Bis(pentane-2,4-dionato-O,O')zinc

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Materials and methods are well-documented.

Data source

Reference

Reference Type:

publication

Title:

2,4-Pentanedione: 9-Day and 14-Week Vapor Inhalation Studies in Fischer-344 Rats.

Author:

Dodd, D.E., Garman, R.H., Pritts, I.M., Troup, C.M., Snellings, W.M., and Ballantyne, B.

Year:

1986

Bibliographic source:

Fundam. Appl. Toxicol. 1986, 7, 329-339.

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Materials and methods are well-documented.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pentane-2,4-dione

EC Number:

204-634-0

EC Name:

Pentane-2,4-dione

Cas Number:

123-54-6

Molecular formula:

C5H8O2

IUPAC Name:

pentane-2,4-dione

Test material form:

liquid

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY, USA).
- Age at study initiation: 34 to 38 days
- Acclimation period: 2 weeks
- Housing: cage
- Light/dark: 12 h / 12 h
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Temperature: 23 to 24 °C
- Humidity: 40 to 48 %

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Chamber concentrations were analyzed approximately every 33 minutes during the exposure by a gas chromatograph equipped with a flame ionization detector.

Duration of treatment / exposure:

In the subchronic (14-week) study, rats were exposed (6 hr/day; 5 days/week) to 650, 307, 101, and 0 (control) ppm of 2,4-pentanedione vapor, using groups containing 20 males and 20 females, with halfbeing sacrificed at the end of the exposure period and the remainder kept for a 4-week postexposure recovery period.

Frequency of treatment:

In the subchronic (14-week) study, rats were exposed (6 hr/day; 5 days/week) to 650, 307, 101, and 0 (control) ppm of 2,4-pentanedione vapor, using groups containing 20 males and 20 females, with halfbeing sacrificed at the end of the exposure period and the remainder kept for a 4-week postexposure recovery period.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

650 ppm

Remarks:

14-week study

Doses / concentrations 2

Dose / conc.:

307 ppm

Remarks:

14-week study

Doses / concentrations 3

Dose / conc.:

101 ppm

Remarks:

14-week study

Doses / concentrations 4

Dose / conc.:

0 ppm

Remarks:

14-week study

No. of animals per sex per dose:

20 m, 20 f for 14-week study

Control animals:

yes, concurrent no treatment

Details on study design:

20 male and 20 female rats per group, with half being sacrificed at the end of exposure period and the remaining after a 4 week recovery period for the determination of the reversibility of observable effects, were exposed to nominal concentrations of 0, 101, 307 and 650 ppm test substance, respectively.

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: before the first exposure, preceding the second, fifih, sixth, and seventh exposures

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day of sacrifice, sacrification by methoxyflurane

Sacrifice and pathology:

Necropsy was performed, and weights of the brain, liver, kidneys, lungs, heart, thymus, and testes were determined.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Signs of toxicity in the 650-ppm group: complete or partial eyelid closure, periocular, perinasal, and perioral encrustation, wetness around the urogenital area, hypoactivity, lack of coordination, paresis, ataxia, irregular gait, hypothermia, and emaciation

Mortality:

mortality observed, treatment-related

Description (incidence):

In the 650-ppm group all females and 10 of the 30 males dies between the second and the sixth week of exposure.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights of the 650-ppm males were reduced throughout the 14-week exposure period, but there was considerable weight increase during the 4-week recovery period. However, final weights were still statistically significantly below those for the control males. Before death, body weights of the female rats of the 650-ppm group were considerably reduced.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

no effects observed

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

For the 650-ppm males and the 307-ppm females, the respective mean erythrocyte counts were 11 and 4% below control values. The decrease in red blood cell count was accompanied with slight increases in MCV and MCH and a mild decrease in hematocrit. The white blood cell count was increased in the 650-ppm male rats, due to an increase in lymphocytes.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Clinical chemistry detenninations which deviated from controls were an increase in urea nitrogen and alkaline phosphatase activity, and a decrease in creatinine, calcium, and aspartate aminotransferase (AST) activity in the 650-ppm males. Serum calcium was also decreased in males and females of the 307-ppm group.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Urinalysis showed minimal alterations in males, which included low pH (6.0 vs 7.0 in controls) at 650 ppm, and slightly increased bilirubin and urobilinogen at 650 and 307 ppm.

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

After 14-weeks of 2,4-PD vapor exposure,a statistically significant decrease in most absolute organ weights was observed for the 650-ppm males, but organ weights relative to body weight had increased.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

The brain lesions observed in 7 of 10 male and 18 of 20 female rats that died during the exposure regimen took the form of acute degenerative changes in the vestibular nuclei, deep cerebellar nuclei, and corpora striata.

Neuropathological findings:

effects observed, treatment-related

Description (incidence and severity):

The most noticeable feature in this study was the presence of degenerative changes in the deep cerebellar and vestibular nuclei and the corpora striata in animals that died following repeated exposures to 650 ppm of 2,4-PD vapor.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The most noticeable feature in this study was the presence of degenerative changes in the deep cerebellar and vestibular nuclei and the corpora striata in animals that died following repeated exposures to 650 ppm of 2,4-PD vapor.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Effect levels

1

Key result

Dose descriptor:

NOEC

Effect level:

101 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effect observed

2

Key result

Dose descriptor:

LOEC

Effect level:

307 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

haematology

histopathology: non-neoplastic

urinalysis

3

Key result

Dose descriptor:

LOAEC

Effect level:

650 ppm (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

gross pathology

haematology

histopathology: non-neoplastic

mortality

urinalysis

Target system / organ toxicity

1

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

307 ppm (analytical)

System:

respiratory system: lower respiratory tract

Organ:

lungs

Treatment related:

yes

2

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

650 ppm (analytical)

System:

other: several organs

Organ:

brain

heart

kidney

liver

lungs

testes

Treatment related:

yes

Applicant's summary and conclusion

Conclusions:

The most noteworthy systemics observations in the 14-week inhalation study were the brain and thymus lesions in animals that died due to inhalation of 650 ppm of 2,4-pentanedione. Mild squamous metaplasia in the nasal mucosa was observed in the 650 ppm rats. Perhaps inflammation in the nasal mucosa is a transient response at 2,4-pentanedione concentrations of 307 ppm and higher. Rats exposed to 100 ppm of 2,4-pentanedione for 14 weeks showed no signs of irritancy or toxicity (nominal concentrations, corresponding to 413; 1,255 and 2,657 mg/m3)
It can be stated that for the inhalative repeated dose toxicity for 2,4-pentanedione for an axposure duration of 14 weeks the NOEC is 101 ppm, the LOEC is 307 ppm and the LOAEC is 650 ppm, respectively, for both male and female.