Disodium sebacate

Endpoint summary

Description of key information

After 6 months repeated exposure in feed the derived NOEL of the test substance was > 1000 mg/kg bw in rats and > 1500 mg/kg bw in rabbits.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

6 month exposure period.

Principles of method if other than guideline:

Two groups of twenty Wistar rats (ten ♂ and ten ♀) were fed for 6 months a pellet diet containing Disodium sebacate at two different dosages.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Average weight at study initiation:
♂ 174.6 ±6.3 g; 176.8 ±13.2 g
♀ 142.2 ±7.13 g; 141.7 ±7.54 g

Route of administration:

oral: feed

Vehicle:

other: pellet diet containing the test substance

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 months

Frequency of treatment:

continuously

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes

Observations and examinations performed and frequency:

BODY WEIGHT: Yes
- Time schedule for examinations: every 15 days

ORGAN: yes
- Time schedule for examination: at death or after sacrifice.
- Organs examined: no data

CLINICAL CHEMISTRY and HAEMATOLOGY: Yes
- Parameters checked: plasma, glucose, BUN, serum creatinin, SGOT, SGPT, Hb.

Sacrifice and pathology:

Surviving animals were sacrificed 181 days after the start of the treatment. Macro- and microscopic examinations of the organs were performed.

Statistics:

The disodium sebacate concentration used and percentage of mortality were respectively plotted on abscissa and ordinate of a logarithmic paper according to Miller and Tainter The best fitting straight line of the plotted points allows calculation of the LD50 which is the dosage value at 50 % of mortality. The standard error (s .e.) was estimated by this formula : (doses 84 % - 16 %) x square root of 2N, where N is the number of animals contributing to the values plotted.

Clinical signs:

no effects observed

Description (incidence and severity):

The general conditions of the animals determined by physical examination and general observation did not show qualitative toxic signs.

Mortality:

no mortality observed

Description (incidence):

No death were observed during the chronic toxicity study.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food and water consumption were normal, as confirmed by the analysis of body weight gains which were not different from those values obtained from the controls.

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Biological parameters (plasma glucose, BUN, serum creatinine, SGOT,SGPT and Hb) were similar to those of the controls .

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

No histological alterations were observed in any of the tissues and organs examined.

Details on results:

CLINICAL CHEMISTRY:

Key result

Dose descriptor:

NOEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no adverse effects reported

Key result

Critical effects observed:

no

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

yes

Remarks:

6 month exposure period, rabbit as non-rodent, 2 doses levels

GLP compliance:

not specified

Species:

rabbit

Strain:

other: New Zealand

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Average weight at study initiation:
♂: 1.33 ±0.140 and 1.36 ±0.10 kg
♀: 1.17 ±0.110 and 1.22 ±0.08 kg

Route of administration:

oral: feed

Vehicle:

other: pellet diet containing the test substance

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 months

Frequency of treatment:

continously

Dose / conc.:

750 mg/kg bw/day (nominal)

Dose / conc.:

1 500 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: every 15 days

ORGANS: yes
- Time schedule for examination: at death or after sacrifice.

CLINICAL CHEMISTRY and HAEMATOLOGY: Yes
- Parameters checked: plasma, glucose, BUN, serum creatinin, SGOT, SGPT, Hb.

Sacrifice and pathology:

Surviving animals were sacrificed 181 days after start of the exposure period. Macro- and microscopic examinations of the organs were performed.

Statistics:

The disodium sebacate concentration used and percentage of mortality were respectively plotted on abscissa and ordinate of a logarithmic paper according to Miller and Tainter. The best fitting straight line of the plotted points allows calculation of the LD50 which is the dosage value at 50% of mortality. The standard error (s.e.) was estimated by this formula : (doses 84% - 16%) x square root of 2N, where N is the number of animals contributing to the values plotted.

Clinical signs:

no effects observed

Description (incidence and severity):

The general conditions of the animals determined by physical examination and general observation did not show any qualitative toxic signs.

Mortality:

no mortality observed

Description (incidence):

No death were observed during the chronic toxicity study.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food and water consumption were normal, as confirmed by the analysis of body weight gains which were not different from thoses values obtained from the controls.

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

Biological parameters (plasma glucose, BUN, serum creatinine, SGOT, SGPT and Hb) were similar to those of the controls.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

No histological alterations were observed in any of the tissues and organs examined.

Histopathological findings: neoplastic:

not examined

Key result

Dose descriptor:

NOEL

Effect level:

>= 1 500 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: no adverse effects reported

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

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

In the published subchronic key study (Greco, 1990), 10 rats per sex and dose (and also rabbits) were orally exposed to disodium sebacate for 6 months. Doses in rats were 500 and 1000 mg/kg bw/day, in rabbits 750 and 1500 mg/kg bw/day. No death or qualitative toxic clinical signs were observed. Food and water consumption, body weight gain, histology and clinical chemistry were similar to control.

In addition, long-term toxicity data are available for the structurally related compound adipic acid.

In a 19-week study, groups of 8 to 10 male rats received sodium adipate (0, 50, 100, 200 and 400 mg/day, approximately 0, 420, 840, 1700 and 3400 mg/kg bw/day) in a protein deficient diet. After 7 weeks and (probably) at the end of the experiment, rats were killed and examined grossly. Weight gain and general behaviour were recorded and histopathology of liver, kidneys and intestine was performed. Rats fed with 400 mg/day showed reduced weight gain and lower weight after 19 weeks. No obvious symptoms were observed. Several unexplained intercurrent deaths in control and dose groups occurred, and only 5-7 animals in each group survived 19 weeks. Only at 400 mg/day slight effects were seen on liver and irritation of intestine. The NOAEL is 1700 mg/kg bw (Lang and Bartsch 1953). The study is limited in its reliability because no details are provided on the distribution of intercurrent deaths amongst the treatment/control groups and only kidneys, liver and intestine have been examined histopathologically.

In a 33-week study, groups of 13-15 male and female rats received adipic acid (neutralized with NaOH) in a standard diet (0, 400, 800 mg/day, approximately 0, 1600 and 3200 mg/kg bw/day) for 33 weeks. Weight gain and general behavior were recorded. After 8, 23 and 25 weeks, rats were killed and histopathology of liver, kidneys and intestine was performed. The administration of 400 mg/day of adipic acid had no effect on weight gain and general behavior of the animals. Ten out of 14 rats fed with 800 mg/day died during the first 4 weeks. The surviving animals showed retarded weight gain, appeared unkempt and apathetic and suffered from heavy diarrhea during the first three weeks. They recovered by the fifth week, and after 33 weeks, the weights of the high-dose rats were the same as that of the 400 mg/day group. The authors did not record the body weight of control animals at the end of the experiment, i.e. at 33 weeks. Histopathology: slight effects were seen on liver and inflammation of intestine at 400 mg/day. No NOAEL was obtained in this study (Lang and Bartsch 1953). The study is very limited in its reliability because only kidneys, liver and intestine have been examined histopathologically.

In a two-year study, groups of 20 male rats were given 0, 0.1, 1, 3 and 5 % of adipic acid in the diet (equivalent to doses of 0, approximately 75, 750, 2250 and 3750 mg/kg bw/day). Groups of 10 or 19 female rats received food containing 0 or 1 % adipic acid (0 and approx. 750 mg/kg bw/day, respectively). Body weights, food consumption and general appearance were recorded weekly throughout the experimental period. After 2 years, surviving rats were weighed, killed, and examined grossly. The brain, thyroid, lung, heart, liver, spleen, kidneys, adrenals and stomach of the animals were weighed. Microscopic examination of thyroid, lung, heart, liver, spleen, kidneys, adrenals, stomach, pancreas, bone marrow, large and small intestine uterus, ovaries and testes on a representative number of animals (no further information) was performed. The percent survival for each test group was higher than for the control group. There were no body weight differences during the test period in female and male rats treated with 0, 0.1 and 1 % adipic acid. The weight gains of the male rats receiving 3 and 5 % adipic acid were significantly less than the control groups. At necropsy there was no treatment related effect observed. Results of microscopic examination of the organs revealed no compound related effect. The NOAEL was 1 % for male and female rats (approx. 750 mg/kg bw/day) (Horn et al. 1957). The study does not fully comply with the guidelines for chronic studies because microscopic examination of 15 tissues was done on a representative number of animals for each group, females received only one concentration, the MTD was reached only for males, and the purity of adipic acid is not indicated.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. The NOAEL was greater than 1000 mg/kg bw. As a result the substance is not considered to be classified for repeated dose oral toxicity under Regulation (EC) No. 1272/2008, as amended for the ninth time in (EC) No. 2016/1179.