Pentane-2,4-dione

Endpoint summary

Description of key information

In a 14 week repeated dose inhalation toxicity study in rats 2,4-pentanedione showed substance related effects on hematological parameters, clinical and urinary chemistry at doses of 300 and 650 ppm (1,217 and 2,711 mg/m3), respectively.  Based on reversible hematological, clinical as well as urinary chemical effects in the 300 ppm group and the histopathological findings in the brains and thymus in the 650 ppm group the NOEL and LOAEL of this study is defined to be 100 ppm (417 mg/m3) and 650 ppm (2711 mg/m3), respectively. These doses can be converted to a NOAEL of 144.1 mg/kg bw/d and a LOAEL of 936.7 mg/kg bw/d assuming a respiratory minute volume of 0.24 l/min and an average weight of 250 g/rat. 
After repeated treatment of rabbits dermally, effects on thymus, spleen and lymph nodes, hemorrhage and neuronal degeneration in several sections of the brain were seen. 

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

417 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

244 mg/kg bw/day

Additional information

The toxicity of 2,4-pentanedione was investigated by the oral, dermal and inhalation route of administration, respectively.

Oral administration (Eastman Kodak 1979, not entered in the IUCLID as members of the joint submission are not owner of this report)

In the oral study, doses given by gavage to rats (5 animals per group, strain and sex not specified) were 0, 100, 500 and 1,000 mg/kg bw, respectively. Test substance was administered for 1-15 days in 1-11 applications. In the highest dose group all animals died within 1 hour after dosing. In the 500 mg/kg bw group 3/5 animals died and 2/5 were sacrificed due to poor condition after four applications. Various substance related systemic effects were observable in this dose group such as distended bladder, congested lungs, clouding of cornea, thymic necrosis, hepatocyte swelling and congestion, nephrosis, lymphadenitis of mesenteric lymph nodes and inflammation of the heart. In the lowest dose group (100 mg/kg bw) no histopathological or gross pathological changes and no differences in weight gain, organ weights, hematology, clinical chemistry or clinical signs were evident. The lowest dose of 100 mg/kg bw was applied 10 times over a 14 days period. According to the results of this study a NOAEL of 100 mg/kg bw could be derived.

Dermal administration (Ballantyne 2001, Union Carbide Corp. Bushy Run Research Center 1995)

Male and female New Zealand White rabbits were treated dermally under occluded conditions with doses of 244, 975 and 1,463 mg/kg bw, respectively, for 9 days (5 days first week and 4 days second week). Six animals/sex/group were used in the low and mid dose group, 12 animals/sex/group in the control and high dose group. Application of 1,463 mg/kg bw resulted in death of approx. 50 % of animals of either sex while in the mid dose group 1/6 males and 3/6 females died. Beside local skin irritating effects evident in all dose groups such as acanthosis, subcutaneous edema, dermatitis, hemorrhage, congestion and/or necrosis, only in the mid and high dose group systemic toxicity was observable and characterised by hypoactivity, prostration, salivation, tremors, gasping, convulsions and cyanosis as derived from blue cutis of the nasal area. Pathological examination of the mid and high dose animals identified the brain as a target with hemorrhage and neuronal degeneration in several sections of this organ. On both day 4 and 12, the thymus or thymic region, spleen and/or lymph nodes of several animals of both sexes from the mid and high dose groups were congested and/or hemorrhaged; some animals also had lymphoid depletion/necrosis. In the opinion of the authors, this observation, combined with decreased lymphocyte and eosinophil counts in the high dose group at day 4, suggested possible effects on the immune system. Since the animals from the mid and high dose group had severe skin irritation and many signs of systemic effects a definitive conclusion regarding a treatment related response to the immune system is not possible. In contrast, no substance related differences from controls were reported in the low dose group. According to the systemic effects observed 244 mg/kg bw and 975 mg/kg bw correspond to the NOAEL and LOAEL of this dermal study, respectively.

Administration by Inhalation (Dodd et al. 1986, Union Carbide Corp. Bushy 1984)

In a 14 weeks inhalation study 20 male and 20 female F344 rats per dose were exposed to 0, 100, 300 and 650 ppm (nominal concentrations, corresponding to 0; 417; 1,217 and 2,711 mg/m3) of 2,4- pentanedione vapour for 6h/d, 5d/w. 10 animals per sex and dose group were included for a four weeks recovery period and additional 10 animals were added to the control and high dose group for glutaraldehyde perfusion and subsequent examination of sciatic nerves. Test substance concentrations were monitored every 33 minutes during the daily 6 h exposure. In the 650 ppm group all females and one third of the males died during the 2nd and 6th week. In this dose group several clinical abnormalities such as lacrimation, ataxia, hypoactivity and hypothermia were observable. Surviving animals of the 650 ppm group showed decreased body weight gains, decreased absolute organ weights (brain, liver, kidney, heart, lungs), but increased relative organ weights, and minor alterations in hematology (i.e. reduced hematocrit and red blood cell counts, increased mean corpuscular hemoglobin and volume and increased lymphocytes), serum chemistry and urinary chemistry. On (histo)-pathological examination acute degeneration in the deep cerebellar and vestibular nuclei, in the corpora striata and acute lymphoid degenerations in the thymus were noteworthy lesions in dead animals of the 650 ppm exposure group. Survivors of this exposure group had gliosis and malacia in the same brain regions but no peripheral neuropathy, minimal squamous metaplasia in the nasal mucosa, and lymphocytosis. Most of the observable substance related effects in the 650 ppm group decreased in frequency and severity during the four weeks recovery period in surviving animals. In the 100 ppm group there were no substance related mortalities in either sex and on comparison with untreated controls no differences in clinical and urinary chemistry, hematology or after histopathological examination were detectable. In the 300 ppm group minor alterations in haematology, serum (serum calcium) and urine chemistry were observable in rats of both sexes while slight decreases in body weight gains (final body weight 5 % decreased) were found in females of this dose group only. All effects in this dose group were completely reversible during the four weeks recovery period and no statistically significant differences between absolute body weight means for controls and the 300 ppm group were observable. Consequently, based on the reversibility of effects in the 300 ppm group the NOEL, LOEL and LOAEL of this study is defined to be 100 ppm (417 mg/m3), 300 ppm (1,217 mg/m3) and 650 ppm (2,711 mg/m3), respectively. These doses can be converted to a NOAEL of 144.1 mg/kg bw/d, a LOEL of 432.3 mg/kg bw/d and a LOAEL of 936.7 mg/kg bw/d assuming a respiratory minute volume of 0.24 l/min (14.4 l/h) and an average weight of 250 g/rat.

An inhalation study in male and female F344 rats applied a two weeks exposure regimen with inclusion of a two days non-exposure period, i.e. a total of 9 exposures (5 days and 4 days). Nominal concentrations were 0, 200, 400 and 800 ppm (corresponding to 0; 834; 1,668 and 3,336 mg/m3) of 2,4-pentanedione vapour, respectively, and test substance concentrations were metered every 33 minutes throughout the exposure period. No substance related mortalities were found in any of the exposure groups. Body weight gains were reduced in either sex of the 800 ppm group and in males only of the 400 ppm group (2 – 4 %) while in the 200 ppm group no differences from control body weight gains were detectable. Absolute organ weights were reduced in the 800 ppm group for brain, liver, kidneys, lungs/bronchi and thymus. Relative thymus weights were decreased in the 800 ppm males and females. In the 400 ppm group thymus weights in male animals only were lowered (15 % absolute, 11 % relative) and no differences from controls were found in the lowest exposure group of 200 ppm. At 800 ppm leucocytosis in both sexes and a statistically significant increase in lymphocyte count, increased mean corpuscular hemoglobin concentration and mean corpuscular hemoglobin in male rats were detected. Hemoglobin alterations were considered not to be toxicologically significant. No differences from control animals were found for hematological parameters in the 200 and 400 ppm exposure group, respectively. On histopathological examination no gross lesions were observable in any of the exposure groups. A dosage related irritation, manifested as inflammation, congestion and superficial necrosis of the upper respiratory tract, was observed in all 2,4-pentanedione treated groups. Necrosis of the nasal mucosa was frequently observed in the 800 ppm group, occasionally in the 400 ppm group and absent in the 200 ppm group. The degree of mucosal epithelial vacuolisation and lymphocytic infiltration in the submucosa appeared exposure-related. No lesions were found in the lower respiratory tract. Based on the reduction of thymus weights in males of the 400 ppm exposure group the NOAEL and LOAEL of the study is defined to be 200 and 400 ppm, respectively, corresponding to 288.2 mg/kg bw/d and 576.4 mg/kg bw/d assuming a respiratory minute volume of 0.24 l/min (14.4 l/h) and an average weight of 250 g/rat. In conclusion after administration by the oral route substance related systemic effects were evident in thymus, liver, lungs, kidneys, bladder and lymph nodes. Beside unspecific central nervous symptoms and irritation in the nasal mucosa and both irritation and inflammation of the respiratory tract substance related systemic effects after inhalation were characterized by changes in hematology, clinical and urinary chemistry as well as organ changes in the region of the brain and thymus. On repeated dosing via the dermal route beside local skin irritating effects signs of toxicity were evident as hemorrhage and neuronal degeneration in the region of the brains as well organ changes or hemorrhage in spleen, thymus and lymph nodes. In a 14-week inhalation study the NOAEL was 417 mg/m3 and the LOAEL 2711 mg/m3. [modified from OECD SIDS Dossier]

 

Repeated dose toxicity: inhalation - systemic effects (target organ) neurologic: brain (multiple sections); respiratory: nose

Repeated dose toxicity: dermal - systemic effects (target organ) cardiovascular / hematological: thymus; neurologic: brain (multiple sections)

Justification for classification or non-classification

The results are not sufficient for classification.