Propane-1,2,3-triyl 3,5,5-trimethylhexanoate

Endpoint summary

Description of key information

Subchronic (90-day) oral repeated dose toxicity (OECD 408): NOAEL (rat, m/f) = 120 mg/kg bw/day (worst-case assumption based on read-across from 3,5,5-trimethylhexanoic acid [CAS 3302-10-1]). Supported by additional subacute, subchronic and chronic studies with 3,5,5-trimethylhexanoic acid (CAS 3302-10-1), glycerol trioctanoate (CAS 538-23-8), propane-1,2,3-triyl 2-ethylhexanoate (CAS 7360-38-5), glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0), and glycerol (CAS 56-81-5) accounted for in a Weight-of-Evidence approach.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Remarks:

Summary of available data used for the endpoint assessment of the target substance

Adequacy of study:

weight of evidence

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

120 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Refer to 'Remarks'

Remarks on result:

other: Source: CAS 3302-10-1, BASF, 2013

Key result

Critical effects observed:

no

Further supporting studies:

NOAEL (28-day) = 50 mg/kg bw/day (Source: CAS 3302-10-1, BASF, 2002)

NOAEL (2-yr) = 10000 mg/kg bw/day (Source: CAS 56-81-5, Hine, 1953a)

NOAEL (31-day) = 1908 mg/kg bw/day (Source: CAS 538-23-8, Ohta, 1970)

NOAEL (2-yr) = 4770 mg/kg bw/day (Source: CAS 538-23-8, NTP, 1994)

NOAEL (28-day) >= 1000 mg/kg bw/day (Source: CAS 7360-38-5, Envigo, 2019a)

NOAEL (28-day) = 1000 mg/kg bw/day (Source: CAS 91052-13-0, Notox, 2010b)

Executive summary:

The repeated dose toxicity of the target substance is estimated based on an adequate and reliable subchronic (90-day) study of the hydrolysis product 3,5,5-trimethylhexanoic acid in a worst-case approach (BASF, 2013). In this study peroxisome proliferation and α2µ nephropathy were observed in male and female rats. Since these effects - although adverse in the rat - are not relevant to humans according to the ECHA Guidance on the Application of the CLP Criteria, the highest dose tested of 120 mg/kg bw/day is considered to constitute the No-Observed-Adverse-Effect-Level (NOAEL). Therefore, a subchronic oral NOAEL (rat, m/f) of 120 mg/kg bw is considered for the hazard assessment and C&L purposes of the target substance. As explained in the analogue justification, the differences in molecular structure between the target and the source substances are unlikely to lead to differences in repeated dose toxicity.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

120 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises adequate and reliable (Klimisch score 1) subacute and subchronic studies from the source substance (hydrolysis product) 3,5,5-trimethylhexanoic acid. Read-across is justified based on the fact that (i) propane-1,2,3-triyl 3,5,5-trimethylhexanoate undergoes enzymatic hydrolysis resulting in the formation of 3,5,5-trimethylhexanoic acid and that (ii) 3,5,5-trimethylhexanoic acid is a known hazardous substance. Hence, the read-across is based on a worst-case assumption. The study providing the NOAEL value used for the hazard assessment of the registered substance is supported by several studies with additional source substances. The selected studies are thus sufficient to fulfil the standard information requirements set out in Annexes VIII - X, Item 8.6, in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006.

Organ:

kidney

liver

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

There are no data available on the repeated dose toxicity of propane-1,2,3-triyl 3,5,5-trimethylhexanoate (CAS 56554-53-1). In order to fulfil the standard information requirements set out in Annex VIII, Item 8.6.1, in accordance with Annex XI, Item 1.5, of Regulation (EC) No. 1907/2006, read-across from structurally related substances and common hydrolysis products is 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 out 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 and/or hydrolysis/biodegradation products (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 physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0), propane-1,2,3-triyl 2-ethylhexanoate (CAS 7360-38-5) and glycerol trioctanoate (CAS 538-23-8) were selected as glyceride source substances for assessment of the oral repeated dose toxicity of propane-1,2,3-triyl 3,5,5-trimethylhexanoate. In addition, the hydrolysis products 3,5,5-trimethylhexanoic acid (CAS 3302-10-1) and glycerol (CAS 56-81-5) were chosen as source substances. The read-across is based on structural similarity and on the metabolism of propane-1,2,3-triyl 3,5,5-trimethylhexanoate, in particular on the fact that the substance undergoes enzymatic hydrolysis resulting in the formation of 3,5,5-trimethylhexanoic acid and glycerol. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of repeated dose oral toxicity

CAS#	56554-53-1	3302-10-1	56-81-5	538-23-8	7360-38-5	91052-13-0
Chemical name	Propane-1,2,3-triyl 3,5,5-trimethyl-hexanoate	3,5,5-Trimethylhexanoic acid	Glycerol	Glycerol trioctanoate	Propane-1,2,3-triyl 2-ethylhexanoate	Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates
Molecular weight	512.78	158.24	92.10	470.69	470.69	302.36 - 442.63
Subacute	RA: CAS 3302-10-1 RA: CAS 538-23-8 RA: CAS 7360-38-5 RA: CAS 91052-13-0	Experimental result: NOAEL (rat, m/f) = 50 mg/kg bw/day	--	Experimental result: NOAEL (rat, m) = 1908 mg/kg bw/day	Experimental result: NOAEL (rat, m/f) ≥ 1000 mg/kg bw/da	Experimental result: NOAEL (rat, m/f) ≥ 1000 mg/kg bw/da
Subchronic/chronic	RA: CAS 3302-10-1 RA: CAS 56-81-5 RA: CAS 73398-61-5 RA: CAS 538-23-8	Experimental result: NOAEL (rat, m/f) = 120 mg/kg bw/day	Experimental result: NOAEL (rat, m/f) = 10000 mg/kg bw/day	Experimental result: NOAEL (rat, m) = 4770 mg/kg bw/day	--	--

--: Data lacking

Studies on glyceride source substances

CAS 7360-38-5

A subacute oral toxicity study was performed with propane-1,2,3-triyl 2-ethylhexanoate in male and female Wistar rats according to OECD guideline 407 and in compliance with GLP (Envigo, 2019a). All animals were exposed to the test item by oral gavage for a treatment period of 28 days on a daily basis. The test item was dissolved in corn oil and administered at doses of 100, 300 and 1000 mg/kg bw/day to each five male and female animals per dose group. A similar constituted group received the vehicle only and served as control group. Detailed physical examination and arena observation revealed no treatment-related findings. Sensory reactivity, grip strength and motor activity as well as body weight gain and food consumption were as well unaffected. Analysis of hematological and blood chemistry parameters revealed minor findings, which were attributed to normal biological variation as a dose-response relationship was not observed and effects were confined to animals of one sex only. In addition, organ weights were unaffected and there were no treatment-related macroscopic or histopathological findings. Based on these results and under the conditions of the study, a NOAEL ≥ 1000 mg/kg bw/day was derived for male and female Wistar rats.

CAS No. 538-23-8

Subacute

A subacute oral toxicity study in Wistar rats was performed with glycerol trioctanoate at dose volumes of 2, 5 and 10 mL/kg bw/day, corresponding to dose levels of 1908, 4770 and 9540 mg/kg bw/day, as calculated from a density of 0.954 g/mL (Ohta et al., 1970). The test substance was diluted in a mixture of 1.2% Tween 80/0.8% Span 80 in water and administered once daily to groups of 10 male and 10 female animals for a period of 31 days via gavage. A similar constituted control group received water as vehicle. After treatment with the test substance at 10 mL/kg bw/day, 2 males and females each died. Further, 2 males and 1 female of 5 mL/kg bw/day dose group died. No changes in body weight development and no changes in food consumption were noted between control and treated groups. At clinical chemistry and hematology, no treatment-related effects on the analysed parameters were observed, except for the concentration of urea nitrogen which was significantly lower in female rats dosed with 5 and 10 mL/kg bw. Urinary parameters were not altered in treated animals compared to controls. In males, a significant reduction in heart weight was observed over all dose groups compared to controls. At 5 and 10 mL/kg bw/day, a significant reduction in spleen and kidney weight was observed in males. The weight of the left testis was significantly decreased in all dose groups compared to controls. In addition, significant reduction in right testis weight was observed at 2 and 10 mL/kg bw/day. No changes in absolute and relative organ weights were found in treated females compared to controls. At necropsy, no treatment-related findings were reported. Histopathology revealed sporadic effects on liver, kidney, heart, lungs, spleen as well as extramedullary hematopoiesis, but these effects were also observed in animals of the control group and were thus not regarded to be treatment-related. Based on the results of the 31-day toxicity study, a NOAEL of 1908 mg/kg bw/day was derived for male and female Hsd Cpb:WU rats.

Chronic

Oral chronic toxicity of glycerol trioctanoate was investigated in a GLP-conform study in male Fischer 344/N rats (NTP, 1994). Sixty animals per test group received the undiluted test substance via gavage at dose volumes of 2.5, 5, 10 mL/kg bw/day, corresponding to doses of 2390, 4770, 9540 mg/kg bw/day, as calculated from a density of 0.954 g/mL. A group of 60 animals remained untreated and served as control group. The animals were treated for a period of 104 weeks, except for 10 animals of each group which were already sacrificed after 15 months for interim examinations. A total of 30 animals died or were humanely killed in extremis after treatment with 9540 mg/kg bw/day. Based on these data, the two-year survival rate was significantly lower in animals of the highest dose compared to controls (31/50 survivors in controls vs. 23/53 survivors in the 9540 mg/kg bw/day dose group). Clinical findings of dyspnoea, ataxia and lethargy were observed in 50/60 animals of the high-dose group. Most of the animals generally recovered prior to the next daily dosing and the incidence of clinical findings declined during the second half of the study. However, 8 of 30 rats died between weeks 45 to 49 when the incidence of clinical findings (dyspnoea, ataxia and lethargy) was highest. In addition, these animals revealed a significantly lower body weight than the mean group body weight (316 g vs. 360 g) after 11 months (44 weeks) of treatment. Mean body weights of high dose group animals were decreased when compared to controls throughout the study, although the difference was less than 5% after week 61. A dose-dependent decrease in food consumption was determined, which was most probably due to the fact that rats received more than 10% of their caloric intake from the test item. Thus, the effects on food consumption were considered to be non-adverse. No changes in clinical chemistry parameters were observed in treated animals compared to controls. Significant changes in hematological parameters (increase in the hematocrit, hemoglobin and erythrocyte levels) were only observed in the high dose group when compared to controls. Statistically significant lower absolute kidney weights were only noted in animals of the mid dose (4770 mg/kg bw/day). Since no dose-dependency occurred, these effects were considered to be incidental and not treatment-related. No adverse effects were reported at gross pathology. Histopathological examination revealed a significant decrease in the incidence of nephropathy between animals of the high dose group and controls, which was due to the lower protein intake as a result of lower food consumption A dose-related increase in the incidences of pancreatic exocrine hyperplasia and adenoma as well as proliferative lesions of the forestomach was observed in the treated animals. Based on the results of this study, the NOAEL for male Fischer 344/N rats was set at 4770 mg/kg bw/day.

CAS No. 91052-13-0

The subacute oral toxicity of glycerides, C8-18 and C18-unsatd. mono- and di-, acetates was investigated in Crl:WI (Han) rats according to OECD guideline 422 and in conformity with GLP (Notox, 2010b). Dilutions of the test substance in polyethylene glycol were administered once daily to groups of 10 male and 5 female rats at doses of 100, 300 and 1000 mg/kg bw/day for 28 days via gavage. A similar constituted group received the vehicle and served as control. In addition, satellite groups of 5 males and 5 females each for the control and high dose group were used to investigate reversibility of effects during a 14-day post-exposure recovery period. No substance-related mortalities and clinical signs occurred during the whole study period. All parameters assessed at neurobehavioural examination were found to be normal and comparable to controls. Food consumption was similar between treated and control animals and no toxicologically relevant changes in body weights and body weight gain were noted up to 1000 mg/kg bw/day. Any statistically significant changes in clinical biochemistry and haematology parameters were considered to be of no toxicological relevance as these occurred in the absence of a clear treatment-related trend and remained within the range considered normal for rats of this age and strain. Any statistically significant changes in organ weights and organ to body weight ratios were considered to be of no toxicological relevance as these occurred in the absence of a clear treatment-related trend. Further, organ weight changes were within the range considered normal for rats of this age and strain and/or were present at the end of the recovery period only. In addition, no histopathological correlates were noted which could support organ weight changes. At necropsy, all incidental findings remained within the background range of findings that are encountered among rats of this age and strain. Since no dose-related trend was observed, these findings were considered to be of no toxicological relevance. Based on the results of this subacute toxicity study, the NOAEL for Crl:WI rats was considered to be ≥ 1000 mg/kg bw/day.

Studies on hydrolysis products

CAS No. 56-81-5

The chronic oral toxicity of glycerol was investigated in a two-year feeding study in male and female Long-Evans rats (Hine et al., 1953a). Natural or synthetic glycerol was administered 7 days/week ad libitum for a period of 105 weeks to groups of 22 animals per sex at dietary concentrations of 5 and 10, corresponding to calculated doses levels of 2500 and 5000 mg/kg bw/day, respectively. A control group of 26 animals received the plain diet. A further treatment group of 22 animals per sex was included in the study, which received natural or synthetic glycerol for a period of 52 weeks at a dietary concentration of 20%, corresponding to 10000 mg/kg bw/day. No information on mortalities and clinical signs was provided. Body weights and body weight gains in treated animals of all dose groups were comparable to those of controls. A slight (statistically significant) increase in food consumption was reported for males fed 5 and 10% of natural test substance, in comparison with the corresponding group administered the synthetic test substance. Hemoglobin determinations conducted after 3, 6, 12, 18 and 24 months of treatment did not demonstrate any difference between control and test groups. At urinalysis, a high incidence of albuminuria was reported among all dose groups and was also found at high incidence in the control group. Due to the random distribution and wide variation in degree of albuminuria throughout the experimental groups, no significance could be attributed to these effects. Statistically significant increases and decreases in relative organ weights of liver, lung, heart, kidney and spleen were incidentally observed in almost all treatment groups compared to controls. Since there was no apparent relationship to treatment, these changes were not considered to be toxicologically relevant. At necropsy, no gross lesions attributable to treatment were noted. At histopathological examination, non-neoplastic findings involved inflammatory lesions in a total of 27 animals evenly distributed among groups. The most frequent abnormalities were bronchiectasis, pneumonia and pulmonary abscesses. Taenia infestation of the liver was rarely observed. In several animals, hydronephrosis and pyelonephritis were noted. Neoplastic lesions involved the incidence of malignant and benign tumours in almost all groups (control and treatment) without clear evidence for a treatment-related increase in the incidence of neoplastic lesions. The determination of glycogen and lipid content in the liver did not reveal any differences between animals given 20% natural and synthetic glycerol for a period of 52 weeks. However, the relevance of these findings was unclear as no control values were available. Based on the overall effects of the study, a NOAEL of 10000 mg/kg bw/day was derived for male and female Long-Evans rats.

CAS 3302-10-1

Subacute

3,5,5-Trimethylhexanoic acid was tested in a 28-day repeated dose oral toxicity study according to OECD guideline 407 and under GLP conditions (BASF, 2002). The test material was administered to male and female Wistar rats by gavage for 4 weeks at dose levels of 10, 50 and 200 mg/kg bw/day. The vehicle used was an aqueous solution of 0.1% Cremophor EL in aqua bidest. and the administration volume was 10 mL/kg bw. A concurrent vehicle control group was included in the study. Control and high-dose groups consisted of each 10 animals per sex, whereas low- and mid-dose groups consisted of each 5 animals per sex. After 4 weeks of treatment, 5 animals per sex of all dose groups were sacrificed (main groups). The remaining 5 animals per sex of control and high-dose groups were maintained for another 14 days without administration of the test substance (recovery groups). The following substance-related findings were obtained for the 200 mg/kg bw/day group: decrease in motor activity values concerning single intervals in females; decrease in the value regarding overall motor activity in females; increase in cyanide-insensitive palmitoyl-CoA-oxidation and urinary volume in males and females; increase in cloudy urines, urinary blood, renal tubular epithelial cells, degenerated transitional epithelial cells, squameous epithelial cells, granular casts and epithelial cell casts in the urine of males; increase in alanine aminotransferase in females; decrease in urinary specific gravity in males and females; decrease in albumin in males; decrease in total protein and globulins in females; decrease in globulins in recovery females; significant increase in mean absolute (males) and relative (males and females) liver and kidney weights; diffuse alpha2µ globulin accumulation in the proximal tubules of the kidneys of all male rats; (multi)focal tubular dilatation in the kidneys of two males; peripheral fatty infiltration of liver cells in one male and all females. In the recovery animals of the high-dose group, the observed effects included a significant increase in mean absolute and relative kidney weights in males; (multi)focal tubular dilatation in the kidneys of two males; basophilic (regenerating) tubules in the renal cortex of 4 males. In the 50 mg/kg bw/day group, substance-related effects consisted of an increase in urinary volume, urinary blood, renal tubular epithelial cells, degenerated transitional epithelial cells, squameous epithelial cells, granular casts and epithelial cells casts in the urine of males; increase in cyanide-insensitive palmitoyl-CoA-oxidation in females; decrease in urinary specific gravity in males; significant increase in the mean relative kidney weight in males and females; diffuse alpha2µ globulin accumulation in the proximal tubules of the kidneys of all males; (multi)focal tubular dilatation in the kidneys of one male; peripheral fatty infiltration of liver cells in four females. Treatment-related effects at 10 mg/kg bw/day were an increase in degenerated transitional epithelial cells in the urine of males and diffuse alpha2µ globulin accumulation in the proximal tubules of the kidneys of four males.

Due to the findings the target organs were liver and kidneys in both sexes. In male animals adverse kidney effects were noted at 10 mg/kg bw/day and above. No complete recovery was obtained after cessation of 200 mg/kg bw/day in males. However, these findings (alpha2µ globulin-induced nephropathy) are specific for male rats and therefore have no relevance for humans. In female animals no signs of toxicity were observed at 10 mg/kg bw/day. The observed findings at 50 mg/kg bw/day (minimal fatty infiltration of liver and increased kidney weights in females) are not considered to be adverse: An increase in cyanide-insensitive palmitoyl-CoA-oxidation in liver is indicative of species-specific peroxisome proliferation. Therefore the accompanying minimal liver effects at this dose (fully reversible) are also not regarded to be of relevance for human risk assessment. The increased kidney weights in females (reversible and without concomitant histological alterations even at the highest dose tested) are also not regarded as adverse effect. Therefore, the NOAEL of this study is considered to be 50 mg/kg bw/day.

Subchronic

A subchronic (90-day) oral repeated dose toxicity study according to OECD guideline 408 under GLP conditions was performed with 3,5,5-trimethylhexanoic acid (BASF, 2013a). The test substance was administered daily for 92 and 93 days to male and female Wistar rats, respectively, by gavage. Dose levels employed were 5, 30 and 120 mg/kg bw/day. Test groups consisted of 10 male and 10 female rats. Corn oil was used as vehicle. Based on the observations made in the 28-day study performed according to OECD guideline 407 (BASF, 2002), an additional parameter was included in the study protocol: Cyanide-insensitive Palmitoyl-CoA-oxidation in liver homogenate was measured with an automatic analyser. Also, immediately after necropsy and organ weight determination the right testis and cauda epididymis were taken from all male animals and sperm motility examined.

No treatment-related clinical signs of toxicity and effects on estrous cycle length and the number of estrous cycles were observed up to the highest dose tested. Salivation occurred immediately after dosing for a short period. However, this finding is attributed to the bad taste of the test substance or to local effects on the upper digestive tract. This finding was, therefore, not considered to be adverse.

The kidneys and the liver were identified as target organs. Clinical pathology examinations revealed effects on liver cell function. A higher cyanide-insensitive Palmitoyl-CoA oxidation (PAL CoA) in liver tissue of male and female rats in the high-dose group and of females in the mid-dose group as well as lower serum albumin levels in females of the high-dose group were observed. Findings of higher PAL CoA levels are indicative of an increased β-oxidation of long-chained fatty acids in peroxisomes of liver cells. In addition, fat vacuoles in the liver of males of the high-dose group and the liver and kidneys of females of the mid- and high-dose groups were observed. The increased PAL CoA oxidation was considered to reflect a disturbance of the fat metabolism of the animals consequently leading to an increased fat storage in the liver and the kidneys. All these effects were regarded to be treatment-related and adverse in the rat.

The absolute and relative kidney weights of male animals in the high-dose group were significantly increased by 15% and 17%, respectively. Moreover, the relative kidney weight of male animals in the mid-dose group was also increased (8%). Eosinophilic droplets, increased basophilic tubules and granular casts were observed in males of these dose groups (mid- and high-dose). These findings were responsible for the macroscopically detected light brownish discoloration and the weight increase of the kidneys. The eosinophilic droplets in the proximal convoluted tubules were identified to be alpha2µ globulin, a poorly hydrolysable, low molecular weight protein characteristic for male rats. Increased basophilic tubules are indicative of the regeneration of the kidney tubules and the granular casts observed were constituted of cellular debris within the tubules. Hence, the latter two effects are secondary to the alpha2µ globulin storage in the kidneys. It is important to note that none of these effects were observed in female rats at any dose level, as alpha2µ globulin-induced nephropathy is specific to male rats.

In conclusion, peroxisome proliferation and alpha2µ globulin formation were the main effects observed in the mid- and high-dose groups. No effects occurred in animals of the low-dose group and the NOAEL was therefore set at 5 mg/kg bw/day. However, according to the ECHA Guidance on the Application of the CLP Criteria, the effects observed - although adverse in the rat - are not relevant to humans. The dose level relevant to the hazard assessment is then 120 mg/kg bw/day 3,5,5-trimethylhexanoic acid (corresponding to the highest dose tested). Therefore, the hazard assessment of the target substance is based on a NOAEL of 120 mg/kg bw/day.

Conclusions for repeated dose toxicity

Due to the fact that there are no data on the repeated dose toxicity of propane-1,2,3-triyl 3,5,5-trimethylhexanoate, studies performed with glyceride source substances and with the expected hydrolysis products are considered. As described in detail in the analogue approach justification (refer to the document attached to section 13 of the technical dossier), only the data obtained with 3,5,5-trimethylhexanoic acid   are considered for the hazard assessment of propane-1,2,3-triyl 3,5,5-trimethylhexanoate in a worst-case approach.

The subacute (28-day) oral NOAEL of 3,5,5-trimethylhexanoic acid in male and female rats was determined to be 50 mg/kg bw/day, based on liver and kidney effects. The Lowest-Observed-Adverse-Effect-Level (LOAEL) in this study was 200 mg/kg bw/day, corresponding to the highest dose tested. In addition, the subchronic (90-day) oral repeated dose toxicity of 3,5,5-trimethylhexaonic acid has also been investigated. The NOAEL originally determined in this study is 5 mg/kg bw/day. However, this NOAEL is based on peroxisome proliferation and alpha2µ globulin-induced nephropathy observed in male and female rats. According to the ECHA Guidance on the Application of the CLP Criteria, these effects are not relevant to humans. In consequence, the hazard assessment of the target substance is based on a dose of 120 mg/kg bw/day (corresponding to the highest dose tested). The subchronic study is considered for the hazard assessment of the target substance because it is of longer duration (subchronic vs. subacute) and thus reflects the actual exposure situation of workers better, and because the LOAEL value of 200 mg/kg bw/day determined in the subacute repeated dose toxicity study and in the prenatal developmental toxicity study (refer to section 7.8.2 of the technical dossier) is higher than the NOAEL of the subchronic study.

Justification for classification or non-classification

Based on read-across following an analogue approach, the available data on the repeated dose toxicity of propane-1,2,3-triyl 3,5,5-trimethylhexanoate do not meet the classification criteria according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.