Acetone oxime

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose 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: The analogue methyl isobutyl ketoxime, which shares the same functional groups with acetone oxime, also has comparable values for the relevant molecular properties and they are toxicologically equivalent.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: Read-across

Title:

Unnamed

Year:

2012

Materials and methods

Principles of method if other than guideline:

Read-across approach from experimental results (test method according to OECD Guideline 408, GLP study) on the analogue substance MIBKO

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-methylpentan-2-one oxime

EC Number:

203-298-2

EC Name:

4-methylpentan-2-one oxime

Cas Number:

105-44-2

IUPAC Name:

4-methylpentan-2-one oxime

Details on test material:

- Name of test material (as cited in study report): Methyl isobutil ketoxime (MIBKO)
- Molecular formula (if other than submission substance): C6H13NO
- Molecular weight (if other than submission substance): 115.1735
- Smiles notation (if other than submission substance): CC(C)CC(\C)=N\O
- InChl (if other than submission substance): 1/C6H13NO/c1-5(2)4-6(3)7-8/h5,8H,4H2,1-3H3/b7-6+
- Structural formula attached as image file (if other than submission substance): see Fig.

Results and discussion

Results of examinations

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):

no effects observed

Food efficiency:

no effects observed

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

Based on the experimental results obtained in the analogue substance MIBKO, where the NOAEL for 90 days oral exposure in male and female rats was determined to be 15 mg/kg bw/day based on the effects on red blood cells, resulting in associated changes in the spleen), the read-across approach was applied and the NOAEL (90 days, oral) for acetone oxime in rats was estimated to be 9.52 mg/kg bw/day in rats.

Effect levels

Dose descriptor:

NOEL

Effect level:

9.52 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: (Read-across approach from an analogue substance) (Basis for effect: effects on red blood cells, resulting in associated changes in the spleen)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

As indicated in the European Chemical Agency Practical Guide 6 “How to report read –across and categories”, the structural grouping was realized using “OECD QSAR APPLICATION TOOL BOX” version 2.1.2. Presented results show that both substances have common (eco)toxicological behavior (attachment).

Table 1: Data Matrix, Analogue Approach:

CAS Number			Source chemical 105-44-1	Target chemical 127-06-0
CHEMICAL NAME			MIBKO Methyl isobutyl ketoxime	Acetone oxime
PHYSICO-CHEMICAL DATA
Melting/Freezing point			Calculated data: Melting point: -45.56 ºC (EPI-Suite, MPBWIN v1.43).	Measured data (Handbook): 60 ºC
Boiling Point			Calculated data: 186.67ºC (EPI-Suite, MPBWIN v1.43).	Measured data (Handbook): 134.8 ºC
Relative density			Company data (density): 0.88 g/mL	Measured data (Handbook): 0.9113 at 62 ºC
Vapour Pressure			Calculated data (EPI-Suite, US EPA v4.1): 21.8 Pa at 25 ºC	Calculated data (EPI-Suite, US EPA v4.1): 164 Pa at 25 ºC
Partition Coefficient (log Kow)			Measured data: 1.53 (OECD 107, GLP)	Measured data (Jaros F et al., 2007): 0.20 Calculated data (EPI-Suite, US EPA v4.1): 1.2
Water solubility			Calculated data: 626.3 mg/L at 25 ºC (EPI-Suite, WSKO v1.42).	Measured data (Rosene MR et al., 1976): 334 g/L
ENVIRONMENTAL FATE and PATHWAY
Aerobic Biodegradation			Experimental data: Inherently biodegradable. OECD 302B, GLP Calculated data (EPI-Suite, US EPA v4.1): Not readily biodegradable	Experimental data: Not readily biodegradable OECD 301D, GLP study Calculated data (EPI-Suite, US EPA v4.1): Not readily biodegradable
ENVIRONMENTAL TOXICITY
Acute Toxicity to Fish			No data.	Experimental data: LC50 (96 h) = 558 mg/L (Pimephales promelas) (basis for effect: mortality) (Geiger et al. 1990; Method similar to OECD 203).
Acute Toxicity to Aquatic Invertebrates			Experimental data: EC50 (48h) > 93 mg/L (Daphnia magna) (basis for effect: mobility) (OECD 202, GLP study)	Experimental data: EC50 (48h) = 544.34 mg/L (Daphnia magna) (basis for effect: mobility) (OECD 202, GLP study)
Toxicity to Aquatic Plants			No data.	Experimental data: EC50 (72h) = 252.92 mg/L NOEC (72h) = 50 mg/L (Pseudokirchneriella subpicata) (Basis for effect: growth rate) (OECD 201, GLP study)
MAMMALIAN TOXICITY
Acute Toxicity: Oral			Experimental data: LD50 > 1.5 ml/kg bw (> 1320 mg/kg bw, rabbits, male/female) (Equivalent to OECD 401, GLP study)	Read-across from EAC3: LD50 > 2005.13 mg/kg bw (rat, female) (OECD 423, GLP study). Supporting data (Sax’s Handbook): LD0 > 500 mg/kg bw (rats).
Acute Toxicity: Inhalation			No data.	No data.
Acute Toxicity: Dermal			Experimental data: LD50 > 3 ml/kg bw (> 2640 mg/kg bw, rabbits, male/female) (Equivalent to OECD 402, GLP study)	Experimental data: LD50 > 2000 mg/kg bw/day (rat, male/female) (OECD 402, GLP study)
Skin irritation			Experimental data: PDI = 3.6 (rabbits). According to CLP scoring system: Non-irritant (rabbits). (PDI, GLP study)	Experimental data: According to CLP scoring system: Non-irritant (rabbits) (PDI, equivalent to OECD 404, GLP study)
Eye irritation			Experimental data: According to CLP scoring system: Irritant, Category 2 (rabbits) (Acute eye irritation, GLP study)	Experimental data: According to CLP scoring system: Eye damage, Category 1 (rabbits) (Acute eye irritation, equivalent to OECD 405, GLP study)
Skin Sensitization			Experimental data: Non skin sensitizer (guinea pig, female) (GPMT, Equivalent to OECD 406, GLP study)	Experimental data: Not skin sensitizer (mice, female) (Local Lymph Node Assay, OECD 429, GLP study).
Repeated Dose Toxicity			Experimental data: 90day-NOAEL = 15 mg/kg bw/day (rats, male/female) (effects on red blood cells, resulting in associated changes in the spleen) (OECD 408, GLP study)	Read-across from Wasox-VMAC2: 28day-NOEL = 12.82 mg/kg bw/day (rats, male/female) (basis for effect: damage to peripheral erythrocytes without an impairment of the blood cell production in the bone marrow). (OECD 407, GLP study) Read-across from Wasox-MMAC2: 28day-NOEL = 13.26 mg/kg bw/day (rats, male/female) (basis for effect: damages to mature erythrocytes in the peripheral blood, with a parallel marked increase production of your erythrocytes by the presence of hematopoiesis in the spleen). (OECD 407, GLP study) Read-across from MIBKO: 90day-NOAEL = 9.52 mg/kg bw/day (rats, male/female) (effects on red blood cells, resulting in associated changes in the spleen) (OECD 408, GLP study)
Genetic Toxicity in vitro		Gene mutation in bacteria	Experimental data: Negative with and without metabolic activation inSalmonella typhimuriumTA98, TA100, TA1535, TA1537, TA1538. (Equivalent to OECD 471, GLP study)	Experimental data: Negative with and without metabolic activation inSalmonella typhimuriumTA100, TA 97, TA 1535, and TA 98. (Equivalent to OECD 471, GLP study).   Supporting study: Negative with and without metabolic activation inSalmonella typhimuriumTA98, TA100, TA2637 andE. coliWP2 uvrA/pKM101. (Similar to OECD 471, Araki A et al., 1986)
		Chromosomal aberration	No data	Read-across from Wasox-VMAC2: Positive without metabolic activation with 20h treatment; negative with and without metabolic activation with 3 h treatment, in human lymphocytes. (OECD 473, GLP study) Read-across from Wasox-MMAC2: Negative with and without metabolic activation in human lymphocytes. (OECD 473, GLP study)
		Mammalian gene mutation	Experimental data: Negative without metabolic activation and equivocal with metabolic activation at the TK +/- locus in L5178Y cells. (Equivalent to 476, GLP study)	Experimental data: Negative with and without metabolic activation at the TK +/- locus in L5178Y cells. (OECD 476, GLP study).   Supporting studies: Not genotoxic in V79 chinese hamster cells as mutations to 6 -thioguanine (TG). (Similar to OECD 479, Haas-Jobelius M et al., 1991) Acetone oxime did not induce DNA repair synthesis (indicator of genotoxic) in rat hepatocytes (Haas-Jobelius et al. 1991), V79 cells (Haas-Jobelius et al. 1991; Andrae et al. 1999 and Kreis et al. 2000) and OSV cells (Kreis et al. 1998). (Similar to OECD 482).
Genetic Toxicity in vivo			No data.	Read-across from Wasox-VMAC2: Negative, the test substance did not produce relevant increases of the numbers of micronuclei in polychromatic erythrocytes. (Mammalian Erythrocyte Micronucleus Test, OECD Guideline 474, GLP Study).
Reproductive Toxicity	Toxicity to reproduction		Experimental study: NOAEL (parental toxicity) = 30 mg/kg bw/day (male/female, rats) (based on histological effects on the spleen) NOAEL (P, reproductive toxicity) > 100 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) NOAEL (F1 toxicity toxicity) > 100 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) NOAEL (F1, developmental and sexual maturation) > 100 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) (OECD 415, GLP).   Supporting study: In the 90d RDT study, no effects were observed in the reproductive organs or tissues up to the highest dose tested.	Read-across from MIBKO: NOAEL (parental toxicity) = 19.04 mg/kg bw/day (male/female, rats) (based on histological effects on the spleen) NOAEL (P, reproductive toxicity) > 63.47 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) NOAEL (F1 toxicity toxicity) > 63.47 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) NOAEL (F1, developmental and sexual maturation) > 63.47 mg/kg bw/day (male/female, rats) (no effects observed at highest dose) (OECD 415, GLP).   Supporting study: Read-across from MIBKO: In the 90d RDT study, no effects were observed in the reproductive organs or tissues up to the highest dose tested. Read-across from Wasox-VMAC2: In the 28d RDT study, no effects were observed in the reproductive organs or tissues up to the highest dose tested Read-across from Wasox-MMAC2: In the 28d RDT study, no effects were observed in the reproductive organs or tissues up to the highest dose tested
	Developmental toxicity		No data.	No data.

Applicant's summary and conclusion

Conclusions:

Based on the read-across approach from experimental data on analogue substance MIBKO (OECD Guideline 408, GLP study), the NOAEL of acetone oxime for 90 days oral exposure in rats was determined to be 9.52 mg/kg bw/day.

Executive summary:

A 90 days oral repeated dose toxicity test was performed on the analogue substance MIBKO according to OECD Guideline 407 and GLP. The NOAEL was determined to be 15 mg/kg bw/day in rats based on the effects on red blood cells, resulting in associated changes in the spleen were observed at 50 mg/kg bw/day. Based on these results, the read-across was applied and the NOAEL of acetone oxime for 90 days oral exposure in rats was estimated to be 9.52 mg/kg bw/day under the test conditions (effects at an estimated concentration of 31.73 mg/kg bw/day).