Cyclopentanone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

61 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Modified dose descriptor starting point:

NOAEC

Explanation for the modification of the dose descriptor starting point:

Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for workers: (NOAEC rabbit = 3040 mg/m3)

 

NAEC_corrected= NOAEC_{inhalatory rabbit}× 6h/8h× 6.7 m3/10 m3

NAEC_corrected= 388.43 ppm (1527.6 mg/m3) 

 

6.7 m3/person: respiratory volume without activity for general population (8h exposure);

10 m3/person: respiratory volume light activity for workers (8h exposure)

6h:time exposure of rabbits in Treon study

8h:time exposure of workers

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

2

Justification:

ECHA R8 guidance default value (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default value for workers

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

211 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

LOAEC

Modified dose descriptor starting point:

LOAEC

Explanation for the modification of the dose descriptor starting point:

Conversion of an inhalatory rats LOAEC into a corrected inhalatory LAEC for workers:

 

LAECcorrected= LOAEC inhalatory, rat × 6.7 m3/10 m3

LAECcorrected= 3149 mg/m3 

 

6.7 m3/person: respiratory volume without activity for general population (8h exposure)

10 m3/person: respiratory volume light activity for workers (8h exposure)

AF for dose response relationship:

3

Justification:

LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default value for workers

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

150 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

5

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

1

Justification:

Not needed for local effect such as skin or eye irritation

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed for local effect such as skin or eye irritation

AF for other interspecies differences:

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default value for workers

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Modified dose descriptor starting point:

NOAEL

Value:

723 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Corrected dermal NAEL = oral NOAEL x 1 = 723 mg/kg bw/day.

Since no specific data are available on cyclopentanone and on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e factor 1) was used when performing oral-to-dermal extrapolation.

 

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

2

Justification:

ECHA R8 guidance default value (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default value for workers

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is needed.

AF for dose response relationship:

1

Justification:

Not needed

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

5

Justification:

ECHA R8 guidance default value for workers

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

1. Acute / short-term exposure - systemic effects

Cutaneous route

In the study retained as a key study for this endpoint (Nunziata A, 1999 - reliability 2), groups of Sprague-Dawley male and female rats (3/group) were dermally exposed to cyclopentanone (99.8% purity) undiluted at doses of 400 and 2000 mg/kg bw/day. Animals then were observed for 14 days. At the lower dose (400 mg/kg), no clinical signs were observed. At the highest dose (2000 mg/kg/day), piloerection and staining of skin/fur were observed during period of exposure and disappeared within 24 hours. Based on this study a NOAEL of 400 mg/kg/day can be identified for piloerection and staining of skin/fur in rats.

A DNEL can be derived from this study for effects induced after acute dermal exposure.

NOAEL rat = 400 mg/kg/day (the time of exposure was not precise in the study).

Assessment factor (AF):

- Intraspecies factor: 5 (default value for worker variability as recommended in the guidance R8)

- Interspecies factor: 4 x 2.5 (default assessment factor for interspecies variability - Rats as recommended in the guidance R8)

Overall assessment factor (OAF) = 50

DNEL= NOAEL / OAF = 400 mg/kg/day / 50 = 8 mg/kg/day

A DNEL of 8 mg/kg/day is proposed for dermal acute exposure based on piloerection and staining of skin/fur in rats.

Inhalation

One study by inhalation was retained as a key study (ESSO, 1965). In this study, groups of Wistar rats (10 males/group) were exposed by inhalation (whole body) to cyclopentanone (purity unknown) for 4 hours at concentrations of 4.7, 12, 15, 17.8, 19.5 mg/L. Animals were observed for 14 days. No mortality were observed in male rats at 4.7, 12, 15 mg/L of cyclopentanone. Three and 4 rats died respectively at 17.8 and 19.5 mg/L. During exposure, dyspnea, depression and decreased activity were observed at all the doses. Moreover, ataxia and prostration were also noted at the two highest levels. These signs disappeared within 48 hours. Based on this study, a LOAEC of 4.7 mg/L (4700 mg/m3) was identified for dyspnea, depression and decreased activity in rats.

LOAEC rat = 4700 mg/m3 (for 4 hours of exposure)

Modification of the starting point: Conversion of an inhalatory rats LOAEC into a corrected inhalatory LAEC for workers:

 

LAEC_corrected= LOAEC _{inhalatory, rat} × 6.7 m³/10 m³

LAEC_corrected= 3149 mg/m3 

 

6.7 m3/person: respiratory volume without activity for general population (8h exposure)

10 m3/person: respiratory volume light activity for workers (8h exposure)

 

Assessment factor (AF):

- For LAEC to NAEC: 3

- Intraspecies factor: 5 (default value for worker variability as recommended in the R8 guidance)

- Interspecies factor: 2.5 (default value for toxicodynamic differences as recommended in the R8 guidance)

Overall assessment factor (OAF) = 37.5

DNEL= LAEC human/OAF = 3149 mg/m3 / 37.5= 84 mg/m3 (for 4 hours of exposure)

The modified Haber's law was used to propose a DNEL by inhalation for 15 minutes : Cⁿx t = k       

C: concentration ; n: regression coefficient ; t: exposure time ; k : constant

A default value of n=3 was applied for extrapolating from longer to shorter exposure durations.

DNEL= 211 mg/m3 (for 15 minutes of exposure)

 

A DNEL of 211 mg/m3 is proposed for inhalation acute exposure based on dyspnea, depression and decreased activity in rats.

 

2. Acute / short-term exposure - local effects

 

Irritation and corrosion

- Skin irritation

Cyclopentanone is officially classified as irritant for skin according to CLP Regulation (EC) n°1272/2008. In a primary dermal irritation study (Guillot JP, 1982 - reliability 2) retained as a key study, New Zealand White rabbits (6/group) were dermally exposed to 0.5 mL of cyclopentanone (purity unknown) undiluted for 4 hours to the flanks. Test sites were covered with an occlusive dressing for 4 hours. Animals then were observed for 3 days. Irritation was scored by the method of Draize. In this study, cyclopentanone is slightly irritating to the skin in rabbit. Based on this study, no DNEL can be calculated for skin irritation because only one dose was tested.

However, a qualitative approach to risk assessment and management is therefore required because cyclopentanone is classified as irritant for skin (chapter R8, appendix R8 -9).  

- Eye irritation

Cyclopentanone is officially classified as irritant for eyes according to Regulation (EC) n°1272/2008. Two studies with reliability 2 according to Klimisch were available, and showed that Cyclopentanone was irritating to the eyes. In the key study, a primary eye irritation study (Guillot, 1982 - reliability 2), 0.1 mL of undiluted cyclopentanone (purity unknown) was instilled into the conjunctival sac of the eye of New Zealand White rabbits (6/group). The eyes were not rinsed or rinsed after 4 or 30 sec. Animals then were observed for at least 7 days. No DNEL can be derived from this study because only one dose was tested. Therefore, a qualitative approach to risk assessment and management is therefore required because cyclopentanone is classified as irritant for eyes (chapter R8, appendix R8 -9).  

- Respiratory tract irritation No data are available.

 

Sensitizer

For this endpoint, two studies are available and had the reliability 2 according to Klimisch rating. In these studies Cyclopentanone was not sensitizing in maximization test on guinea pig.

In the key study, a dermal sensitization study (Nunziata A, 1999) with cyclopentanone (99.8% purity) in PEG 200, Dunkin-Hartley guinea pigs were tested using the method of maximization. In an attempt to induce sensitisation, test animals were intradermally injected with an emulsion of Freund's complete adjuvant and the test substance in both the selected vehicle and an emulsion of Freund's complete adjuvant. One week later this was boosted by topical application of the test substance over the injection sites which had been pre-treated with sodium lauryl sulphate to promote an irritant reaction. Control group animals were treated in the same manner but the selected vehicle was used in place of the test substance. Two weeks after the second induction stage, all animals were challenged by topical application of both the vehicle and the test substance. Irritation to the test substance was noted and challenge was repeated 1 week later using the test substance at a lower concentration.

The results indicate that the test substance does not elicit a sensitisation response in the guinea pig, there being no evidence of reaction at challenge following a period of induction exposure to the substance.

Therefore, since cyclopentanone is not a skin sensitizer it is not relevant to derive a DNEL for this endpoint.

 

3. Long-term exposure - systemic effects

Cutaneous route

No data are available for systemic effects induced by cyclopentanone dermal exposure. However, since some studies performed on cyclohexanone showed that this substance may be absorbed by the skin, it's appears relevant to derive a DNEL for cyclopentanone and for long term exposure by cutaneous route.

A route to route extrapolation was realised (oral-to-dermal) based on an oral long term study performed on cyclohexanone (Lijinsky W, 1986).

In this study, cyclohexanone (96% purity) was administered daily during 25 weeks to F344 rats in water at dose levels of 0, 190, 400, 800, 1600, 3300, 4700, 6500 ppm (equiv. to ca. 29, 61, 122, 246, 508, 723, 1000 mg/kg bw/day). Cyclohexanone did not affect survival. The body weight gain was 10% lower than controls in both male and female rats at the highest dose (1000 mg/kg bw/day). The NOAEL was 4700 ppm (723 mg/kg bw/day) and the LOAEL at 6500 ppm (1000 mg/kg bw/day) for body weight gain reduction in rats. NOAEL rat (oral) = 723 mg/kg bw/day

Modification of the starting point

Corrected dermal NAEL = oral NOAEL x 1 = 723 mg/kg bw/day.

Since no specific data are available on cyclopentanone and on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e factor 1) was used when performing oral-to-dermal extrapolation.

Assessment factor (AF):

- Interspecies factor: 4 x 2.5(default assessment factor for interspecies variability - Rats as recommended in R8 guidance)

- Intraspecies factor: 5(default value for worker variability as recommended in R8 guidance)

- Time duration: 2 (default value for sub-chronic to chronic exposure as recommended in R8 guidance).

- Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 100

 

DNEL= NAEL /OAF = 723 mg/kg/day /100

= 7 mg/kg/day (for chronic exposure by cutaneous route)

A DNEL of 7 mg/kg/day is proposed for dermal long term exposure based on boby weight gain reduction in rats.

Inhalation

Two studies are available for cyclopentanone inhalation exposure. However, the reliability of these studies is 3 in Klimisch rating. Therefore it's appears no relevant to derive a DNEL based on these studies. A study available on cyclohexanone after inhalation exposure is available and was selected as a key study (Treon, 1949a) (Read-across between cyclopentanone and cyclohexanone). Based on this study performed on cyclohexanone, a DNEL can be derived for long term inhalation exposure.

In Treon, 1949a study, cyclohexanone (purity unknown) was administered to rabbits (4/group), by exposure at concentrations of 0.75,1.21,3.04,5.56 mg/L for 6 hours per day, 5 days/week for a total of 10 weeks. At the highest concentration (1414 ppm or 5560 mg/m3), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure. A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm (1210 mg/m3) and 773 ppm (3040 mg/m3) while slight salivation was observed under the latter conditions (773 ppm). Based on this study, a NOAEC of 190 ppm (750 mg/m3) and a LOAEC of 309 ppm (1210 mg/m3) can be identified for local effects (ocular irritation). For systemic effects (lethargy, distension of the ear veins) a NOAEC of 773 ppm (3040 mg/m3) and a LOAEC of 1414 ppm (5560 mg/m3) can be identified. Based on these latest values, a DNEL for systemic effect can be derived for cyclopentanone.

NOAEC rabbits = 773 ppm (3040 mg/m3) (for sub-chronic exposure and systemic effects).

Modification of the starting point: Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for workers:

 

NAEC_corrected= NOAEC_{inhalatory rabbit} × 6h/8h× 6.7 m3/10 m3

NAEC_corrected= 388.43 ppm (1527.6 mg/m3) 

 

6.7 m3/person: respiratory volume without activity for general population (8h exposure);

10 m3/person: respiratory volume light activity for workers (8h exposure)

6h:time exposure of rabbits in Treon study

8h:time exposure of workers

 

Assessment factor (AF):

- Interspecies factor: 2.5 (default factor for toxicodynamic differences as recommended in the R8 guidance)

- Intraspecies factor: 5 (default value for worker variability as recommended in R8 guidance)

- Time duration: 2 (default value for sub-chronic to chronic exposure as recommended in R8 guidance).

- Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 25

 

 

DNEL= NAEC corrected for human/OAF = 388.43 ppm (1527.6 mg/m3) / 25

= 15.5 ppm or 61 mg/m3 (for chronic exposure by inhalation)

  

A DNEL of 61 mg/m3 is proposed for systemic effects after chronic exposure by inhalation.

Carcinogenicity

No study is available on cyclopentanone. However, a read-across was made with cyclohexanone.

One study performed on cyclohexanone was selected as a key study (Lijinsky, 1986). In this study rats and mice were exposed by drinking water at different concentrations of cyclopentanone during 104 weeks. No carcinogenic effect was observed in rats neither in mice. By analogy with cyclohexanone, cyclopentanone is not considered as carcinogenic.

Since cyclopentanone is not considered as carcinogenic (by read-across with cyclohexanone), no DNEL or DMEL should be derived for this endpoint.

 

 

Reprotoxicity

Three studies are available, one performed on cyclopentanone and cyclohexanone and two on cyclohexanone. Only one study showed fertility effects on the second generation after cyclohexanone exposure at the highest doses (14000 ppm). At this dose, general toxic effects are also observed. The other studies showed that cyclopentanone and cyclohexanone have no impact on mice and rats fertility or showed that the depressions in male fertility were reversible. Tacking into account all the data, cyclopentanone is not considered as toxic for the fertility.

One developmental study performed on cyclopentanone was selected as a key study. In this study, cyclopentanone administrated in rats by gavage from days 6 through 15 of gestation at 50 or 300 mg/kg bw/day induce no developmental effects. Four other studies were performed on cyclohexanone. In all these studies no maternal or embryotoxic effects were observed at the tested level.

Since, cyclopentanone is not considered as reprotoxic, no DNEL should be derived for this endpoint.

 

 

4. Long-term exposure - local effects

Cutaneous route

No data available.

 

Inhalation

Two studies are available for cyclopentanone inhalation exposure. However, the reliability of these studies is3 inKlimisch rating. Therefore it's appears no relevant to derived a DNEL based on these studies. A study available on cyclohexanone after inhalation exposure is available and was selected as a key study (Treon, 1949a). Based on this study performed on cyclohexanone, a DNEL can be derived for long term inhalation exposure and for local effects.

In Treon, 1949a study, cyclohexanone (purity unknown) was administered to rabbits (4/group), by exposure at concentrations of 0.75,1.21,3.04,5.56mg/L for 6 hours per day, 5 days/week for a total of 10 weeks. At the highest concentration (1414 ppm or 5560 mg/m3), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure. A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm (1210 mg/m3) and 773 ppm (3040 mg/m3) while slight salivation was observed under the latter conditions (773 ppm). Based on this study, a NOAEC of 190 ppm (750 mg/m3) and a LOAEC of 309 ppm (1210 mg/m3) can be identified for local effects (ocular irritation). For systemic effects (lethargy, distension of the ear veins) a NOAEC of 773 ppm (3040 mg/m3) and a LOAEC of 1414 ppm (5560 mg/m3) can be identified. Therefore, based on this study a DNEL can be derived for local effects (ocular irritation).

NOAEC= 190 ppm (750 mg/m3) for ocular irritation.

Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for workers: no conversion is necessary since the effect is local (ocular effect). Indeed, such effect is mainly driven by concentration exposure and is not time-dependent.

 

Assessment factor (AF):

- Interspecies factor: 1 (default value for ocular irritation as recommended in R8 guidance)

- Intraspecies factor: 5 (default value for worker variability as recommended in R8 guidance)

- Time duration: 1(As recommended in R8 guidance, no factor has been applied since the effect is local and therefore not time dependent).

- Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 5

 

DNEL= NAEC corrected for human/OAF = 190 ppm (750 mg/m3) / 5

= 38 ppm or 150 mg/m3 (for chronic exposure by inhalation)

 

A DNEL of 150 mg/m3 is proposed for local effect after chronic exposure by inhalation

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

15 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEC

Explanation for the modification of the dose descriptor starting point:

Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for general population:

 

NAECcorrected= NOAECinhalatory rabbit × 6h/24h

NOAECcorrected= 193.25 ppm (760 mg/m3)

 

6h:time exposure of rabbits in Treon study.

24h:time exposure of general population.

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

2

Justification:

ECHA R8 guidance default value (subchronic to chronic)

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

105 mg/m³

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

75

Modified dose descriptor starting point:

LOAEC

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is needed.

AF for dose response relationship:

3

Justification:

LOAEC to NOAEC

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

75 mg/m³

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

1

Justification:

Not needed for effects such as skin and eye irritation

AF for interspecies differences (allometric scaling):

1

Justification:

Not needed for effects such as skin and eye irritation

AF for other interspecies differences:

1

Justification:

Not needed if the starting point comes from an inhalation study

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

Corrected dermal NAEL = oral NOAEL x 1 = 723 mg/kg bw/day.

Since no specific data are available on cyclopentanone and on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e factor 1) was used when performing oral-to-dermal extrapolation.

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

2

Justification:

ECHA R8 guidance default value (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is needed.

AF for dose response relationship:

1

Justification:

Not needed

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

200

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is needed.

AF for dose response relationship:

1

Justification:

Not needed

AF for differences in duration of exposure:

2

Justification:

ECHA R8 guidance default value (subchronic to chronic)

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Modified dose descriptor starting point:

NOAEL

Explanation for the modification of the dose descriptor starting point:

No modification is needed.

AF for dose response relationship:

1

Justification:

Not needed

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA R8 guidance default value for rats

AF for other interspecies differences:

2.5

Justification:

ECHA R8 guidance default value

AF for intraspecies differences:

10

Justification:

ECHA R8 guidance default value for general population

AF for the quality of the whole database:

1

Justification:

Not needed

AF for remaining uncertainties:

1

Justification:

Not needed

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - General Population

1. Acute / short-term exposure - systemic effects

Cutaneous route

In the study retained as a key study for this endpoint (Nunziata A, 1999 - reliability 2), groups of Sprague-Dawley male and female rats (3/group) were dermally exposed to cyclopentanone (99.8% purity) undiluted at doses of 400 and 2000 mg/kg bw/day. Animals then were observed for 14 days. At the lower dose (400 mg/kg), no clinical signs were observed. At the highest dose (2000 mg/kg/day), piloerection and staining of skin/fur were observed during period of exposure and disappeared within 24 hours. Based on this study, a NOAEL of 400 mg/kg/day can be identified for piloerection and staining of skin/fur in rats.

A DNEL for general population can be derived from this study in order to protect against effects induced after acute dermal exposure.

NOAEL rat = 400 mg/kg/day (the time of exposure was not precise in the study).

Modification of the starting point: No modification of the starting point is needed.

Assessment factor (AF):

- Intraspecies factor: 10 (default value for general population variability as recommended in the guidance R8)

- Interspecies factor: 4 x 2.5 (default assessment factor for interspecies variability - Rats as recommended in the guidance R8)

Overall assessment factor (OAF) = 100

DNEL= NOAEL / OAF = 400 mg/kg/day / 100 = 4 mg/kg/day

A DNEL of 4 mg/kg/day is proposed for general population and for dermal acute exposure.

Inhalation

One study by inhalation was retained as a key study (ESSO, 1965). In this study, groups of Wistar rats (10 males/group) were exposed by inhalation (whole body) to cyclopentanone (purity unknown) for 4 hours at concentrations of 4.7, 12, 15, 17.8, 19.5 mg/L. Animals were observed for 14 days. No mortality were observed in male rats at 4.7, 12, 15 mg/L of cyclopentanone. Three and 4 rats died respectively at 17.8 and 19.5 mg/L. During exposure, dyspnea, depression and decreased activity were observed at all the doses. Moreover, ataxia and prostration were also noted at the two highest levels. These signs disappeared within 48 hours. Based on this study, a LOAEC of 4.7 mg/L (4700 mg/m3) was identified for dyspnea, depression and decreased activity in rats.

LOAEC rat = 4700 mg/m3 (for 4 hours of exposure)

Modification of the strating point: No modification of the starting point is needed.

 

Assessment factor (AF):

- For LAEC to NAEC: 3

- Intraspecies factor: 10 (default value for general population variability as recommended in the R8 guidance)

- Interspecies factor: 2.5 (for toxicodynamic differences as recommended in the R8 guidance)

Overall assessment factor (OAF) = 75

DNEL= LAEC human/OAF = 3149 mg/m3 / 75= 41.9 mg/m3 = 42 mg/m3 (for 4 hours of exposure)

The modified Haber's law was used to propose a DNEL by inhalation for 15 minutes : Cⁿx t = k      

C: concentration ;n: regression coefficient; t: exposure time ; k : constant

A default value of n=3 was applied for extrapolating from longer to shorter exposure durations.

DNEL= 105 mg/m3 (for 15 minutes of exposure)

 

A DNEL of 105 mg/m3 is proposed for inhalation acute exposure in order to protect general population.

Oral route

One oral study performed on cyclopentanone was considered as a key study (RCC, 1999). In this study, male and female Sprague-Dawley rats were exposed by gavage (single exposure) at 500 and 2000 mg/kg bw/day. No mortality was noted after a 14 day period of observation. At 500 mg/kg bw/day, reduced activity, piloerection, hunched posture and hair loss were noted following dosing. These effects disappear within 14 days. Necropsy showed no abnormalities. At 2000 mg/kg bw/day, reduced activity/lethargy, piloerection, hunched posture, part-closed eyes and staining of skin/fur were observed following dosing. These effects disappear within 10 days. Necropsy after 14 days showed no abnormalities. Since no abnormalities were noted after necropsy, these effects were not considered as adverse. Reduction of body weight gain was observed only at 2000 mg/kg/day. Based on this study a NOAEL of 500 mg/kg bw/day can be identified in rats for body weight gain reduction.

 

Modification of the starting point: No modification of the starting point is needed.

 

Assessment factor (AF):

- Intraspecies factor:10 (default value for general population variability as recommended in the R8 guidance)

- Interspecies factor: 4 x 2.5 (default value for interspecies differences (rats) as recommended in the R8 guidance)

Overall assessment factor (OAF) = 100

DNEL= NOAEL / OAF = 500 mg/kg/day / 100 = 5 mg/kg/day

A DNEL of 5 mg/kg/day is proposed for general population and for oral acute exposure.

2. Acute / short-term exposure - local effects

 

Irritation and corrosion

- Skin irritation

Cyclopentanone is officially classified as irritant for skin according to CLP Regulation (EC) n°1272/2008. In a primary dermal irritation study (Guillot JP, 1982 - reliability 2) retained as a key study, New Zealand White rabbits (6/group) were dermally exposed to 0.5 mL of cyclopentanone (purity unknown) undiluted for 4 hours to the flanks. Test sites were covered with an occlusive dressing for 4 hours. Animals then were observed for 3 days. Irritation was scored by the method of Draize. In this study, cyclopentanone is slightly irritating to the skin in rabbit. Based on this study, no DNEL can be calculated for skin irritation because only one dose was tested.

However, a qualitative approach to risk assessment and management is therefore required because cyclopentanone is classified as irritant for skin (chapter R8, appendix R8 -9). 

- Eye irritation

Cyclopentanone is officially classified as irritant for eyes according to Regulation (EC) n°1272/2008.Two studies with reliability 2 according to Klimisch were available, and showed that Cyclopentanone was irritating to the eyes. In the key study, a primary eye irritation study (Guillot, 1982 - reliability 2), 0.1 mL of undiluted cyclopentanone (purity unknown) was instilled into the conjunctival sac of the eye of New Zealand White rabbits (6/group). The eyes were not rinsed or rinsed after 4 or 30 sec. Animals then were observed for at least 7 days. No DNEL can be derived from this study because only one dose was tested.Therefore, a qualitative approach to risk assessment and management is therefore required because cyclopentanone is classified as irritant for eyes (chapter R8, appendix R8 -9). 

- Respiratory tract irritation: No data available.

 

Sensitizer

For this endpoint, two studies are available and had the reliability 2 according to Klimisch rating. In these studies Cyclopentanone was not sensitizing in maximization test on guinea pig.

In the key study, a dermal sensitization study (Nunziata A, 1999) with cyclopentanone (99.8% purity) in PEG 200, Dunkin-Hartley guinea pigs were tested using the method of maximization. In an attempt to induce sensitisation, test animals were intradermally injected with an emulsion of Freund's complete adjuvant and the test substance in both the selected vehicle and an emulsion of Freund's complete adjuvant. One week later this was boosted by topical application of the test substance over the injection sites which had been pre-treated with sodium lauryl sulphate to promote an irritant reaction. Control group animals were treated in the same manner but the selected vehicle was used in place of the test substance. Two weeks after the second induction stage, all animals were challenged by topical application of both the vehicle and the test substance. Irritation to the test substance was noted and challenge was repeated 1 week later using the test substance at a lower concentration.

The results indicate that the test substance does not elicit a sensitisation response in the guinea pig, there being no evidence of reaction at challenge following a period of induction exposure to the substance.

Therefore, since cyclopentanone is not a skin sensitizer it is not relevant to derive a DNEL for this endpoint.

 

3. Long-term exposure - systemic effects

Cutaneous route

No data are available for systemic effects induced by cyclopentanone dermal exposure. However, since some studies performed on cyclohexanone showed that this substance may be absorbed by the skin, it's appears relevant to derive a DNEL for cyclopentanone and for long term exposure by cutaneous route.

A route to route extrapolation was realised (oral-to-dermal) based on an oral long term study performed on cyclohexanone (Lijinsky W, 1986).

In this study, cyclohexanone (96% purity) was administered daily during 25 weeks to F344 rats in water at dose levels of 0, 190, 400, 800, 1600, 3300, 4700, 6500 ppm (equiv. to ca. 29, 61, 122, 246, 508, 723, 1000 mg/kg bw/day). Cyclohexanone did not affect survival. The body weight gain was 10% lower than controls in both male and female rats at the highest dose (1000 mg/kg bw/day).The NOAEL was 4700 ppm (723 mg/kg bw/day) and the LOAEL at 6500 ppm (1000 mg/kg bw/day) for body weight gain reduction in rats. NOAEL rat (oral) = 723 mg/kg bw/day

Modification of the starting point:

Corrected dermal NAEL = oral NOAEL x 1 = 723 mg/kg bw/day.

Since no specific data are available on cyclopentanone and on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i.e factor 1) was used when performing oral-to-dermal extrapolation.

Assessment factor (AF):

- Interspecies factor: 4 x 2.5 (default assessment factor for interspecies variability - Rats as recommended in R8 guidance)

- Intraspecies factor: 10 (default value for general population variability as recommended in R8 guidance)

- Time duration: 2 (default value for sub-chronic to chronic exposure as recommended in R8 guidance).

- Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 200

 

DNEL= NAEL /OAF = 723 mg/kg/day / 200

= 3.6 mg/kg/day = 3.5 mg/kg/day (for chronic exposure by cutaneous route)

A DNEL of 3.5 mg/kg/day is proposed for general population and for dermal long term exposure.

Inhalation

Two studies are available for cyclopentanone inhalation exposure. However, the reliability of these studies is 3 in Klimisch rating. Therefore it's appears no relevant to derived a DNEL based on these studies. A study available on cyclohexanone after inhalation exposure is available and was selected as a key study (Treon, 1949a). Based on this study performed on cyclohexanone, a DNEL can be derived for long term inhalation exposure.

In Treon, 1949a study, cyclohexanone (purity unknown) was administered to rabbits (4/group), by exposure at concentrations of 0.75,1.21,3.04,5.56mg/L for 6 hours per day, 5 days/week for a total of 10 weeks. At the highest concentration (1414 ppm or 5560 mg/m3), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure. A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm (1210 mg/m3) and 773 ppm (3040 mg/m3) while slight salivation was observed under the latter conditions (773 ppm). Based on this study, a NOAEC of 190 ppm (750 mg/m3) and a LOAEC of 309 ppm (1210 mg/m3) can be identified for local effects (ocular irritation). For systemic effects (lethargy, distension of the ear veins) a NOAEC of 773 ppm (3040 mg/m3) and a LOAEC of 1414 ppm (5560 mg/m3) can be identified. Based on these latest values, a DNEL for systemic effect can be derived for cyclopentanone.

NOAEC rabbits = 773 ppm (3040 mg/m3) (for sub-chronic exposure and systemic effects).

Modification of the starting point: Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for general population:

 

NAEC_corrected= NOAEC_{inhalatory rabbit} × 6h/24h

NOAEC_corrected= 193.25 ppm (760 mg/m3) 

6h:time exposure of rabbits in Treon study.

24h:time exposure of general population.

 

Assessment factor (AF):

- Interspecies factor: 2.5 (default factor for toxicodynamic differences as recommended in the R8 guidance)

- Intraspecies factor: 10 (default value for general population variability as recommended in R8 guidance)

- Time duration: 2 (default value for sub-chronic to chronic exposure as recommended in R8 guidance).

-Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 50

 

 

DNEL= NAEC human/OAF = 193.25 ppm (760 mg/m3) / 50

= 3.86 ppm or 15.3 mg/m3 (for chronic exposure by inhalation)

  

A DNEL of 15 mg/m3 is proposed for systemic effects after chronic exposure by inhalation in order to protect general population.

Orale route

An oral long term study performed on cyclohexanone selected as a key study is retained in order to calculate an oral long term DNEL for general population (Lijinsky W, 1986).

In this study, cyclohexanone (96% purity) was administered daily during 25 weeks to F344 rats in water at dose levels of 0, 190, 400, 800, 1600, 3300, 4700, 6500 ppm (equiv. to ca. 29, 61, 122, 246, 508, 723, 1000 mg/kg bw/day). Cyclohexanone did not affect survival. The body weight gain was 10% lower than controls in both male and female rats at the highest dose (1000 mg/kg bw/day).The NOAEL was 4700 ppm (723 mg/kg bw/day) and the LOAEL at 6500 ppm (1000 mg/kg bw/day) for body weight gain reduction in rats. NOAEL rat (oral) = 723 mg/kg bw/day

Modification of the starting point: no modification of the starting point is needed.

Assessment factor (AF):

- Interspecies factor: 4 x 2.5 (default assessment factor for interspecies variability - Rats as recommended in R8 guidance)

- Intraspecies factor: 10 (default value for general population variability as recommended in R8 guidance)

- Time duration: 2 (default value for sub-chronic to chronic exposure as recommended in R8 guidance).

- Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 200

 

DNEL= NAEL /OAF = 723 mg/kg/day / 200

= 3.6 mg/kg/day =3.5 mg/kg/day (for chronic exposure by cutaneous route)

A DNEL of 3.5 mg/kg/day is proposed for general population and for oral long term exposure.

Carcinogenicity

No study is available on cyclopentanone. However, a read-across was made with cyclohexanone.

One study performed on cyclohexanone was selected as a key study (Lijinsky, 1986). In this study rats and mice were exposed by drinking water at different concentrations of cyclopentanone during 104 weeks. No carcinogenic effect was observed in rats neither in mice. By analogy with cyclohexanone, cyclopentanone is not considered as carcinogenic.

Since cyclopentanone is not considered as carcinogenic (by read-across with cyclohexanone), no DNEL or DMEL should be derived for this endpoint.

 

 

Reprotoxicity

Three studies are available, one performed on cyclopentanone and cyclohexanone and two on cyclohexanone. Only one study showed fertility effects on the second generation after cyclohexanone exposure at the highest doses (14000 ppm). At this dose, general toxic effects are also observed. The other studies showed that cyclopentanone and cyclohexanone have no impact on mice and rats fertility or showed that the depressions in male fertility were reversible. Tacking into account all the data, cyclopentanone is not considered as toxic for the fertility.

One developmental study performed on cyclopentanone was selected as a key study. In this study, cyclopentanone administrated in rats by gavage from days 6 through 15 of gestation at 50 or 300 mg/kg bw/day induce no developmental effects. Four other studies were performed on cyclohexanone. In all these studies no maternal or embryotoxic effects were observed at the tested level.

Since, cyclopentanone is not considered as reprotoxic, no DNEL should be derived for this endpoint.

 

 

4. Long-term exposure - local effects

Cutaneous route

No data available.

 

Inhalation

Two studies are available for cyclopentanone inhalation exposure. However, the reliability of these studies is3 inKlimisch rating. Therefore it's appears no relevant to derived a DNEL based on these studies. A study available on cyclohexanone after inhalation exposure is available and was selected as a key study (Treon, 1949a). Based on this study performed on cyclohexanone, a DNEL can be derived for long term inhalation exposure and for local effects.

In Treon, 1949a study, cyclohexanone (purity unknown) was administered to rabbits (4/group), by exposure at concentrations of 0.75,1.21,3.04,5.56 mg/L for 6 hours per day, 5 days/week for a total of 10 weeks. At the highest concentration (1414 ppm or 5560 mg/m3), slight lethargy, distention of the ear veins, salivation and conjunctival irritation manifested by congestion, lacrimation, and secretion of mucus were noted throughout the daily periods of exposure. A lesser degree of ocular irritation resulted from exposure to the concentrations at 309 ppm (1210 mg/m3) and 773 ppm (3040 mg/m3) while slight salivation was observed under the latter conditions (773 ppm). Based on this study, a NOAEC of 190 ppm (750 mg/m3) and a LOAEC of 309 ppm (1210 mg/m3) can be identified for local effects (ocular irritation).For systemic effects (lethargy, distension of the ear veins) a NOAEC of 773 ppm (3040 mg/m3) and a LOAEC of 1414 ppm (5560 mg/m3) can be identified. Therefore, based on this study a DNEL can be derived for local effects (ocular irritation).

NOAEC= 190 ppm (750 mg/m3) for ocular irritation.

Conversion of an inhalatory rabbits NOAEC into a corrected inhalatory NAEC for workers: no conversion is necessary since the effect is local (ocular effect). Indeed such effect is mainly driven by concentration exposure and is not time-dependent.

 

Assessment factor (AF):

- Interspecies factor:1 (default value for ocular irritation as recommended in R8 guidance)

- Intraspecies factor: 10 (default value for general population variability as recommended in R8 guidance)

- Time duration:1 (As recommended in R8 guidance, no factor has been applied since the effect is local).

-Analogy with cyclohexanone: no assessment factor was applied for this point because all studies performed on cyclopentanone and cyclohexanone showed that cyclohexanone toxicity is a bit higher than cyclopentanone toxicity.

Overall assessment factor (OAF) = 10

 

DNEL= NAEC human/OAF = 190 ppm (750 mg/m3) / 10

= 19 ppm or 75 mg/m3 (for chronic exposure by inhalation)

 

A DNEL of 75 mg/m3 is proposed for local effect after chronic exposure by inhalation