Nonan-4-olide

Endpoint summary

Description of key information

- Acute toxicity: oral: Males LD50 = 6600 mg/kg bw (eq. OECD 401, K, rel.2)
- Acute toxicity: dermal: LD50 > 50000 mg/kg bw/d (WoE)
- Acute toxicity: inhalation: waiving

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1972

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted similarly to OECD Guideline 401 with minor deviations: certificate of analysis not included, few details on test animals and environmental conditions, no data on number of animals showing signs of toxicity and pathological findings.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no data on age and source of animals; no data on housing and environmental conditions, number of animals showing signs of toxicity and pathological findings

Principles of method if other than guideline:

Not applicable

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200-250 g
- Fasting period before study (minimum): 16 h
- Food and water: ad libitum

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

No data

Doses:

4000, 5000, 6250, 7800 and 9700 mg/kg bw

No. of animals per sex per dose:

10 males/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Observations for mortality were made at 1 and 6 h after dosing and daily thereafter for 14 days.
- Necropsy of survivors performed: Yes

Statistics:

None

Preliminary study:

None

Sex:

male

Dose descriptor:

LD50

Effect level:

6 600 mg/kg bw

Based on:

test mat.

95% CL:

5 800 - 7 400

Mortality:

- Deaths occurred overnight to two days following administration of the test material.
- Mortalities in rats were 0, 30, 40, 80 and 100 % at 4000, 5000, 6250, 7800 and 9700 mg/kg bw, respectively.

Clinical signs:

other: Piloerection and lethargy

Gross pathology:

No data

Other findings:

None

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The oral LD50 of γ-Nonalactone is higher than 5000 mg/kg bw in male rats therefore it is not classified according to the Directive 67/548/EEC and of the Regulation (EC) No. 1272/2008 (CLP).

Executive summary:

In an acute oral toxicity study performed similarly to OECD test Guideline No. 401, groups of Wistar rats (10 males/dose) were given a single oral dose of γ-Nonalactone at 4000, 5000, 6250, 7800 or 9700 mg/kg bw. Animals were then observed for mortality at 1 and 6 h after dosing and daily thereafter for 14 days. Gross necropsies were performed on all survivors.

Mortalities in rats were 0, 30, 40, 80 and 100 % at 4000, 5000, 6250, 7800 and 9700 mg/kg bw, respectively. Clinical signs noted were piloerection and lethargy.

Oral LD50 Males = 6600 mg/kg bw (5800-7400).

The oral LD50 of γ-Nonalactone is higher than 5000 mg/kg bw in male rats therefore it is not classified according to the Directive 67/548/EEC and the Regulation (EC) No. 1272 /2008 (CLP). This study is considered as acceptable and satisfies the requirement for acute oral toxicity endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

6 600 mg/kg bw

Quality of whole database:

The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies.

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

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1976

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment. Substance purity is not mentioned.

Reason / purpose for cross-reference:

reference to same study

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

Standard acute method (limit test)

GLP compliance:

no

Remarks:

pre-GLP

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

no details

Type of coverage:

not specified

Vehicle:

not specified

Details on dermal exposure:

no details

Duration of exposure:

Single treatment

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

Total animals: 4

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Statistics:

none

Preliminary study:

not applicable

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

One animal died on Day 1

Clinical signs:

other: No data

Gross pathology:

No data

Other findings:

Erythema lasted for 24 h

None

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The dermal LD50 of γ-Nonalactone is higher than 5000 mg/kg bw in rabbits therefore it is not classified according to the Directive 67/548/EEC and the Regulation (EC) No. 1272/2008 (CLP).

Executive summary:

In an acute dermal toxicity (limit test) study, a group of 4 rabbits were administered a single dermal dose of γ-Nonalactone at 5000 mg/kg bw. Animals were then observed for 14 days.

During the observation period, one animal died on Day 1. Erythema lasted for 24 h.

Dermal LD50 > 5000 mg/kg bw.

The dermal LD50 of γ-Nonalactone is higher than 5000 mg/kg bw in rabbits therefore it is not classified according to the Directive 67/548/EEC and the Regulation (EC) No. 1272 /2008 (CLP).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

50 000

Quality of whole database:

The available information as a whole meets the tonnage driven data requirement of REACH. Moreover, reliability and consistency are observed across the different studies.

Additional information

Acute toxicity: oral

A key study was identified (Moreno, 1972, rel.2). In this acute oral toxicity study performed similarly to OECD test Guideline No. 401, male rats were given a single oral dose of γ-Nonalactone at 4000, 5000, 6250, 7800 or 9700 mg/kg bw. The oral LD50 (Males) was determined to be 6600 mg/kg bw. Clinical signs noted were piloerection and lethargy.

This result is supported by the study of Jenner (1964, rel.4) which estimated a combined rat LD50 of 9780 mg/kg bw (7480-12810) and a combined guinea-pig LD50 of 3440 mg/kg bw. A rat LD50 higher than 5000 mg/kg bw was also found by Levenstein (1976, rel.4).

By comparison, the combined LD50 of γ-Caprolactone, the “worst-case” substance used in the read-across approach (see §”Toxicokinetics” for read-across justification), was higher than 2000 mg/kg bw in a limit test performed similarly to the OECD test guideline No. 420 (Sunaga, 2002, rel. 2).

Acute toxicity: dermal

Two limit acute dermal toxicity studies were conducted on γ-Nonalactone, both showing LD50 values higher than 5000 mg/kg bw.

The first one (Moreno, 1972, rel.3) was conducted under non-standard conditions(i.e. abraded skin and occlusive dressing), and animals were observed only for 7 days.

The second one (Levenstein, 1976) was poorly documented but animals were observed for 14 days.

Therefore a weight of evidence approach was built using these two studies to substantiate the absence of acute dermal toxicity of γ-Nonalactone. Indeed, although several deviations were found in the first study, worst-case conditions were applied and only one animal died on Day 1. In the same way, although poorly described, observation period duration of the second study was available, confirming the results observed with a shortened observation period.

The dermal LD50 of γ-Nonalactone was therefore considered to be higher than 5000 mg/kg bw.

Acute toxicity: inhalation

No data was available. However, in accordance with column 2 of REACH Annex VIII (§8.5), the acute toxicity by inhalation does not need to be conducted since the acute toxicity study is already provided for both the oral and the dermal route. Moreover, γ-Nonalactone has a low vapor pressure (1.9 Pa at 25 °C) and therefore the potential for the generation of an inhalable form is low.

Justification for selection of acute toxicity – oral endpoint
Key study conducted on γ-Nonalactone (eq. OECD 401, K, rel.2).

Justification for selection of acute toxicity – inhalation endpoint
No data was available. However, in accordance with column 2 of REACH Annex VIII (§8.5), the acute toxicity by inhalation does not need to be conducted since the acute toxicity study is already provided for both the oral and the dermal route.

Justification for selection of acute toxicity – dermal endpoint
Weight of evidence approach with two studies conducted on γ-Nonalactone.

Justification for classification or non-classification

Harmonized classification:

γ-Nonalactone has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP2.

Self classification:

Based on the available data no additional self-classification is proposed regarding:

- both acute oral and dermal toxicity and,

- specific target organ toxicity - single exposure

according to the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EEC. No data were available by inhalation.