Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.28 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Value:
3.53 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation oral to inhalation:1 because oral absorption is 100%, difference in respiratory volumes: 0.38x(10/6.7)=0.5746
AF for dose response relationship:
1
Justification:
There is no clear evidence for developmental dose effects in rats at exposure levels up 2mg/kg/day. This is supported by other developmental rat study. Application of a factor to take account of uncertainties in the dose-response relationship above the NOAEL is not justified.
AF for differences in duration of exposure:
1
Justification:
The dose descriptor was obtained from a developmental study in the rat. AF for exposure duration not necessary as long as the experimental exposure covers adequately the pregnancy of the rat.
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied.
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to HMX in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.72 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Modified dose descriptor starting point:
NOAEC
Value:
139.58 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation oral to inhalation:2, difference in respiratory volumes: 0.12x(10/6.7)=0.18
AF for dose response relationship:
3
Justification:
The NOAEC was derived from a LOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. This study demonstrated that the rabbit was the most sensitive animal, the worst case. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties

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:
0.6 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal N(L)OAEL=oral (N(L)OAEL*( ABSoral/ABSdermal) with ABSoralrat=90% and ABSdermalhuman=0.06; Dermal N(L)OAEL=2*(0.9/0.06)=30
AF for dose response relationship:
1
Justification:
There is no clear evidence for developmental dose effects in rats at exposure levels up 2mg/kg/day. This is supported by other developmental rat study. Application of a factor to take account of uncertainties in the dose-response relationship above the NOAEL is not justified.
AF for differences in duration of exposure:
1
Justification:
The dose descriptor was obtained from a 2 generation study in the rat. This AF is not applied
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a 2 generation study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to HMX in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.36 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):
150
Modified dose descriptor starting point:
NOAEL
Value:
504 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The difference in exposure time in the animal study compared with a day at work for the worker. The rabbit exposure was 24h while a day at work is 8h. Therefore the starting NOAEL is corrected by multiplying by a 1/3
AF for dose response relationship:
5
Justification:
The NOAEL was derived from a LOAEL and at this LOAEL toxic effects were marked.
AF for interspecies differences (allometric scaling):
2.4
Justification:
The dose descriptor is obtained from a developmental study in the rabbit. It is therefore necessary to apply an allometric scaling factor of 2.4 to take account of differences in basal metabolic rates between rabbits and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. This study demonstrated that the rabbit was the most sensitive animal, the worst case. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties

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

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.14 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
3.53 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation oral to inhalation:1 because oral absorption is 100%, difference in respiratory volumes: 0.38x(10/6.7)=0.5746
AF for dose response relationship:
1
Justification:
There is no clear evidence for developmental dose effects in rats at exposure levels up 2mg/kg/day. This is supported by other developmental rat study. Application of a factor to take account of uncertainties in the dose-response relationship above the NOAEL is not justified.
AF for differences in duration of exposure:
1
Justification:
The dose descriptor was obtained from a developmental study in the rat. AF for exposure duration not necessary as long as the experimental exposure covers adequately the pregnancy of the rat.
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied.
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to HMX in the human population. The default factor of 10 forgeneral population will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.86 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Modified dose descriptor starting point:
NOAEC
Value:
139.58 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation oral to inhalation:2, difference in respiratory volumes: 0.12x(10/6.7)=0.18
AF for dose response relationship:
3
Justification:
The NOAEC was derived from a LOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. This study demonstrated that the rabbit was the most sensitive animal, the worst case. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties

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:
0.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Dermal N(L)OAEL=oral (N(L)OAEL*( ABSoral/ABSdermal) with ABSoralrat=90% and ABSdermalhuman=0.06%; Dermal N(L)OAEL=2*(0.9/0.06)=30
AF for dose response relationship:
1
Justification:
There is no clear evidence for developmental dose effects in rats at exposure levels up 2mg/kg/day. This is supported by other developmental rat study. Application of a factor to take account of uncertainties in the dose-response relationship above the NOAEL is not justified.
AF for differences in duration of exposure:
1
Justification:
The dose descriptor was obtained from a 2 generation study in the rat. This AF is not applied
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a 2 generation study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to HMX in the human population. The default factor of 10 forthe general population will therefore be used to take account of intraspecies differences
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.68 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):
300
Modified dose descriptor starting point:
NOAEL
Value:
504 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The difference in exposure time in the animal study compared with a day at work for the worker. The rabbit exposure was 24h while a day at work is 8h. Therefore the starting NOAEL is corrected by multiplying by a 1/3
AF for dose response relationship:
5
Justification:
The NOAEL was derived from a LOAEL and at this LOAEL toxic effects were marked.
AF for interspecies differences (allometric scaling):
2.4
Justification:
The dose descriptor is obtained from a developmental study in the rabbit. It is therefore necessary to apply an allometric scaling factor of 2.4 to take account of differences in basal metabolic rates between rabbits and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. This study demonstrated that the rabbit was the most sensitive animal, the worst case. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties

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:
0.02 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
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
Value:
2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No extrapolation
AF for dose response relationship:
1
Justification:
There is no clear evidence for developmental dose effects in rats at exposure levels up 2mg/kg/day. This is supported by other developmental rat study. Application of a factor to take account of uncertainties in the dose-response relationship above the NOAEL is not justified.
AF for differences in duration of exposure:
1
Justification:
The dose descriptor was obtained from a developmental study in the rat. AF for exposure duration not necessary as long as the experimental exposure covers adequately the pregnancy of the rat.
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a developmental study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.28 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
180
Modified dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No extrapolation
AF for dose response relationship:
3
Justification:
The NOAEL was derived from a LOAEL
AF for interspecies differences (allometric scaling):
2.4
Justification:
The dose descriptor is obtained from a developmental study in the rabbit. It is therefore necessary to apply an allometric scaling factor of 2.4 to take account of differences in basal metabolic rates between rabbits and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for HMX to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of acute exposure to HMX in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of animal studies conducted to methods equivalent to modern regulatory standards. A similar series of studies is available for the mouse and rat. This study demonstrated that the rabbit was the most sensitive animal, the worst case. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

DNELs for acute toxicity by the inhalation and dermal route have been derived as oral and dermal acute toxicity hazards (leading to CLP) have been identified for HMX and there is a potential for high peak exposures (section R8.1.2.5 of chapter R.8 of the Guidance on Information Requirements and Chemical Safety Assessment).

The results of repeated dose toxicity, teratogenicity and 2-generation studies performed with HMX or RDX have been used for the derivation of the long term DNELS. The studies performed with RDX will provide very conservative DNELs since RDX is toxic at lower doses than HMX (due to difference in oral absorption rate).

Table1. Available dose-descriptor(s) per endpoint for the submission substance as a result of its hazard assessment

Endpoint

Quantitative dose descriptor or other information on potency

Associated relevant effect

Remarks on the study

Local effect

Systemic effect

Acute toxicity

Oral

 

LOAEL= 2421mg/kg

CNS (Piloerection, hyperkinesia)

Rat study (Cuthbert et al., 1985)

Oral

 

LOAEL= 956mg/kg

CNS (hyperkinesia)

Mouse study (Cuthbert et al., 1985)

Oral

 

LOAEL= 50mg/kg/day

Severe CNS effects and death

Rabbit study (Cuthbert et al., 1985)

Dermal

 

LD50>5000mg/kg

No clinical signs, no deaths

Rat study (Cuthbert et al., 1985)

Dermal

 

LOAEL= 168mg/kg

Severe CNS effects

Rabbit study (Cuthbert et al., 1985)

Irritation/corrosivity

Eye

Not irritant

 

 

 

Skin

Not irritant

 

 

 

Respiratory tract

Not irritant

 

 

 

Sensitisation

Skin

Not sensitiser

 

 

 

Respiratory tract

Not sensitiser

 

 

 

Repeated dose toxicity (sub-acute/sub-chronic/chronic)

Oral

 

LOAEL 1280 mg/kg/day

Lymphocyte depletion in thymus and spleen, congestion of the kidneys, hepatocyte hyperplasia and cytoplasmic eosinophilia in liver

Rat 14 d dietary study, actual doses(Greenhough et al., 1985a)

Oral

 

NOAEL 51 mg/kg/day

Enlarged centrilobular cells with dark cytoplasm and focal tubular atrophy, dilatation and increased kidney weigh,Reduced body weight gains and food consumptions were observed,

more so at higher dose levels.

rat 13 week dietary study, actual doses (Everett et al., 1985)

Oral

 

LOAEL 119.5 mg/kg/day

Hyperkinesia,

At 300 mg/kg/day, Lymphocyte depletion in thymus and spleen, congestion of the kidneys, hepatocyte hyperplasia and cytoplasmic eosinophilia in liver

Mouse 14 d dietary study, actual doses(Greenhough et al., 1985b)

Oral

 

NOAEL 75.1 mg/kg/day

Mortalities in higher dose groups

mouse 13 week dietary study, actual doses (Everett and Maddock, 1985)

Carcinogenicity

Oral

-

-

 

 

Dermal

-

-

 

 

Inhalation

-

-

 

 

Reproductive and Developmental toxicity

Oral

 

General and developmental NOAEL= 2mg/kg/day RDX (read across)

 

Maternal effects at 20mg/kg/day were CNS effects and deaths and affected reproduction and pup development (pup number and weight

Rat teratogenicity study by gavage from day 6 to 19 using RDX (Cholakis et al., 1980)

Oral

 

General and developmental NOAEL= 6mg/kg/day 

RDX (read across)

Reduced fetal weight and length in pups, maternal effects (CNS effects and deaths) at 20mg/kg/day

Rat teratogenicity study by gavage from day 6 to 20 of gestation using RDX (Angerhofer et al., 1986)

Oral

 

General and developmental NOAEL= 20mg/kg/day 

RDX (read across)

Slight difference in weight gain of dams (not statistical) and not teratogenic at doses up to 20mg/kg bw.

Rabbit teratogenicity study by gavage from day 7 to 29 using RDX (Cholakis et al., 1980)

Oral

 

General and reproductive NOAEL=16mg/kg/day RDX (read across)

Death, reduced body weight, reduced

feed consumption,reduced number of pregnancies

and a poor survival of the offspring from the pregnanciesat the highest dose of 50mg/kg/day

Rat 2 generation dietary study study, nominal doses using RDX (Cholakis et al., 1980)

Developmental NOAEL= 5mg/kg/day

Decrease in F2 pup body

weightat 16mg/kg/day andincrease in number of

stillbirths; decrease in

pup survival in F1at 50mg/kg/day