Registration Dossier

Administrative data

Description of key information

WoE:
The subacute systemic oral NOAEL for diisodecyl azelate was found to be 1100 mg/kg bw/day.
Read Across substance: CAS No. 27178-16-1, CAS No. 103-23-1 and CAS No. 103-23-1:
CAS No. 27178-16-1 - subacute (28 day) NOAEL of 1000 mg/kg bw/day
CAS No. 103-23-1 - subacute (28 day) NOAEL of 200 mg/kg bw/day
CAS No. 103-24-2 - subacute (28 day) NOAEL of 300 mg/kg bw/day
CAS No. 103-23-1 - subchronic (90 day) NOAEL of 630 mg/kg bw/day and >2187 mg/kg bw/day was found for male and female rats
CAS No. 103-23-1 - subchronic (90 day) NOAEL of 200 mg/kg bw/day and 387 mg/kg bw/day was found for male and female mice

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given, although only short summary of the study.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
; only 14 days of administration, no clinical chemistry, ophthalmoscopy or neurology analyses performed. Lack of detailed reporting, lack of details on test substance, only 7 animals tested
GLP compliance:
no
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 130-160 g
Route of administration:
oral: unspecified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 days
Frequency of treatment:
once daily
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
7
Control animals:
yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: daily

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Animals were bled 24 hours after the last dose.
- How many animals: all
- Parameters checked: Hb, PCV, MCHC, MCD, Reticulocytes, Differential White Blood cells, Platelets, Kaolin-Cephalin, Prothrombin

CLINICAL CHEMISTRY: No

URINALYSIS: Yes
- Time schedule for examinations: The final 24-hour urine was tested for bilirubine, glucose, protein and pH.

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: liver weights were measured
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
2 male and 2 female animals were killed for histological examination 24 hours after the last dose and the remainder were killed seven days later.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
There were no toxic signs during the experiment and liver weights and body weight gains were comparable with controls.
Haematological examination of the rats showed no changes. No changes were found in the urine.
At autopsy there were no abnormalities detected either macroscopically or microscopically.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight; haematology; urinalysis; gross pathology; organ weights; histopathology;
Critical effects observed:
not specified
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:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance.

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 only limited data available on the repeated dose toxicity of diisodecyl azelate (CAS 28472-97-1). In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances 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

Repeated dose toxicity oral

Repeated dose toxicity inhalation

Repeated dose toxicity dermal

28472-97-1 (a)

WoE:

RA: CAS 27178-16-1
RA: CAS 103-23-1
RA: CAS 103-24-2

--

--

27178-16-1 (b)

Subacute: NOAEL >= 1000 mg/kg bw

--

--

103-23-1

Subacute: NOAEL = 200 mg/kg bw (not relevant for human hazard)

Subchronic (rat): NOAEL = 630 and >2187 mg/kg bw (male and female) (not relevant for human hazard)

Subchronic (mouse): NOAEL = 200 and 387 mg/kg bw (male and female) (no relevant for human hazard)

--

--

103-24-2

Subacute: NOAEL = 300 mg/kg bw (not relevant for human hazard)

--

--

(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 diisodecyl azelate (CAS 28472-97-1). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

CAS 27178-16-1

In a subacute study with a Read Across substance, seven male and seven female rats received daily oral doses of diisodecyl adipate (CAS 27178-16-1) at 1000 mg/kg bodyweight for 14 days (Conning, 1970). The animals were observed daily for clinical signs. Body weights were recorded daily during the exposure period. Haematologic and urine parameters were analyzed from all animals 24 hours after the last dosing. Upon necropsy of all animals, liver weights were determined. In two male and two female animals histological examinations were performed. Based on the absence of abnormalities in clinical signs, mortality, body weight, haematology, urinalysis, gross pathology, organ weights and histopathology the NOAEL was found to be 1000 mg/kg bw/d in male and female rats. This is equivalent to an NOAEL of 1100 mg/kg/day calculated by the molecular weights for diisodecyl adipate (CAS 27178 -16 -1) of 426.68 and diisodecyl azelate (CAS 28472-97-1) of 468.75.

 

CAS 103-23-1

In a study according to OECD 407, bis(2-ethylhexyl) adipate (CAS 103-23-1) in corn oil was administered daily via oral gavage to 10 Crj: CD(SD) rats per sex and group at dose levels of 40, 200 and 1000 mg/kg bw/day (Miyata et al., 2006).

After 28-day treatment with the test substance, no treatment-related mortalities were observed in the animals. The relative organ weight of kidney was significantly increased in males and females at 1000 mg/kg bw/day. At the same dose level, increased relative adrenal weights in females and increased relative liver weights in both sexes were observed. The changes in kidney weights at 1000 mg/kg bw/day were accompanied by clear spotty pattern in kidney of 2 male rats as well as increased eosinophilic bodies (7/10 males) and hyaline droplets (8/10 males) at microscopic examination. These kidney effects are specific to male rats (alpha-2 micro globulin nephropathy syndrome) and of no concern to man. Further findings at histopathology involved increased ovarian follicle atresia in 4/10 females at 1000 mg/kg bw/day. Examination of vaginal smears revealed prolongation of the estrous stage in 2/10 females of the 1000 mg/kg bw/day dose group. No substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males.

Based on the results of this study, the NOAEL for male and female Crj:CD(SD) rats was established at 200 mg/kg bw/day.

 

CAS 103-24-2

In a subacute oral toxicity study according to OECD 422 and GLP, male and female Crj:CD(SD)IGS rats were exposed to bis(2-ethylhexyl) azelate (technical product of CAS 103-24-2; analytical purity 77.2%)at doses of 100, 300 and 1000 mg/kg bw/day (Shirota, 2003).

The test substance in corn oil was administered daily to 13 animals per sex and dose via gavage. Males were treated for a period of 42 days (14 days before mating and 28 days thereafter), whereas females were exposed to the test substance 14 days prior to mating and until Day 3 of lactation (42-53 days). A similar constituted group received the vehicle and acted as a control. No mortality and no clinical signs were observed during the study period. At the end of the study, body weight gain was significantly suppressed in males receiving 1000 mg/kg bw/day compared to controls. However, no effects on food consumption were observed in treated animals. No abnormal findings were noted at gross pathology in any of the treated animals. At 1000 mg/kg bw/day, relative weights of liver and kidney were increased in both sexes. The changes in liver weight were accompanied by an increased incidence of centrilobular hypertrophy and a reduction in the occurrence of periportal fatty change in males treated with 1000 mg/kg bw/day. Haematology did not reveal any treatment-related changes in males, but a non-adverse decrease in white blood cells and a shorter activated partial thromboplastin time were observed in females at 1000 mg/kg bw/day. The analysis of clinical chemistry parameters showed a slight, but statistically significant increase in the ratio of albumin to globulin in males at 1000 mg/kg bw/day and females at ≥ 300 mg/kg bw/day. The increase in ratio of albumin to globulin noted in females at 300 mg/kg bw/day was not considered as an adverse effect because of no accompanying changes in total protein or albumin at this dose. Furthermore, concentrations of creatinine, total protein and calcium in blood were significantly reduced in females at 1000 mg/kg bw/day. Neurobehavioural examination did not reveal any treatment-related effects in the animals compared to controls.

Based on these results, the NOAEL for male and female Crj:CD(SD)IGS rats was established at 300 mg/kg bw/day.

Subchronic

CAS 103-23-1

A subchronic oral toxicity study similar to OECD 408 was performed with bis(2-ethylhexyl) adipate (CAS 103-23-1) in Fischer 344 rats and B6C3F1 mice 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. In mice, an adverse decrease in body weight gain compared to controls was noted starting at 3100 ppm in males and at 6300 or 25000 ppm in females, respectively. In rats, 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 and species. No adverse effects were noted at histopathological examination in rats and mice. Clinical chemistry and haematological parameters were not reported in this study. Based on these results, a NOAEL of 1600 ppm was derived for male B6C3F1 mice, corresponding to an actual ingested dose of 200 mg/kg bw/day. In male rats, the NOAEL was set at 6300 ppm, which was equivalent to a 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.

 

The effect of bis(2-ethylhexyl) adipate (CAS 103-23-1) on the fertility of Alpk:APfSD (Wistar-derived) rats was investigated in a GLP-conform study similar to OECD guideline 415 (Tinston, 1988). Groups of 15 male and 30 female parental animals were exposed daily to the test substance at dietary concentrations of 300, 1800 or 12000 ppm, corresponding to mean achieved dose levels of 52, 178 and 2102 mg/kg bw/day for males and 61, 203 and 2399 mg/kg bw/day for females, respectively. Male and female rats were continuously treated 10 weeks prior to mating and throughout mating. Male rats were sacrificed after mating. Treatment of female rats was continued until Day 36 post-partum and then sacrificed. A similar constituted group of animals received the plain diet and served as controls. There was no evidence for any clear effect on bodyweight or food consumption. An increase in absolute and relative liver weight was observed in both male and female rats receiving dietary levels of 12000 ppm. No treatment-related findings were observed at gross pathology, except for accentuated lobular pattern in the liver of two female rats fed diets containing 12000 ppm of the test substance. No histological changes were noted in the reproductive organs of those males and females suspected of being infertile. Based on the results of this study the NOAEL for systemic toxicity was considered to be at 1800 ppm, equivalent to dose levels of 178 and 203 mg/kg bw/day in males and females, respectively.

Based on the study results, a NOAEL of 178 mg/kg bw/day was derived for bis(2-ethylhexyl) adipate based on the effects seen in females in the fertility study.

 

Conclusions for repeated dose oral toxicity

There are no data available on repeated dose toxicity of Diisodecyl azelate (CAS 28472-97-1).

However, oral toxicity after repeated exposure was investigated in seven studies using structurally related substances. Subacute oral administration of the diisodecyl adipate (CAS 27178-16-1) showed no adverse systemic effects, resulting in NOAELs of ≥ 1000 mg/kg bw/day. In contrast, adverse effects have been reported in oral studies (21 to 90 days) for structural analogues with 2-ethylhexanol as alcohol portion of the diester, namely bis(2-ethylhexyl) adipate (CAS 103-23-1) and bis(2-ethylhexyl) azelate (CAS 103-24-2). The NOAEL for subacute oral toxicity of the structural analogue bis(2-ethylhexyl) azelate in rats was established at 300 mg/kg bw/day. In subacute to subchronic oral toxicity studies with bis(2-ethylhexyl) adipate a systemic NOAEL of 200 mg/kg bw/day was identified.

Reduced body weight gain, increased liver weight associated with centrilobular hypertrophy, and a reduction in the grade of periportal fatty change were main findings after repeated oral exposure to bis(2-ethylhexyl) dicarboxylic acid esters. These effects are attributed to the strong rodent specific activation of peroxisome proliferation, predominantly via the peroxisome proliferator activated receptor (PPAR) alpha pathway (Reddy et al., 1986; Keith et al., 1992). Marked species differences have been observed for PPAR alpha activation. While rodents are very susceptible to hepatic peroxisome proliferation, guinea pigs and marmosets did not respond to bis(2-ethylhexyl) adipate (CAS 103-23-1) exposure with a marked increase in hepatic PPAR alpha activity (Cornu et al., 1992). This is supported by the finding that bis(2-ethylhexyl) adipate (CAS 103-23-1) metabolism in marmosets in contrast to rats does not lead to the formation of significant amounts of 2-ethylhexanoic acid, a known PPAR alpha agonist (Elcombe, 1986). Thus, the observed effects after oral application are considered to be not relevant for humans.

In conclusion, no human hazard for systemic toxicity after repeated oral exposure was identified for Diisodecyl azelate (CAS 28472-97-1).

 


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 substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

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.