Diisodecyl sebacate

Endpoint summary

Description of key information

No standard acute toxicity studies were available on DIDS.
The acute oral toxicity of DIDA was at least 10,000 mg/kg bw in rats and mice in early, pre-GLP studies (Conning, 1970). Similarly high oral LD50 values (> 2000 mg/kg bw) were seen in limited studies involving rodents and ferrets (Conning, 1970; Fiume et al. 2012; Takahashi, 1976).
No acute inhalation data were available on DIDS. Only limited acute inhalation data are available on DOS and DEHS, which provide no convincing evidence that DIDS should be classified. The low volatility of these substances indicates that exposure via the inhalation route is not expected. 
A guideline study, to GLP, reported an acute dermal LD50 of more than 2000 mg/kg bw in rats treated dermally with DIDA (van Otterdijk, 2010b).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions, performed on a read-across compound

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

3 animals used per sex per group (5 recommended), animals observed for 7 days (14 recommended), insufficient detail to further judge compliance with guideline

GLP compliance:

no

Remarks:

predates GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Alderley Park SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Alderley Park
- Age at study initiation: no data
- Weight at study initiation: 160 to 260 g
- Fasting period before study: no data
- Housing: no data
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): no data
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data

IN-LIFE DATES: no data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: no data

Doses:

2500, 5000 or 10,000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7 days
- Frequency of observations and weighing: no data
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, histopathology (at least on kidney)

Statistics:

No data

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths were seen within seven days of treatment

Mortality:

No animals died within seven days of treatment.

Clinical signs:

other: Animals given 5000 or 10,000 mg/kg bw were incontinent for four days after dosing.

Gross pathology:

The kidneys of all treated animals were reticulated at autopsy (seven days after dosing), but were microscopically normal.

Other findings:

- Organ weights: no data
- Histopathology: small chronic inflammatory foci and mild stress changes were seen in the thymus. Gastric irritation and non-specific stress changes were seen in a further group of 3 males given 10,000 mg/kg bw and killed 24 hours later. [These changes may have been macroscopic.]
- Potential target organs: no data

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

In a study similar to that described by OECD Guideline 401, no deaths were seen in rats following a single gavage administration of DIDA at up to 10,000 mg/kg bw.

Executive summary:

The acute oral toxicity of diisodecyl adipate (DIDA) has been investigated in Alderley Park SPF rats, in a study similar to that described by OECD Guideline 401.

Groups of rats (3/sex) were given a single gavage treatment with undiluted DIDA at 2500, 5000 or 10,000 mg/kg bw. Rats were observed for clinical signs of toxicity until autopsy seven days after treatment. An additional group of rats was given 10,000 mg/kg bw and killed after 24 hours.

No deaths were observed before scheduled necropsy. The LD50 was therefore determined to be more than 10,000 mg/kg bw. According to the EU guidelines, DIDA does not require classification as acutely toxic via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

10 000 mg/kg bw

Quality of whole database:

There were no standard acute oral toxicity studies available on DIDS. Pre-GLP studies on DIDA, similar to existing OECD guidelines, are available in rats and mice. The secondary literature cites two further LD50s in rodents, and a ferret study is also available. Several studies are also available on DEHS/DOS.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

No studies were identified on the acute toxicity of DIDS (or DIDA). Limited data are available on DOS and DEHS. Exposure via inhalation is unlikely due to the low volatility of these substances.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Study period:

01 to 15-July-2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study on a read-across compound has been performed according to OECD and EC guidelines and according to GLP principles.

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nousan, Notification No 8147, November 2000; including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Wistar strain, Crl:WI (Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Young adult animals (approx.11 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean.
- Housing: Individually housed in labeled Macrolon cages (MIII type, height 18 cm.) containing sterilized sawdust as bedding material (Woody-Clean type 3/4, Tecnilab-BMI BV, Someren, The Netherlands) and paper as cage-enrichment (Enviro-dri, Tecnilab-BMI BV, Someren, The Netherlands).
- Diet (e.g. ad libitum): Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment under laboratory conditions.
- Health inspection: A health inspection was performed prior to treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from any abnormality.

Results of analysis for diet (nutrients and contaminants), sawdust, paper and water were assessed and did not reveal any findings that were considered to have affected the study integrity. All certificates and results of analysis are retained in the NOTOX archives.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 – 21.6ºC
- Humidity (%): 42 - 79%
Temporary deviations from the maximum level of relative humidity occurred. Laboratory historical data do not indicate an effect of the deviations.
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day.

IN-LIFE DATES: From: 01-jul-2010 to 15-jul-2010

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

One day before exposure (Day -1) an area of approximately 5x7 cm on the back of the animal was clipped.

The test substance was applied in an area of approx. 10% of the total body surface, i.e. approx. 25 cm² for males and 18 cm² for females. The formulation was held in contact with the skin with a dressing, consisting of a surgical gauze patch (Surgy 1D)*, successively covered with aluminum foil and Coban elastic bandage*. A piece of Micropore tape* was additionally used for fixation of the bandages in females only.
*. Manufacturers: Laboratoires Stella s.a., Liege, Belgium (surgical gauze) and 3M, St. Paul, Minnesota, U.S.A. (Coban & Micropore).

Frequency: Single dosage, on Day 1.

Washing: Following application, dressings were removed and the skin cleaned of residual test substance using tap water.

Duration of exposure:

24 hours.

Doses:

2000 mg/kg (2.17 mL/kg) body weight.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

Dose level (volume): 2000 mg/kg (2.17 mL/kg) body weight.
Dose volume calculated as dose level (g/kg) / specific gravity.

DOSAGE PREPARATION: The test substance was dosed undiluted as delivered by the sponsor.

Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily
Body weights: Days 1 (pre-administration), 8 and 15.
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15. The symptoms were graded according to fixed scales and the time of onset, degree and duration were recorded.
- Necropsy of survivors performed: yes
- Other examinations performed: none.

Statistics:

None.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No deaths reported

Mortality:

No mortality occurred.

Clinical signs:

other: Chromodacryorrhoea (snout) was noted for all males and two females on Day 1 and/or 2. Flat posture was observed for two males on Day 1. No clinical signs were noted for three females. Scales were seen in the treated skin-area of one male on Day 5.

Gross pathology:

No abnormalities were found at macroscopic post mortem examination of the animals.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The dermal LD50 value of DIDA in Wistar rats exceeded 2000 mg/kg bw in a GLP guideline study.

Executive summary:

The acute dermal toxicity of DIDA (a structally closely-related substance) has been investigated in Wistar rats, in a limit test performed to GLP, and conducted in accordance with OECD Guideline 402.

 

Five male and five female rats were given a 24-hour dermal application of DIDA under occlusion at 2000 mg/kg bw. Animals were observed for 14 days after administration. Clinical signs of toxicity, mortality, and body weights were monitored, and survivors were subject to gross necropsy.

  

No mortalities occurred over the course of the study. Red tears were seen on the snouts of all males and two females on day 1 and/or 2, and flat posture was noted on day 1 in two males. Effects on body weight were within the expected range, and no gross abnormalities were seen at necropsy.

 

The acute dermal LD50 for DIDA was determined to exceed 2000 mg/kg bw. As a result, DIDA does not require classification for acute dermal toxicity under CLP or DSD regulations.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Quality of whole database:

There were no standard acute dermal toxicity studies available on DIDS. A guideline study on rats, performed to GLP, is available on DIDA, supported by a pre-GLP study on rats, similar to the OECD guideline. The secondary literature also reports on an acute dermal study on DEHS in guinea pigs.

Additional information

Acute oral toxicity

No standard acute oral toxicity studies were available on DIDS.

Relevant read-across data:

Several acute oral toxicity studies have been conducted on DIDA. In studies similar to those described by OECD Guideline 401, an acute oral LD₅₀ of at least 10,000 mg/kg bw was seen for SPF rats and SPF mice treated acutely (Conning, 1970). Secondary sources cite LD₅₀ values for DIDA of 20,500 mg/kg bw for rats and more than 2000 mg/kg bw for male mice (Fiume et al. 2012; Takahashi, 1976). No deaths occurred when two female ferrets were given a single oral administration of 5000 mg/kg bw (Conning, 1970). None of these studies warrant classification of DIDA as acutely toxic via the oral route. As such, it is considered that DIDS does not warrant classification as acutely toxic by the oral route.

In addition, LD₅₀ values far in excess of the limit concentration of 2000 mg/kg bw (and often more than 10,000 mg/kg bw) are reported in the majority of studies on the acute oral toxicity of DOS/DEHS in rodents (Bibra, 1996). An LD₅₀ of 1280 mg/kg bw has been reported for DOS in rats (Williams, 1981).

Acute inhalation toxicity

No studies were identified on the acute toxicity of DIDS following exposure by inhalation.

Relevant read-across data:

A number of limited acute inhalation studies have been described on DEHS. No deaths were seen in rats treated with unspecified concentrations (generated by heating DEHS to 100 °C) for 6 hr, or with up to 250 mg/m³ for 4 hr. As part of a limited repeated dose (10-day) toxicity study, no deaths were seen in 4 rats, 2 guinea pigs, 2 rabbits and 1 cat exposed to 400 mg/m³, 7 hr/day for 10 days (Bibra, 1996). Toxicity was negligible when three different samples of DEHS (one fresh, the second heated to 170 °C and collected from a boiler, and the third taken from a deposit of aerosolised DEHS) were instilled intratracheally at a concentration of 2.5% into the lungs of groups of 6 hamsters (resulting in a dose of about 37.5 mg/kg bw). The inhalation exposure of the treated and control animals also contained about 13.3 mg/ml of surface-active material (SAM). About 24 hr later, animals were killed and assessed for markers of inflammation, oedema, bleeding, macrophage phagocytosis, cell injury and cell secretion. No significant changes were observed in the lungs of treated hamsters compared to those from controls given saline and SAM (Brain et al. 1996).

In a study with very limited reporting, deaths were seen in rats [unspecified numbers] following treatment with DOS at 800 mg/m³ for 4 hr. Effects on the nervous system were seen following exposure to 600 mg/m³ (Izmerov et al. 1977).

Acute dermal toxicity

No standard acute toxicity studies were available on DIDS following dermal exposure.

Relevant read-across data:

In a study on Wistar rats, performed to GLP and in accordance with OECD Guideline 402, the acute dermal toxicity of DIDA was assessed in a limit test following a 24-hr occlusive application. The acute dermal LD₅₀ was determined to be more than 2000 mg/kg bw (van Otterdijk, 2010b). In another acute dermal toxicity study on DIDA, female rats were given 5000 mg/kg bw in a test similar to OECD Guideline 434 (Conning, 1970). No deaths occurred in either study.

An LD₅₀ of more than 10 ml/kg bw [roughly 10,000 mg/kg bw] was seen for DEHS in guinea pigs, according to a secondary source (Bibra, 1996).

 

 

References

Brain JD, Blanchard JD, Heyder J, Wolfthal SF and Beck BD (1996). Relative toxicity of di(2-ethylhexyl) sebacate and related compounds in an in vivo hamster bioassay. Inhalation Toxicology 8, 579-593.

 

Izmerov N, Sanotsky I and Siderov K (1977). Toxicometric parameters of industrial toxic chemicals under single exposure. IRPTC Translation, UNEP.

 

Williams DF (1981).The toxicology of additives in medical plastics. Systemic Aspects of Biocompatibility, Vol. II, Williams DF (Ed), CRC Series in Biocompatibility, CRC Press, Inc. Boca Raton, Florida, pp.145-157.

Justification for selection of acute toxicity – oral endpoint
Reliable, pre-GLP study comparable to existing guidelines, performed on a read-across compound

Justification for selection of acute toxicity – inhalation endpoint
Data waiver

Justification for selection of acute toxicity – dermal endpoint
GLP guideline study performed on a read-across compound

Justification for classification or non-classification

According to the CLP Regulation (EC) No 1272/2008 and the Dangerous Substances Directive 67/548/EEC, classification for oral or dermal toxicity is required when a substance has an LD50 of up to 2000 mg/kg bw. Although relevant studies were not available on DIDS, the weight of the evidence for DIDA, DEHS and DOS do not indicate a need to classify DIDS as acutely toxic via the oral or dermal routes of exposure.

No data were available on the acute toxicity of DIDS following inhalation exposure. The weight of evidence for DEHS and DOS do not indicate a need to classify DIDS as acutely toxic via the inhalation route. Based on the low acute toxicity seen in the oral and dermal studies with DIDA, DEHS and DOS, and the low volatility of these substances (and also DIDS), classification is not warranted.