Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29.3 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Modified dose descriptor starting point:
NOAEC
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:
DNEL (Derived No Effect Level)
Value:
9.04 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

DNEL DERIVATIONS FOR HEDIONE

(CAS 24851-98-7)

 

1. Introduction and Summary

 

Hedione primarily has consumer applications that include household products and cosmetics. 

 

Tests assessing the mutagenic potential of Hedione in vitro and in vivo provided no evidence of mutagenic or genotoxic activity. Indications of reprotoxic potential were not observed in a 90-day repeat dose toxicology study or prenatal developmental study, or evidence of hyperplasia (taken as some evidence of no potential for carcinogenicity) in the repeat dose study.

Summarized in Table 1 are the critical preliminary DNEL values.

 

Table 1: Critical Preliminary DNEL Values for Hedione

Exposure Pattern

DNEL

Workers

General Population

Acute – inhalation, systemic

not calculated1

not calculated1

Acute – inhalation, local

not calculated1

not calculated1

Acute – dermal, systemic

not calculated1

not calculated1

Acute – dermal, local

not calculated1

not calculated1

Acute – oral, systemic

not calculated1

not calculated1

Long-term – inhalation, systemic

29.3 mg/m3

8.69 mg/m3

Long-term – inhalation, local

not calculated

not calculated

Long-term – dermal, systemic

9.04 mg/kg bw/day

5.43mg/kg bw/day

Long-term – dermal, local

not calculated

not calculated

Long-term – oral, systemic

not calculated

2.5mg/kg bw/day

1ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity do not always need to be determined

 if no acute toxicity hazard, that leads to classification, has been identified.

 

Summarized in Table 2 is the critical toxicological study and values identified for Hedione.

 

Table 2: Dose descriptor for key study of toxicological concern

Endpoint

Descriptor

Key Reference

Effects/Comments

Repeated dose toxicity (Oral, diet)

NOAEL = 100 mg/kg bw/d in rats (taken as being the same as the NOEL for the calculation of the DNELs).

 

Doses were 10; 50 and 100 mg/kg/day for 90 days.

ST 08 C99: A 3-month OECD 408 dietary toxicity study in rats. CM Kelly, 2000, report No. 99-2643.

There were no adverse effects noted at any dose level, in terms of clinical findings, macroscopic and microscopic findings. The maximum dose level was limited by palatability issues and therefore the NOEL was 100 mg/kg/day and the NOAEL was considered to be >100 mg/kg/day.

 

2.Descriptions and Rationale for DNEL Derivations

 

2.1 Acute toxicity

The oral LD50 of Hedione was determined to be greater than 5 g/kg and less than 10 g/kg and is therefore not classified according to either FHSA or CLP. The dermal LD50 was determined to be greater than 5 g/kg and Hedione is not classified according to either FHSA or CLP. The inhalation LC50 was determined to be >4.93 mg/l (no deaths occurred at this concentration) and is not classified according to CLP.

 

2.2 Irritation/Sensitisation

Dermal and eye irritation properties were assessed on New Zealand white rabbits according to OECD 404 and OECD 405 respectively. In the acute dermal study no signs of dermal irritancy were noted in any of three animals after occlusive application of the pure substance for 4 hours. None of the exposed animals showed clinical signs or behavioural alterations. In the acute eye irritation study, 0.1 ml of pure substance was instilled into the eyes of three rabbits; no corneal opacity was noted during the study. Accordingly Hedione is considered to be non irritant, both for the skin and the eye and does not meet the criteria for classification according to EU labelling regulations Commission Directive 2001/59/EC or according to CLP.

 

Hedione has been tested in both an LLNA and a GPMT, both according to OECD test guidelines. Both studies show that Hedione has no sensitising potential and, in addition a Buehler study has been performed that provides supporting evidence of the non-sensitising potential of Hedione. Furthermore, three tests in humans, including two HRIPT (human repeated insult patch test) studies, demonstrate the non-sensitising potential of Hedione.

 

2.3 Repeated dose toxicity

 

A study was performed that is compliant with the OECD 408 test guideline. The study investigated the potential for Hedione (ST 08 C 99) to cause systemic toxicity when administered orally to rats via the diet. Food consumption was evaluated weekly and Hedione intake measurements were performed weekly in order to calculate the received dose. The animals (10/sex/group) were exposed to 10, 50 and 100 mg/kg/day for a period of 90 days. The dose levels were established on the basis of the results of a 14-day range-finding study, where it was shown that palatability restricted the maximum dose level to 100 mg/kg/day. Control animals received standard laboratory diet. Clinical observations and body weight measurements were performed on all animals. Motor activity, functional observational battery and ophthalmology observations were performed pre-test and during the 12thweek of dosing. After 90-days of dosing, haematology, coagulation and clinical chemistry evaluations were performed and complete macroscopic post-mortem examinations on all animals and histological evaluation of all tissues collected for the animals in the control and 100 mg/kg/day groups.

 

The administration of dietary concentrations equivalent to 10, 50 and 100 mg/kg/day of Hedione, to rats for up to 90 days, did not result in any adverse toxicological effects. Therefore the NOEL was 100 mg and the NOAEL value used for the DNEL derivation was 100 mg/kg/day.

 

2.4 Genetic toxicity

Hedione has been shown to be non-mutagenic in two bacterial mutagenicity tests performed according to the OECD 471 test guideline and non-mutagenic to L5178Y mouse lymphoma cells in a study performed according to the OECD 478 test guideline. An in vivo test for chromosome aberrations (mouse micronucleus assay) was also shown to be negative at an oral dose level of 1180 mg/kg (estimated to be 80% of the LD50 in mice) and at two lower dose levels of 280 and 560 mg/kg. In a UDS assay in the rat liver, Hedione was shown to be non-toxic via the oral route at 2000 mg/kg but did show some toxicity using the intra-peritoneal route. The IP route was used in the UDS assay at 333 and 1000 mg/kg and no evidence of genotoxic potential was observed. Hedione is concluded to be non-mutagenic and has no Genotoxicology concerns.

 

2.5 Carcinogenicity

 

The potential for Hedione to cause cancer in animals has not been investigated. However, a thorough battery of in vitro and in vivo genotoxicity tests have shown no evidence of genotoxic potential and a 90-day repeat dose toxicology study has shown no evidence of histopathological changes that may be associated with neoplasia.

 

2.6 Reproductive / developmental toxicity

 

A pre-natal developmental toxicology study was performed on rats dosed orally by gavage with Hedione at 40, 80 and 120 mg/kg/day for 13 weeks during gestation. No adverse toxicological effects were seen in the foetuses and the modest reduction in foetal bodyweight in the 120 mg/kg dose group was considered to be not related to exposure because the difference was small and within the historical range. In the adult females there was a modest but significant reduction in bodyweight gain at the maximum dose level of 120 mg/kg and therefore the maternal NOAEL was 80 mg/kg/day.

 

3. Mode of Action Considerations

 

For the critical study identified in Table 2, a threshold mode of action was assumed.

4. Modification of Relevant Dose Descriptors to the Correct Starting Point

 

Relevant dose descriptors were corrected from the values provided in Table 2 for the different endpoints and routes of exposure. The values are provided in Table 3 (see Guidance Document, Chapter R.8, Appendix R.8-2). For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed. In the absence of specific absorption data for the oral route it is assumed that 100% absorption occurs via this route. Dermal absorption has been shown experimentally to be approximately 46% and it is reasonable to assume that oral absorption is at least as high as via the dermal route. Hence, an estimate of 100% absorption via the oral route is considered justified in this case.

 

4.1 Dermal route:

No more than 45.9% absorption of the applied dose was observed in a skin absorption study. Therefore a factor of 46% was applied when performing oral-to-dermal extrapolation (see Guidance Document, Chapter R.8, pp 25).

 

The corrected dermal NOAEL is:

 

corrected dermal NOAEL = oral NOAEL x ABS oral-rat/ABS derm-human

        corrected dermal NOAEL = 100 x 100/46 = 217 mg/kg bw/day

 

Thus, the corrected dose descriptor for dermal route is 217 mg/kg/day.

 

4.2 Inhalation:

In the absence of specific data it was assumed that 100% 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). However, because 100% absorption via both the oral and inhalation routes has been assumed, it was not necessary to adopt the 2-fold factor suggested on page 25 of Guidance Document, Chapter R.8. To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h or 1.15 m3/kg bw/24 h).

 

For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period).

 

The corrected inhalation NOAEC for workers is:

 

corrected inhalation NOAEL = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRV

corrected inhalation NOAEL = 100 x 1/0.38 x 100/100 x 6.7/10 = 176 mg/m3

 

 

The corrected inhalation NOAEC for general population is:

 

corrected inhalation NOAEL = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human

corrected inhalation NOAEL = 100 x 1/1.15 x 100/100 = 86.9 mg/m3

 

Thus, the corrected dose descriptor for inhalation is 176 mg/m3 for workers and 86.9 mg/m3 for general population.

 


 

 

Table 3: Corrected dose descriptors for key studies of toxicological concern

Endpoint

Most relevant dose descriptors

Corrected dose descriptors

 

local

systemic

local

systemic

Repeated dose toxicity- workers

-oral

NC

NOAEL = 100

mg/kg bwt/day

NC

NC

-dermal

NC

(use oral data)

NC

NOAELderm. corr= 217 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOAELinh. corr= 

176 mg/m3

Repeated dose toxicity- general population

-oral

NC

NOAEL = 100

mg/kg bwt/day

NC

NC

-dermal

NC

(use oral data)

NC

NOAELderm. corr= 217 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOAELinh. corr= 

86.9 mg/m3

NC = not calculated

 

5. Application of Assessment Factors to the Corrected Dose Descriptors

 

Endpoint-specific DNEL values for exposures to Hedione were derived from the corrected dose descriptors found in Table 3 with the application of assessment factors (AF). The AFs used in this document were based on the procedures described in the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Technical Report 86 (2003). In this case, the NOAEL is based on a dose level that was limited by a palatability issue and not by oral toxicity. Therefore, in the absence of test substance-related effect, it is assumed that the inter/intra species difference is expected to be very low, which justifies the use of the ECETOC AF values.

 

5.1 Oral route

The assessment factors applied are summarized in Table 4.

 

Table 4: LongTerm DNEL Assessment Factors (Oral)

Assessment Factor

Worker

General Population

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

NA

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

NA

1.0

Intraspecies differences

NA

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

NA

2 (sub-chronic)

Issues related to dose-response

NA

1

Quality of whole database

NA

1

Overall AF

NA

40

NA = not applicable


 

 

5.2 Dermal route

The assessment factors applied are summarized in Table 5.

 

Table 5: LongTerm DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

General Population

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

4 (rat)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1.0

1.0

Intraspecies differences

3

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

2 (sub-chronic)

Issues related to dose-response

1

1

Quality of whole database

1

1

Overall AF

24

40

 

 

5.3 Inhalation

The assessment factors applied are summarized in Table 6.

 

Table 6: LongTerm DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

General Population

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

-

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1.0

1.0

Intraspecies differences

3

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

2 (sub-chronic)

Issues related to dose-response

1

1

Quality of whole database

1

1

Overall AF

6

10

 

Conclusion

 

The calculated DNEL values for Hedione, derived from a sub-chronic dietary study in rats, are summarized in Table 1 at the beginning of this document and in Table 7 below for workers and Table 8 for the general population.

 

 

Table 7: Endpoint-specific DNEL values for Hedione: Worker

 

Endpoint

Corrected dose descriptor

Overall AF

Endpoint-specific worker DNELs

 

local

systemic

 

local

systemic

-oral

NC

NOAELoral=

100 mg/kg bwt/day

NA

NC

NC

-dermal

NC

NOAELderm. corr= 217 mg/kg bwt/day

24

NC

9.04 mg/kg bw/day

-inhalation

NC

NOAELinh. corr= 

176 mg/m3

6

NC

29.3 mg/m3

NC = not calculated, NA = not applicable

 


 

 

Table 8: Endpoint-specific DNEL values for Hedione: General Population

 

Endpoint

Corrected dose descriptor

Overall AF

Endpoint-specific DNELs

 

local

systemic

 

local

systemic

-oral

NC

NOAELoral=

100 mg/kg bwt/day

40

NC

2.5 mg/kg bw/day

-dermal

NC

NOAELderm. corr= 217 mg/kg bwt/day

40

NC

5.43 mg/kg bw/day

-inhalation

NC

NOAELinh. corr= 

86.9 mg/m3

10

NC

8.69 mg/m3

NC = not calculated

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.69 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
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:
DNEL (Derived No Effect Level)
Value:
5.43 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
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

DNEL DERIVATIONS FOR HEDIONE

(CAS 24851-98-7)

 

1. Introduction and Summary

 

Hedione primarily has consumer applications that include household products and cosmetics. 

 

Tests assessing the mutagenic potential of Hedionein vitroandin vivoprovided no evidence of mutagenic or genotoxic activity. Indications of reprotoxic potential were not observed in a 90-day repeat dose toxicology study or prenatal developmental study, or evidence ofhyperplasia(taken as some evidence of no potential for carcinogenicity) in the repeat dose study.

Summarized in Table 1 are the critical preliminary DNEL values.

 

Table 1: Critical Preliminary DNEL Values for Hedione

Exposure Pattern

DNEL

Workers

General Population

Acute – inhalation, systemic

not calculated1

not calculated1

Acute – inhalation, local

not calculated1

not calculated1

Acute – dermal, systemic

not calculated1

not calculated1

Acute – dermal, local

not calculated1

not calculated1

Acute – oral, systemic

not calculated1

not calculated1

Long-term – inhalation, systemic

29.3 mg/m3

8.69 mg/m3

Long-term – inhalation, local

not calculated

not calculated

Long-term – dermal, systemic

9.04 mg/kg bw/day

5.43mg/kg bw/day

Long-term – dermal, local

not calculated

not calculated

Long-term – oral, systemic

not calculated

2.5mg/kg bw/day

1ECHA Guidance R.8 (Chapter R.8.1.2.5) indicates that DNELs for acute toxicity do not always need to be determined

 if no acute toxicity hazard, that leads to classification, has been identified.

 

Summarized in Table 2 is the critical toxicological study and values identified for Hedione.

 

Table 2: Dose descriptor for key study of toxicological concern

Endpoint

Descriptor

Key Reference

Effects/Comments

Repeated dose toxicity (Oral, diet)

NOAEL = 100 mg/kg bw/d in rats (taken as being the same as the NOEL for the calculation of the DNELs).

 

Doses were 10; 50 and 100 mg/kg/day for 90 days.

ST 08 C 99: A 3-month OECD 408 dietary toxicity study in rats. CM Kelly, 2000, report No. 99-2643.

There were no adverse effects noted at any dose level, in terms of clinical findings, macroscopic and microscopic findings. The maximum dose level was limited by palatability issues and therefore the NOEL was 100 mg/kg/day and the NOAEL was considered to be >100 mg/kg/day.

 

2.Descriptions and Rationale for DNEL Derivations

 

2.1 Acute toxicity

The oral LD50 of Hedione was determined to be greater than 5 g/kg and less than 10 g/kg and is therefore not classified according to either FHSA or CLP. The dermal LD50 was determined to be greater than 5 g/kg and Hedione is not classified according to either FHSA or CLP. The inhalation LC50 was determined to be >4.93 mg/l (no deaths occurred at this concentration) and is not classified according to CLP.

 

2.2 Irritation/Sensitisation

Dermal and eye irritation properties were assessed on New Zealand white rabbits according to OECD 404 and OECD 405 respectively. In the acute dermal study no signs of dermal irritancy were noted in any of three animals after occlusive application of the pure substance for 4 hours. None of the exposed animals showed clinical signs or behavioural alterations. In the acute eye irritation study, 0.1 ml of pure substance was instilled into the eyes of three rabbits; no corneal opacity was noted during the study. Accordingly Hedione is considered to be non irritant, both for the skin and the eye and does not meet the criteria for classification according to EU labelling regulations Commission Directive 2001/59/EC or according to CLP.

 

Hedione has been tested in both an LLNA and a GPMT, both according to OECD test guidelines. Both studies show that Hedione has no sensitising potential and, in addition a Buehler study has been performed that provides supporting evidence of the non-sensitising potential of Hedione. Furthermore, three tests in humans, including two HRIPT (human repeated insult patch test) studies, demonstrate the non-sensitising potential of Hedione.

 

2.3 Repeated dose toxicity

 

A study was performed that is compliant with the OECD 408 test guideline. The study investigated the potential for Hedione (ST 08 C 99) to cause systemic toxicity when administered orally to rats via the diet. Food consumption was evaluated weekly and Hedione intake measurements were performed weekly in order to calculate the administered dose. The animals (10/sex/group) were exposed to 10, 50 and 100 mg/kg/day for a period of 90 days. The dose levels were established on the basis of the results of a 14-day range-finding study, where it was shown that palatability restricted the maximum dose level to 100 mg/kg/day. Control animals received standard laboratory diet. Clinical observations and body weight measurements were performed on all animals. Motor activity, functional observational battery and ophthalmology observations were performed pre-test and during the 12thweek of dosing. After 90-days of dosing, haematology, coagulation and clinical chemistry evaluations were performed and complete macroscopic post-mortem examinations on all animals and histological evaluation of all tissues collected for the animals in the control and 100 mg/kg/day groups.

 

The administration of dietary concentrations equivalent to 10, 50 and 100 mg/kg/day of Hedione, to rats for up to 90 days, did not result in any adverse toxicological effects. Therefore the NOEL was 100 mg and the NOAEL value used for the DNEL derivation was 100 mg/kg/day.

 

2.4 Genetic toxicity

Hedione has been shown to be non-mutagenic in two bacterial mutagenicity tests performed according to the OECD 471 test guideline and non-mutagenic to L5178Y mouse lymphoma cells in a study performed according to the OECD 478 test guideline. An in vivo test for chromosome aberrations (mouse micronucleus assay) was also shown to be negative at an oral dose level of 1180 mg/kg (estimated to be 80% of the LD50 in mice) and at two lower dose levels of 280 and 560 mg/kg. In a UDS assay in the rat liver, Hedione was shown to be non-toxic via the oral route at 2000 mg/kg but did show some toxicity using the intra-peritoneal route. The IP route was used in the UDS assay at 333 and 1000 mg/kg and no evidence of genotoxic potential was observed. Hedione is concluded to be non-mutagenic and has no Genotoxicology concerns.

 

2.5 Carcinogenicity

 

The potential for Hedione to cause cancer in animals has not been investigated. However, a thorough battery of in vitro and in vivo genotoxicity tests have shown no evidence of genotoxic potential and a 90-day repeat dose toxicology study has shown no evidence of histopathological changes that may be associated with neoplasia.

 

2.6 Reproductive / developmental toxicity

 

A pre-natal developmental toxicology study was performed on rats dosed orally by gavage with Hedione at 40, 80 and 120 mg/kg/day for 13 days during gestation. No adverse toxicological effects were seen in the foetuses and the modest reduction in foetal bodyweight in the 120 mg/kg dose group was considered to be not related to exposure because the difference was small and within the historical range. In the adult females there was a modest but significant reduction in bodyweight gain at the maximum dose level of 120 mg/kg and therefore the maternal NOAEL was 80 mg/kg/day.

 

3. Mode of Action Considerations

 

For the critical study identified in Table 2, a threshold mode of action was assumed.

4. Modification of Relevant Dose Descriptors to the Correct Starting Point

 

Relevant dose descriptors were corrected from the values provided in Table 2 for the different endpoints and routes of exposure. The values are provided in Table 3 (see Guidance Document, Chapter R.8, Appendix R.8-2). For potential dermal and inhalation exposures, route-to-route extrapolations from the oral NOAEL value were performed. In the absence of specific absorption data for the oral route it is assumed that 100% absorption occurs via this route. Dermal absorption has been shown experimentally to be approximately 46% and it is reasonable to assume that oral absorption is at least as high as via the dermal route. Hence, an estimate of 100% absorption via the oral route is considered justified in this case.

 

4.1 Dermal route:

No more than 45.9% absorption of the applied dose was observed in a skin absorption study. Therefore a factor of 46% was applied when performing oral-to-dermal extrapolation (see Guidance Document, Chapter R.8, pp 25).

 

The corrected dermal NOAEL is:

 

corrected dermal NOAEL - oral NOAEL x ABS oral-rat/ABS derm-human

       corrected dermal NOAEL = 100 x 100/46 = 217 mg/kg bw/day

 

Thus, the corrected dose descriptor for dermal route is 217 mg/kg/day.

 

4.2 Inhalation:

In the absence of specific data it was assumed that 100% 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). However, because 100% absorption via both the oral and inhalation routes has been assumed, it was not necessary to adopt the 2-fold factor suggested on page 25 of Guidance Document, Chapter R.8. To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h or 1.15 m3/kg bw/24 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).

 

The corrected inhalation NOAEC for workers is:

 

corrected inhalation NOAEL = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human x sRVhuman/wRV

corrected inhalation NOAEL = 100 x 1/0.38 x 100/100 x 6.7/10 = 176 mg/m3

 

 

The corrected inhalation NOAEC for general population is:

 

corrected inhalation NOAEL = oral NOAEL x 1/sRVrat x ABSoral-rat/ABSinh-human

corrected inhalation NOAEL = 100 x 1/1.15 x 100/100 = 86.9 mg/m3

 

Thus, the corrected dose descriptor for inhalation is 176 mg/m3for workers and 86.9 mg/m3for general population.

 

Table 3: Corrected dose descriptors for key studies of toxicological concern

Endpoint

Most relevant dose descriptors

Corrected dose descriptors

 

local

systemic

local

systemic

Repeated dose toxicity- workers

-oral

NC

NOAEL = 100

mg/kg bwt/day

NC

NC

-dermal

NC

(use oral data)

NC

NOAELderm. corr= 217 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOAELinh. corr= 

176 mg/m3

Repeated dose toxicity- general population

-oral

NC

NOAEL = 100

mg/kg bwt/day

NC

NC

-dermal

NC

(use oral data)

NC

NOAELderm. corr= 217 mg/kg bwt/day

-inhalation

NC

(use oral data)

NC

NOAELinh. corr= 

86.9 mg/m3

NC = not calculated

 

5. Application of Assessment Factors to the Corrected Dose Descriptors

 

Endpoint-specific DNEL values for exposures to Hedione were derived from the corrected dose descriptors found in Table 3 with the application of assessment factors (AF). The AFs used in this document were based on the procedures described in the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Technical Report 86 (2003). In this case, the NOAEL is based on a dose level that was limited by a palatability issue and not by oral toxicity. Therefore, in the absence of test substance-related effect, it is assumed that the inter/intra species difference is expected to be very low, which justifies the use of the ECETOC AF values.

 

5.1 Oral route

The assessment factors applied are summarized in Table 4.

 

Table 4: LongTerm DNEL Assessment Factors (Oral)

Assessment Factor

Worker

General Population

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

NA

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

NA

1.0

Intraspecies differences

NA

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

NA

2 (sub-chronic)

Issues related to dose-response

NA

1

Quality of whole database

NA

1

Overall AF

NA

40

NA = not applicable


 

 

5.2 Dermal route

The assessment factors applied are summarized in Table 5.

 

Table 5: LongTerm DNEL Assessment Factors (Dermal)

Assessment Factor

Worker

General Population

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

4 (rat)

4 (rat)

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1.0

1.0

Intraspecies differences

3

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

2 (sub-chronic)

Issues related to dose-response

1

1

Quality of whole database

1

1

Overall AF

24

40

 

 

5.3 Inhalation

The assessment factors applied are summarized in Table 6.

 

Table 6: LongTerm DNEL Assessment Factors (Inhalation)

Assessment Factor

Worker

General Population

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

-

-

Interspecies remaining differences (toxicodynamic and toxicokinetic)

1.0

1.0

Intraspecies differences

3

5

Duration extrapolation

(sub-acute/sub-chronic/chronic)

2 (sub-chronic)

2 (sub-chronic)

Issues related to dose-response

1

1

Quality of whole database

1

1

Overall AF

6

10

 

Conclusion

 

The calculated DNEL values for Hedione, derived from a sub-chronic dietary study in rats, are summarized in Table 1 at the beginning of this document and in Table 7 below for workers and Table 8 for the general population.

 

 

Table 7: Endpoint-specific DNEL values for Hedione: Worker

 

Endpoint

Corrected dose descriptor

Overall AF

Endpoint-specific worker DNELs

 

local

systemic

 

local

systemic

-oral

NC

NOAELoral=

100 mg/kg bwt/day

NA

NC

NC

-dermal

NC

NOAELderm. corr= 217 mg/kg bwt/day

24

NC

9.04 mg/kg bw/day

-inhalation

NC

NOAELinh. corr= 

176 mg/m3

6

NC

29.3 mg/m3

NC = not calculated, NA = not applicable

 


 

 

Table 8: Endpoint-specific DNEL values for Hedione: General Population

 

Endpoint

Corrected dose descriptor

Overall AF

Endpoint-specific DNELs

 

local

systemic

 

local

systemic

-oral

NC

NOAELoral=

100 mg/kg bwt/day

40

NC

2.5 mg/kg bw/day

-dermal

NC

NOAELderm. corr= 217 mg/kg bwt/day

40

NC

5.43 mg/kg bw/day

-inhalation

NC

NOAELinh. corr= 

86.9 mg/m3

10

NC

8.69 mg/m3

NC = not calculated