Bis(16-methylheptadecyl) malate

Endpoint summary

Description of key information

RDT oral (OECD guideline 408), rat NOAEL = 630/2187 (males/females) mg/kg bw/day (RA from CAS 103-23-1)

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:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented study report which meets basic scientific principles (no data on haematology, clinical chemistry, urinalysis and behavioural analysis).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

no data on haematology and clinical chemistry

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: NCI Frederick Cancer Research Center, Frederick, Maryland
- Age at study initiation: 3 weeks old
- Housing: 5 per cage in solid bottom suspended polycarbonate cages equipped with disposable nonwoven fiber filter sheets and Aspen-bed hardwood chips as bedding
- Diet: powdered Wayne Lab Blox diet, ad libitum
- Water: available via an Edstrom automatic watering system, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-31
- Humidity (%): 10-88
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): at least every 14 days
- Mixing appropriate amounts with (Type of food): chemical was mixed with aliquot of powdered Wayne Lab Blox animal feed, placing the mixture in a Petterson-Kelly twin-shell intensifier bar V-blender with the remainder of the feed and mix for 10 minutes
- Storage temperature of food: 4 °C for no longer than 14 days

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The amounts of the test substance in 12500 and 25000 ppm samples were determined by vapour phase chromatography. One-gram samples of each of the above mixtures were triturated twice with 50-mL portions of methanol. The supernatant solutions were combined and diluted to a volume of 100 mL and analyzed. The mean of the analytical concentration was usually within 10% of the theoretical.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
1600, 3100, 6300, 12500, 25000 ppm
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
females: 140, 271, 551, 1094, 2187 mg/kg bw/day; males: 160, 310, 630, 1250, and 2500 mg/kg bw/day
Basis:
other: actual ingested (recalculated based on food consumption). Only the corresponding values to 6300 ppm were given in the study report. The other doses were calculated with the mean food consumption used to calculate these given values.

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: doses used are based on an acute study and a 14 day study
(groups of five rats per sex were treated with five dose levels of the test substance in feed (up to 100000 ppm) for 14 days, followed by 1 day of observation with control diet. 1 group per sex were maintained as untreated controls. All surviving animals were killed after 15 days.

Observations and examinations performed and frequency:

CAGE SIDE & CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- no specifics given on how feed consumption was observed

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

one female (1600 ppm) died,

Mortality:

mortality observed, treatment-related

Description (incidence):

one female (1600 ppm) died,

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

dose-related body weight depression up to 18% (males); no effects in females

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
One female rat recieving 1600 ppm died, but its death was not considered to be compound-related.

BODY WEIGHT AND WEIGHT GAIN
Weight gain depression was 11% or more for male rats fed 12500 ppm or 25000 ppm.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No compound-related reduction in feed consumption were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
No compound-related histopathological effects were observed.

Dose descriptor:

NOAEL

Effect level:

630 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight at 1250 mg/kg bw/day

Dose descriptor:

NOAEL

Effect level:

6 300 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight at 12500 ppm

Dose descriptor:

LOAEL

Effect level:

1 250 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight

Dose descriptor:

LOAEL

Effect level:

12 500 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decreased body weight

Dose descriptor:

NOAEL

Effect level:

2 187 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed at the highest dose

Dose descriptor:

NOAEL

Effect level:

25 000 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects observed at the highest dose

Critical effects observed:

not specified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common functional group(s), common precursors/breakdown products, similarities in PC/ECO/TOX properties. The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, 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 - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Justification for grouping of substances and read-across

There are only limited data available on repeated dose toxicity of Diisooctadecyl malate (CAS 67763-18-2). In order to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substance was 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 (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 substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of repeated dose toxicity:

CAS	Chemical name	Molecular weight[g/mol]	Repeated dose toxicity Oral	Repeated dose toxicity Inhalation	Repeated dose toxicity Dermal
67763-18-2 (a)	Diisooctadecyl malate	639.06	RA: CAS 103-23-1	--	--
103-23-1 (b)	Bis(2-ethylhexyl) adipate	370.57	Experimental result: NOAEL = 630/2187 mg/kg bw/day (rat)	--	--

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substances are considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for Diisooctadecyl malate (CAS 67763-18-2). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

No data on repeated dose toxicity is available with Diisooctadecyl malate (CAS 67763-18-2). Therefore, read across from the structurally analogue substances Bis(2-ethylhexyl) adipate (CAS 103-23-1) was applied.

Repeated dose toxicity: Oral

CAS 103-23-1

A reliable subchronic oral toxicity study equivalent or similar to OECD 408 was performed with Bis(2-ethylhexyl) adipate (CAS 103-23-1) in Fischer 344 rats at dose levels of 1600, 3100, 6300, 12500 and 25000 ppm for a period of 90 days (NTP, 1982). Ten animals per sex and dose received the test substance daily via diet, whereas a similar constituted control group was administered the plain diet. No signs of toxic effects and no mortality were observed in any of the animals during the study period. Body weight gain was adversely reduced in males at 12500 and 25000 ppm. Average food consumption was not altered between treated and control groups of both genders. No adverse effects were noted at histopathological examination in all animals. Clinical chemistry and haematological parameters were not reported in this study. Based on these results, a NOAEL of 6300 ppm was derived for male rats, corresponding to an actual ingested dose of 630 mg/kg bw/day. In female rats, the NOAEL was set at 25000 ppm, which was equivalent to a dose of 2187 mg/kg bw/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose.

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 analogue concept is applied to Diisooctadecyl malate (CAS 67763-18-2), data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the analogue read-across approach, the available data on repeated dose toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.