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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2 500 mg/m³
Explanation for the modification of the dose descriptor starting point:

See additional information, workers.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
222 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
45
Dose descriptor starting point:
other: NOAEL

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Worker- DNEL acute for dermal route – sensitizing effects:

l-limonene is a skin sensitizer; therefore an induction specific DNEL by dermal route was derived to judge the remaining/residual likelihood of risks after the RMMs and OCs suggested for moderate sensitizers are implemented.

Data obtained from both local lymph node assays (see 7.4.1) and historical predictive human test data (see 7.10.4) on the structural analogue d-limonene were used to provide information on the potency for induction, as well as on dose-response relationships of l-limonene.

 

In case of LLNAs, the sensitization potency can be categorized based on the EC3value, which can be calculated from the LLNA dose-response data by linear interpolation. Based on the whole available data, the EC3-value for limonene was found to be 68.5% (17125 µg/cm²),indicating a moderate induction potency for d-limonene (as by definition in the R8 guidance document).

This value is slightly higher than the reported LLNA weighed mean EC3values from five LLNA studies conducted by the RIFM (=10075 µg/cm²; Api et al., 2008).

 

These animal data are consistent with the NOEL of 10000 µg/cm2(highest concentration tested with no sensitisation in human), obtained in Human Repeated Insult Patch Test conducted by the RIFM (see section 7.10.4).

 

As there is a good agreement between LLNA EC3 and NOEL derived from HRIPT studies, the lowest value (i.e. 10000 µg/cm2) is used to derive the DNEL and no interspecies AF is applied (R8 guidance document p. 132).

 

Thus, the dose descriptor for sensitisation is 10000 µg/cm2.

 

The following table indicates the induction specific DNEL calculation.

Interspecies differences

-

Intraspecies differences

5

(worker)

Vehicle or matrix effect

3

(Matrix for the product not the same as the experimental conditions and may be designed to enhance penetration)

Exposure considerations

3

(taking into account site of body exposed for workers, dermal integrity, effect of occlusion and environmental conditions)

Overall assessment factor

45

DNEL calculation

222 µg/cm2

The induction specific DNEL is222 µg/cm2for workers exposed to l-limonene.

Worker-DNEL long-term for inhalation route – systemic effects:

For potential inhalation exposure to l-limonene, route-to-route extrapolation from the oral NOAEL obtained with d-limonene value was performed.

Under the test conditions, the LOAEL for beagle dogs exposed 180 days to d-limonene was considered to be 1000 mg/kg bw/day, respectively, based on the increased absolute and relative female kidney weight and relative male kidney weightIn the absence of specific data it was assumed that 50% absorption occurs by the oral route. To secure a conservative external NOAEL a maximum absorption should be assumed for the inhalation route (i.e.; 100%) (see Guidance Document, Chapter R.8, pp 25). To convert the oral NOAEL into inhalatory NOAEC, a dog default respiratory volume was used corresponding to the daily duration of human exposure (sRVdog: 0.134 m3/kg bw/8 h).

For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3for an 8-h exposure period).

 

Thus, the corrected dose descriptor for inhalation is 2500 mg/m3for workers.

 

The following table indicates the inhalation DNEL-long term for systemic effect calculation.

Differences in metabolic rate per b.w. (allometric scaling)

-

Interspecies differences

2.5

(toxicodynamic and toxicokinetic remaining differencies)

Intraspecies differences

5

(worker)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(sub-chronic to chronic extrapolation)

Issues related to dose-response

3

(LOAEL)

Overall assessment factor

75

DNEL calculation

33.3 mg/m3

6.00 ppm

DNELppm= DNELmg/m3* 24.05 / MW at 20°C = 33.3 * 24.45 / 136.2 at 25°C

 

The inhalation DNEL long-term for systemic effects is 33.3 mg/m3for workers exposed to l-limonene.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.33 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
111 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
Overall assessment factor (AF):
90
Dose descriptor starting point:
other: NOAEL

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.76 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
210
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General population -DNEL long-term for oral route – systemic effects:

As no studies were located on l-limonene, the concentration descriptor has been obtained from a subchronic toxicity study by oral route on dogs exposed to d-limonene (Webb, 1990, see § 7.5.1). This study was selected for DNEL derivation since mammalian exposure is more relevant than rodent exposure regarding human health effect assessment. Moreover effects seen in the study were on the target organ of d-limonene and by analogy for l-limonene, the kidney.

Under the test conditions, the LOAEL for beagle dogs was considered to be 1000 mg/kg bw/day, based on the increased absolute and relative female kidney weight and relative male kidney weight.

 

The following Table indicates the oral DNEL-long term for systemic effects calculation of l-limonene.

 

Correct starting point– factor for uncertainties

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

-

(same route of exposure)

Modification for exposure

(experiment and human)

-

(not relevant considering oral exposure)

Correct starting point = relevant dose descriptor / overall factor for uncertainties

100 mg/kg b.w./d

Assessment factors

Differences in metabolic rate per b.w. (allometric scaling)

1.4

(dog)

Interspecies differences

2.5

(toxicodynamic and toxicokinetic remaining differencies)

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(subchronic to chronic extrapolation)

Issues related to dose-response

3

(LOAEL)

Overall assessment factor

210

DNEL calculation

4.76 mg/kg b.w./d

 

The oral DNEL long-term for systemic effect is 4.76 mg l-limonene/kg b.w./d in the general population.

General population -DNEL long-term for inhalation route – systemic effects:

For potential inhalation exposure to l-limonene, route-to-route extrapolation from the oral NOAEL obtained with the structural analogye d-limonene value was performed.

Under the test conditions, the LOAEL for beagle dogs was considered to be 1000 mg/kg bw/day, respectively, based on the increased absolute and relative female kidney weight and relative male kidney weight.

In the absence of specific data it was assumed that 50% absorption occurs by the oral route. To secure a conservative external NOAEL a maximum absorption should be assumed for the inhalation route (i.e.; 100%) (see Guidance Document, Chapter R.8, pp 25). To convert the oral NOAEL into inhalatory NOAEC, a dog default respiratory volume was used corresponding to the daily duration of human exposure (sRVdog: 0.40 m3/kg bw/24 h).

 

Thus, the corrected dose descriptor for inhalation is 217 mg/m3 for general population.

 

The following table indicates the inhalation DNEL-long term for systemic effect calculation.

 

Correction for uncertainty factors

Differences in absorption depending on route of exposure (route-route extrapolation, human/animal)

50/100

Modification for exposure

(experiment and human)

(1/0.4)

Correct starting point

1250 mg/m3

Correction for assessment factors

Differences in metabolic rate per b.w. (allometric scaling)

-

Interspecies differences

2.5

(toxicodynamic and toxicokinetic remaining differencies)

Intraspecies differences

10

(general population)

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2

(sub-chronic to chronic extrapolation)

Issues related to dose-response

3

(LOAEL)

Overall assessment factor

150

DNEL calculation

8.33 mg/m3

1.50 ppm

DNELppm= DNELmg/m3* 24.05 / MW at 20°C = 8.33 * 24.45 / 136.2 at 25°C

 

The inhalation DNEL long-term for systemic effects is 8.33 mg/m3 for the general population exposed to l-limonene.

General population- DNEL acute for dermal route – sensitizing effects:

Like workers, the dose descriptor for sensitisation is 10000 µg/cm2.

 

The following table indicates the induction specific DNEL calculation.

Interspecies differences

-

Intraspecies differences

10

(general population, chapter R8, ECHA)

Vehicle or matrix effect

3

(Matrix for the product not the same as the experimental conditions and may be designed to enhance penetration)

Exposure considerations

3

(taking into account site of body exposed for workers, dermal integrity, effect of occlusion and environmental conditions)

Overall assessment factor

90

DNEL calculation

111 µg/cm2

The induction specific DNEL is 111 µg/cm2 for general population exposed to l-limonene.