights observed in every test group rather than a deleterious effect of the test material. The absence of any abnormalities of these organs upon histopathologic examination would support this conclusion. Some minor histopathologic changes were noted among both the test and control animals, specifically involving lesions in the trachea and lungs. These changes were judged to be due to spontaneous disease (potential pneumonia), and not related to the test material. Based on these results, a NOAEL of ≥25% oleic acid in diet was derived, corresponding to a dose level of 12500 mg/kg bw/day.

 

Subacute

Nonanoic acid (CAS# 112-05-0) was tested in a subacute 28-day study according to OECD guideline 407 and in compliance with GLP (2002). Wistar rats (5 rats/sex/dose) were administered by gavage dose levels of 50, 150, 1000 mg/kg bw/day at a frequency of 7 doses per week. No substance-related mortality occurred. Slight to moderate breathing difficulties (rales and/or gasping) were observed in several high dose animals on some days during week 3. These signs subsided and were absent during week 4. Thus, these clinical signs (generally minimal to mild) were regarded as being of no biological relevance. No signs were noted in the low and intermediate dose groups. Body weights and body weight gain were similar across controls and treated groups. There was no effect on haematology and clinical chemistry parameters. No changes were seen in hearing ability, pupillary reflex, static righting reflex and grip strength, or in motor activity in neurobehavioural functional tests.

At termination, absolute and relative organ weights were similar between control and treated animals. An irregular surface of the forestomach was noted in all high dose animals at necropsy. A thickened glandular mucosa of the stomach was observed in animals receiving the test substance. Since none of these cases could be confirmed microscopically, they were considered to be of no toxicological relevance. Histopathology revealed no other findings than slight to marked hyperplasia of the squamous epithelium of the forestomach in all high dose animals, and at a minimal degree in 3 animals of the 150 mg/kg bw/day dose group.

Based on these results, and taking into account that there is no correlate for the rat’s forestomach in humans the NOAEL for systemic toxicity is considered to be ≥1000 mg/kg bw/day. The effects noted in the forestomach are considered to reflect local irritation at the point of contact. Therefore, the NOAEL for local toxicity is considered to be 150 mg/kg bw/day.

The repeated dose toxicity of docosanoic acid (CAS# 112-85-6) was evaluated in a combined repeated dose and reproductive/developmental toxicity screening test performed under GLP according to OECD guideline 422 (2002). Groups of 13 male and 13 female Sprague-Dawley rats received daily doses of 100, 300 and 1000 mg/kg bw/day of docosanoic acid by gavage, respectively. While the males were treated for 42 days, the females received the test substance from 14 days prior to mating until day 3 of lactation. As a result of this treatment, neither mortality nor abnormalities in general condition were observed. In addition, no changes in body weight, body weight gain and food consumption were found. The observed minor changes in the corpuscular haemoglobin concentration, glucose, chloride, calcium and alkaline phosphate levels were regarded as incidental which also holds true for the observed changes in liver weights in male and kidney weights in females, respectively. All histopathological findings noted in all dose groups were also detected in the control groups, so that all findings could be regarded as not treatment-related. Overall, no treatment-related adverse effect was apparent, so that the highest dose of 1000 mg/kg bw/day is regarded as the NOAEL for docosanoic acid.

An oral 28-day repeated dose toxicity study was performed equivalent to OECD guideline 407 with fatty acids, C8-18 and C18-unsatd., distn. residues in male and female Wistar rats (1983). Ten animals each per sex were treated by gavage with the test substance at 50, 250 and 1000 mg/kg bw/day dissolved in olive oil. Control animals received the vehicle only. The animals were treated 5 days/week resulting in a total of 21 applications within 28 days. No mortalities or abnormal findings occurred in any dose group. No treatment-related effects on body weight gain, clinical chemistry, haematology and urinalysis were observed. No abnormal findings were seen at gross pathology and organ weight determinations. Histopathological examinations revealed inflamed edemas and ulcerations of the forestomach in the low- and mid-dose group as well as in the controls. In the highest dose group, the number of test animals with inflamed edemas and ulcerations in the forestomach were clearly reduced in comparison to the controls. In addition, the signs of local irritation were completely reversed in the recovery animals. Therefore, this effect was related to the vehicle. No treatment-related effects were observed. Therefore, the NOAEL was determined to be ≥ 1000 mg/kg bw/day.

 

Fruthermore there are several publications available, which also point out that fatty acids do not have toxic properties after repeated administration. In general, the following repeated dose studies reported in these publications were not performed according/similar to current guidelines and examine partially only less parameters:

Chronic

The effects of long-term feeding of conjugated linoleic acid (41.9% c9,t11 and 43.5% t10,c12) in Fischer 344 rats were examined by Park et al. (2005). A limited number of weanling male rats were fed either a control diet (n=10) or a diet containing 1% (corresponding to 500 mg/kg bw/day) conjugated linoleic acid over a time period of 18 months. After 12 weeks, 3 control and test animals were randomly selected, sacrificed, and subjected to body fat analysis and water content. At the end of the study period, all animals were euthanized and examined for gross pathological changes and appropriate tissues were examined histopathologically. Organ weights, clinical chemistry, and haematological parameters were determined. Survival rate, weight gain and water consumption did not differ between treatment and control groups. Food consumption was significantly lower in the group fed conjugated linoleic acid compared to controls, however since body weight of test animals did not differ to that of control animals, this effect is not considered adverse. Body fat analysis and water content at 12 weeks revealed no significant difference between groups in percentage body fat, empty carcass weights, or percentage body water. Blood glucose levels were significantly lower and mean corpuscular volume was significantly higher in animals fed conjugated linoleic acid compared to controls. As there were no difference in haematocrit, the observed differences do not indicate health concern. Blood urea nitrogen and cholesterol levels were elevated beyond the normal range in both groups, but were not significantly different between groups. Protein was detected in the urine of animals from both groups; however, the protein levels in the rats fed conjugated linoleic acid were significantly lower than that of the control group. All animals from both groups had chronic renal diseases (chronic interstitial nephritis, nephrosis, and/or glomerulosclerosis). The chronic renal failure was thought by the authors to be due to the high protein content of the diets and was not considered to be compound-related. There were no significant differences between groups in organ weights. The incidences of pituitary or testicular tumors, prostatitis, or lymphoma were not significantly different between groups. Based on the results of this study, the NOAEL was considered to be ≥ 500 mg conjugated linoleic acid/kg bw/day in the diet.

In another chronic study with conjugated linoleic acid, weanling male rats received a diet containing 1.5% of a synthetic conjugated linoleic acid preparation (42.5% c9,tll and/or t9,cl1 isomers, 43% t10,c12, 4.3% other conjugated linoleic acid isomers, 7.1% linoleic acid, and 3.1% other constituents (not further specified)) for 9 months (Scimeca, 1998). Body weights and food consumption were recorded and physical examinations were performed weekly throughout the study. At the end of the study period, all surviving animals were necropsied and examined histologically and organ weights were determined. Haematological and clinical chemistry parameters were measured. According to the authors rats ingested an average daily conjugated linoleic acid dose in a range from 1970 ± 11 to 467 ± 52 mg/kg bw/day from week 1 to study week 36. However, since this is a broad range, an average conjugated linoleic acid intake of 750 mg/kg bw/day was calculated based on an average food consumption of 5g/100g bw/day (WHO, 1987). Animals fed conjugated linoleic acid did not show any clinical signs of toxicity, nor were there any differences in body weight gain or food consumption relative to the control group.

Likewise, there were no significant compound-related histopathological or microscopic changes in the organs, or changes in haematological or clinical chemistry parameters. Based on the results of this study, the NOAEL for conjugated linoleic was determined to be 750 mg/kg bw/day.

Subchronic

Repeated dose toxicity of lauric acid was tested in a study, where 5 male Osborne-Mendel rats were fed a diet containing 10% lauric acid for 18 weeks (Fitzhugh et al., 1960). As results, no clinical effects, no adverse effects on weight gain nor any mortality were noted. The performed gross organ pathology did not reveal any significant differences of individual organ weights between the controls and test animals. Thus, the test concentration of 10% in diet is regarded as the NOAEL, which corresponds to ca. 5000 mg/kg bw/day, based on an average daily food consumption of 5 g/100 g bw/day.

Investigations on the repeated dose toxicity of azelaic acid (CAS# 123-99-9) were carried out in Wistar rats and New Zealand rabbits, fed azelaic acid incorporated into pellets (Mingrone et al., 1983). Rats (10/sex/dose) were given azelaic acid at dose levels of 140 and 280 mg/kg bw/day and rabbits (10/sex/dose) were administered azelaic acid at doses of 200 and 400 mg/kg bw/day for 180 days, respectively. Both species showed normal growth compared to the control animals. No effects on biological parameters of haematology and clinical chemistry were observed and there were no findings at histological examinations (liver, kidneys, suprarenal glands, intestine, testicles, ovaries, uterus, lung, heart and brain). Thus, the NOAELs for the subchronic toxicity study were regarded to be ≥ 280 mg/kg bw/day for rats and ≥ 400 mg/kg bw/day for rabbits, respectively.

The repeated dose toxicity of fatty acids, tall oil (CAS# 61790-12-3) which consists predominantly of C18 unsaturated and saturated fatty acids was examined in a 90-day subchronic toxicity study in Charles River rats (Pine Chemical Association, 2004). The test substance was administered to the animals (10 rats/sex/dose) in the diet at concentrations of 0, 5, 10 and 25% (corresponding to 2500, 5000 and 12500 mg/kg bw/day). No deaths occurred in the test animals; however two control animals died during blood sampling. No clinical signs and no changes in body weight and body weight gain were noted. The food consumption was slightly decreased in the mid- and high-dose group. No changes in haematology, clinical chemistry or urinalysis parameters were determined. At gross pathology, no treatment-related effects were observed in any of the groups. No consistent organ weight changes and no histopathological effects were reported at any dose. Based on this data, the NOAEL for fatty acids, tall oil was considered to be ≥ 12500 mg/kg bw/day.

Subacute

Moody and Reddy (1977) exposed rats to 2, 4 and 8% hexanoic acid (corresponding to 1000, 2000, 4000 mg/kg bw/day; CAS# 142-62-1) in diet for 3 weeks before alterations in body weight gain, liver size, hepatic enzyme activity and hepatic peroxisome proliferation were examined. Since no effects were induced by hexanoic acid, the NOAEL was considered to be ≥ 4000 mg/kg bw/day.

Rodrigues et al. (2010) analysed effects of oleic acid (CAS# 112-80-1) and linoleic acid (CAS# 60-33-3) after repeated dose exposures in male Wistar rats with special focus on neutrophils. In detail, 10 rats per dose group were exposed once daily to 110, 220 and 440 mg/kg bw oleic acid or linoleic acid via gavage over 10 days. Control animals received 220 mg water/kg bw /day. In addition to specific alterations in neutrophils, effects on water, food and calory intake as well as alterations in biochemical parameters including enzyme activities of alanine transaminase (ALT), aspartate transaminase (AST) and lactate dehydrogenase (LDH) were determined Moreover histological examinations on the small intestine including villus:crypt ratio, epithelium, reactivity of the crypt, claciform cells number, payer plates reactivity, muscle layer and nerve plexus were performed. In regard to signs of general toxicity, no mortality or clinical signs such as diarrhoea or hair loss were reported. Food, calorie and water intake were not modified by administration of oleic acid and linoleic acid in all dose groups. Moreover, no alterations in the activity of AST, ALT or LDH were observed in the high-dose group and no changes in the histopathological examinations were determined. Oleic acid and linoleic acid modified several neutrophil functions, indicating that these fatty acids may affect the course of inflammation. As the effects on neutrophils represent cell-specific alterations relevant for the immune system which itself represents an adaptive system to many kinds of stressors and exogenous stimuli, they do not clearly indicate adverse effects on the test animals. In contrast, endpoints covering clinical signs, mortality, food and water consumption, haematological parameter and histopathological findings clearly stand for no significant adverse effects of oleic and linoleic acid. Thus, the highest dose of 440 mg/kg bw is regarded as NOAEL in the conducted study for both test substances.

The effect of linoleic acid on the haemopoietic system was investigated in rats (Khan et al., 1994). Five animals each were administered linoleic acid (CAS# 60-33-3) in mineral oil at a dose level of 0.7 mmol/kg bw/day (equivalent to 200 mg/kg bw/day) by gavage for 1, 7 or 28 days, respectively. No haematological changes were noted in the examined parameters (blood erythrocyte count, haemoglobin, packed cell volume, mean corpuscular volume, mean corpuscular haemoglobin, haematocrit, platelets, white blood cell count, leukocyte differential counts and methaemoglobin). Biochemical assays in serum revealed, that LDH activity was not altered by linoleic acid treatment. Serum AST was diminished to 72% and 74% of control values in animals treated for 7 and 28 days, respectively. Serum ALT activity was decreased in the linoleic acid exposed animals at Days 1 and 7 being 81 and 65% of controls, respectively. On day 28 the changes in serum ALT activity were no longer of statistical significance. Since the changes in these markers of cell or tissue injury were not accompanied by any histopathological findings in the examined organs (heart, liver, lung, brain, spleen, kidneys, thymus, testes and pancreas), the changes in the aminotransferases were not considered as adverse. No organ weight changes were noted and linoleic acid treatment had no effect on splenic iron content at any of the three time points. Thus, based on the results of this study, the NOAEL (subacute) was considered to be ≥ 200 mg linoleic acid/kg bw/day.

Since the members of the fatty acids category share structural and functional properties, these study results can be applied to all members of the category. Thereby, a substance-specific adjustment of the NOAEL is not performed. As overall NOAEL for all fatty acids within the category 1000 mg/kg bw/day is chosen as “worst case” among the available key studies, which were judged with reliability 1 or 2 (reliable). In addition nonanoic acid and docosanoic acid, which elicit a NOAEL ≥ 1000 mg/kg bw/day are representing category members with a low and the highest molecular weight.

It is concluded in the disseminated Dossier of Octanoic acid that the study data do not provide any evidence of systemic toxicity after repeated administration of fatty acids which is supported by the physiological function of fatty acids within the body.

 

References

Fitzhugh, O.G. et al. (1960) Oral toxicities of lauric acid and lauric acid derivates. Toxicol Appl Pharmacol. 2:59 - 67.

Khan, M. F. et al. (1994) Hematopoietic Toxicity of Linoleic Acid Anilide: Importance of Aniline. Fundam Appl Toxicol 25:224 - 232.

Mingrone, G. et al. (1983). TOXICITY OF AZELAIC ACID. DRUGS EXPTL. CLIN. RES. 9(6):447 – 455

Moody, D. E. and Reddy, J.K. (1978). Hepatic Peroxisome (Microbody) Proliferation in Rats Fed Plasticizers and Related Compounds. Toxicol. Appl. Pharmacol. 45:497 – 504.

Park, Y. et al. (2005).Effects of conjugated linoleic acid on long term feeding in Fischer 344 rats. Food and Chemical Toxicology 43:1273 – 79.

Pine Chemical Association (2004). Final Submission for Tall Oil Fatty Acids and Related Substances - VII. Robust Summaries of Data for Tall Oil Fatty Acids and Related Substances.Bibliographic source: no data

Scimeca, J.A. (1998) Toxicological Evaluation of Dietary Conjugated Linoleic Acid in Male Fischer 344 Rats. Food and Chemical Toxicology 36(5):391 - 395.

Rodrigues, H.G. et al. (2010). Dietary Free Oleic and Linoleic Acid Enhances Neutrophil Function and Modulates the Inflammatory Response in Rats. Lipids 45:809 – 819.

 

Prenatal developmental toxicity data

Besides the above mentioned data on repeated dose toxicity, data obtained from prenatal developmental toxicity studies are additionally used in this weight-of-evidence-approach to assess the repeated dose toxicity of the substance.

Two prenatal developmental toxicity studies are available with further read across substances. The source substances (CAS 68583-51-7 and CAS 91031-31-1) are UVCB substances (fatty acids with alcohols) but structurally similar to the above mentioned read across substances. For details, please refer to the read across justification. In both studies no adverse effects could be obtained up to the highest dose tested (i. e. 900 and 1000 mg/kg bw/d, respectively). Therefore, the NOAEL was determined to be the limit dose which is commonly applied for repeated dose toxicity, i. e. 1000 mg/kg bw/d. The treatment period in the pre-natal developmental toxicity study is shorter when compared to a subacute toxicity study (14 days vs. 28 days). However it should be taken into account that pregnant animals were administered being rather more susceptible to xenobiotics. Since no adverse effects were observed at all, it is considered very unlikely that a 14 days longer treatment period would lead to substantial adverse effects.

 

Use profile

In addition to the hazard assessment the use profile of the registered substance should be taken in to account. Assessment of toxicokinetic behaviour being based on physicochemical properties of the registered substance and toxicity data of the structural analogue substances concluded that the test items bioavailability will probably be very low, if not negligible. The registered substance is also applied in cosmetic products. Here, human health safety assessment of the final product is ensured under Cosmetics Regulation 1223/2009.

 

Conclusion

Based on the available data with the read-across source substances, the target substance is considered to be of very low toxicity since no adverse systemic effects were obtained in any of the toxicity studies conducted. The read-across substances Propane-1,3-diol and Octanoic acid taken into account for the assessment of the repeated-dose toxicity of the target substance only require classification for local effects (low potential for skin and eye irritation and skin corrosion 1C, respectively) according to Regulation (EC) No 1272/2008 (CLP).

A QSAR Toolbox query (2020) with the target substance supports the above considerations. There were no structural alerts in regards to specific target organ toxicity, no categorization according to HESS and the Cramer class was predicted to be low (Class I). For the result table, please refer to the 'Attached background material'-field below.

In conclusion and taking into account its low to negligible toxicity, the registered substance raises no concerns in regards to human health risk assessment that would justify a vertebrate repeated dose toxicity study. Neither as a hazard nor in regards to exposure considerations. Thus, conducting a repeated dose toxicity study in vertebrates is not justified. This is in line with REACH Article 25 (1) claiming that animal testing should always be the last resort.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

There are no experimental data available with the registered substance. However, according to REACH Annex XI, 1.2, Weight of Evidence, a sound assessment of the registered substance in regards to repeated dose toxicity is possible. Based on available data with structural analogue subsances, the test item does not require classification as toxic after repeated exposure according to Regulation (EC) No 1272/2008 (CLP), as amended for the fifteenth time in Regulation (EU) No 2020/1182.