Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL value:
0.4 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.15 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL value:
0.15 mg/m³
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:
0.15 mg/kg bw/day
Most sensitive endpoint:
repeated dose 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
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

Assessment of available data indicates that the substance has low acute toxicity by the oral, dermal and inhalation routes. It significantly decreased serum cholinesterase activity in rats following a single oral dose. However, this decrease in serum cholinesterase is not considered to be toxicologically significant. Therefore, there is no concern for acute toxicity.The substance is not a skin or eye irritant and is considered unlikely to be a respiratory irritant.Based on available data, the substance is not considered to be a skin sensitiser.No data are available on the respiratory sensitisation potential of the substance. There is currently no validated test method available to identify respiratory sensitisers. As the substance is produced in a closed system, and has a low vapour pressure, it is expected that exposure of the respiratory tract will be low. The substance is not suspected to be a respiratory sensitiser in humans as no specific cases of suspected respiratory sensitisation in the workplace have been reported.

For these reasons no DNELs need to be derived for short term oral, dermal and inhalation exposure and for local effects after short term or repeated exposure.

In relation to repeated dose toxicity, a NOAEL of 15 mg/kg/day was derived from a 28-day study in rats. It is based on an increase in absolute and relative liver weight combined with slight hepatocellular hypertrophy in females at the next higher dose of 150 mg/kg bw in a 28 day study. A NOAEL of 29 mg/kg bw after at least 77 days of exposure in a 2-generation feeding study in rats affecting the same target organs as also been derived.   The NOAEL is considered conservative as the effects were slight in the mid dose group of 150 mg/kg bw and are rather adaptive in nature. The dose spacing covered a factor of 10. In the longer duration 2-generation study the NOAEL was higher and the same target organs examined.

The substance showed no evidence of mutagenicity, either in vitro or in vivo.There are no carcinogenicity data for the substance. No evidence of mutagenicity was observed in either in vitro or in vivo genotoxicity studies with the substance and there were no indications of concerns for carcinogenicity from repeated dose toxicity studies. Therefore there is at present no concern for a possible carcinogenicity of the substance and no further studies are proposed for this endpoint.No effects were observed on the male or female reproductive systems in the two-generation reproductive toxicity study in rats. Therefore, there is no concern for fertility.EU (2008) derived a NOAEL of 29 mg/kg bw/day is derived for developmental toxicity from the 2 -generation study in rats. This was based on a treatment related increase in the number of runts and a decrease in pup body weight observed in mid and high dose groups. Assuming 100% absorption by the oral route, this leads to an internal body burden of 29 mg/kg/day. However,The original study report only considered reduced body weights and numbers of runts at the end of the lactation period in the high dose group as substance related effects in this study, that were due to direct substance intake via the feed and were not considered as developmental toxicity.Hence, according to the study report there was no developmental toxicity, but systemic toxicity to the offspring in the high-dose groups due to direct intake of the test substance, decreased body weight and numbers of runts at the end of the lactation period in the high dose F1 and F2 pups and decreased relative spleen weight in F2-pups of the high dose group. The toxicity to the developing pup was in the same order than that to adult animals, indicating that children are not a sensitive subgroup with regard to the effects of this substance and no additional assessment factor is needed for children.

Correction of dose descriptors

Route to route extrapolation:

The NOAELs for the different exposure routes are based on oral studies in rats. An in vivo toxicokinetic study with radiolabeled test substance indicated that the substance is completely absorbed in from the gastro-intestinal tract after oral administration (see section 7.1.). Therefore 100 percent absorption is calculated for the oral route. For inhalation exposure no experimental data with the substance are available and therefore the default factor suggested in ECHA, 2008 is used. An in vitro skin absorption study using human skin revealed absorption of 0.5% for the neat material and maximal 6% for a solution in ethanol (21 g/L). These absorption characteristics are considered when calculating the internal dose from dermal exposure as mg/kg bw/day and therefore the oral DNEL is also used for the dermal assessment.

Assessment factors applied:

All assessment factors derived below are consistent with the EU risk assessment report for 2,2-bis(chloromethyl) trimethylene bis(bis(2-chloroethyl) phosphate) (EU, 2008).

Repeated dose toxicity:

Duration extrapolation:

The lowest NOAEL of 15 mg/kg bw/day is derived from a 28-day oral (gavage) study in rats. In this study the dose spacing factor was 10 and the effects observed at the next higher dose level, 150 mg/kg bw/day were slight and rather adaptive in nature. In the 2-generation dietary study in rats pathological and histopathological investigations of the target organs for repeated dose toxicity were also performed and the NOAEL after at least 77 days of exposure was 29 mg/kg bw. Therefore, the NOAEL of 15 mg/kg bw/day can be considered to be relatively robust and an increase in duration of exposure (from sub-acute to sub-chronic) does not increase the severity of the effects seen and does not lower the NOAEL. An additional assessment factor for subacute to chronic extrapolation is therefore not applied. As no chronic data are available, a factor of 2 is applied for subchronic to chronic exposure (ECHA, 2008).

Interspecies differences:

An allometric scaling factor from rats to humans of 4 and an additional factor of 2.5 is applied for remaining uncertainties in the interspecies extrapolation. These factors are consistent with the default factors recommended in ECHA (2008).

Intraspecies factor for workers:

For workers a conservative intraspecies factor of 5 as suggested by ECHA, 2008 is applied..

Total assessment factor for repeated dose toxicity for workers:

2 x 4 x 2.5 x 5 = 100.

Reproductive and developmental toxicity.

Duration extrapolation:

For these endpoints no duration extrapolation is needed (factor 1) as they are based on a 2-generation study.

Interspecies differences:

An allometiric scaling factor from rats to humans of 4 and an additional factor of 2.5 is applied for remaining uncertainties in the interspecies extrapolation. These factors are consistent with the default factors recommended in ECHA (2008).

Intraspecies factor for workers:

For workers a conservative default intraspecies factor of 5 is applied in accordance with ECHA, 2008.

Total assessment factor for reproductive and developmental toxicity for workers:

4 x 2.5 x 5 = 50

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.065 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
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:
0.075 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
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:
0.075 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
200
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

Assessment of available data indicates that the substance has low acute toxicity by the oral, dermal and inhalation routes. It significantly decreased serum cholinesterase activity in rats following a single oral dose. However, this decrease in serum cholinesterase is not considered to be toxicologically significant. Therefore, there is no concern for acute toxicity. The substance is not a skin or eye irritant and is considered unlikely to be a respiratory irritant. Based on available data, the substance is not considered to be a skin sensitiser. No data are available on the respiratory sensitisation potential of the substance. There is currently no validated test method available to identify respiratory sensitisers. As the substance is produced in a closed system, and has a low vapour pressure, it is expected that exposure of the respiratory tract will be low. The substance is not suspected to be a respiratory sensitiser in humans as no specific cases of suspected respiratory sensitisation in the workplace have been reported.

For these reasons no DNELs need to be derived for short term oral, dermal and inhalation exposure and for local effects after short term or repeated exposure.

In relation to repeated dose toxicity, a NOAEL of 15 mg/kg/day was derived from a 28-day study in rats. It is based on an increase in absolute and relative liver weight combined with slight hepatocellular hypertrophy in females at the next higher dose of 150 mg/kg bw in a 28 day study. A NOAEL of 29 mg/kg bw after at least 77 days of exposure in a 2-generation feeding study in rats affecting the same target organs as also been derived.   The NOAEL is considered conservative as the effects were slight in the mid dose group of 150 mg/kg bw and are rather adaptive in nature. The dose spacing covered a factor of 10. In the longer duration 2-generation study the NOAEL was higher and the same target organs examined. The substance showed no evidence of mutagenicity, either in vitro or in vivo. There are no carcinogenicity data for the substance. No evidence of mutagenicity was observed in either in vitro or in vivo genotoxicity studies with the substance and there were no indications of concerns for carcinogenicity from repeated dose toxicity studies. Therefore there is at present no concern for a possible carcinogenicity of the substance and no further studies are proposed for this endpoint. No effects were observed on the male or female reproductive systems in the two-generation reproductive toxicity study in rats. Therefore, there is no concern for fertility. EU (2008) derived a NOAEL of 29 mg/kg bw/day is derived for developmental toxicity from the 2 -generation study in rats. This was based on a treatment related increase in the number of runts and a decrease in pup body weight observed in mid and high dose groups. Assuming 100% absorption by the oral route, this leads to an internal body burden of 29 mg/kg/day. However, The original study report only considered reduced body weights and numbers of runts at the end of the lactation period in the high dose group as substance related effects in this study, that were due to direct substance intake via the feed and were not considered as developmental toxicity. Hence, according to the study report there was no developmental toxicity, but systemic toxicity to the offspring in the high-dose groups due to direct intake of the test substance, decreased body weight and numbers of runts at the end of the lactation period in the high dose F1 and F2 pups and decreased relative spleen weight in F2-pups of the high dose group. The toxicity to the developing pup was in the same order than that to adult animals, indicating that children are not a sensitive subgroup with regard to the effects of this substance and no additional assessment factor is needed for children.

Correction of dose descriptors Route to route extrapolation:

The NOAELs for the different exposure routes are based on oral studies in rats. An in vivo toxicokinetic study with radiolabeled test substance indicated that the substance is completely absorbed in from the gastro-intestinal tract after oral administration (see section 7.1.) Therefore 100 percent absorption is calculated for the oral route. For inhalation exposure no experimental data with the substance are available and therefore the default factor suggested in ECHA, 2008 is used. An in vitro skin absorption study using human skin revealed absorption of 0.5% for the neat material and maximal 6% for a solution in ethanol (21 g/L). These absorption characteristics are considered when calculating the internal dose from dermal exposure as mg/kg bw/day and therefore the oral DNEL is also used for the dermal assessment.

Assessment factors applied: All assessment factors derived below are consistent with the EU risk assessment report for 2,2-bis(chloromethyl) trimethylene bis(bis(2-chloroethyl) phosphate) (EU, 2008).

Repeated dose toxicity:

Duration extrapolation:

The lowest NOAEL of 15 mg/kg bw/day is derived from a 28-day oral (gavage) study in rats. In this study the dose spacing factor was 10 and the effects observed at the next higher dose level, 150 mg/kg bw/day were slight and rather adaptive in nature. In the 2-generation dietary study in rats pathological and histopathological investigations of the target organs for repeated dose toxicity were also performed and the NOAEL after at least 77 days of exposure was 29 mg/kg bw. Therefore, the NOAEL of 15 mg/kg bw/day can be considered to be relatively robust and an increase in duration of exposure (from sub-acute to sub-chronic) does not increase the severity of the effects seen and does not lower the NOAEL. An additional assessment factor for subacute to chronic extrapolation is therefore not applied. As no chronic data are available, a factor of 2 is applied for subchronic to chronic exposure (ECHA, 2008).

Interspecies differences: An allometric scaling factor from rats to humans of 4 and an additional factor of 2.5 is applied for remaining uncertainties in the interspecies extrapolation. These factors are consistent with the default factors recommended in ECHA (2008). Intraspecies factor: For consumers and humans indirectly exposed via the environment a conservative default intraspecies factor of 10 is applied in accordance with ECHA, 2008.

Total assessment factor for repeated dose toxicity for consumers and humans indirectly exposed via the environment:

2 x 4 x 2.5 x 10 = 200

Reproductive and developmental toxicity.

Duration extrapolation:

For these endpoints no duration extrapolation is needed (factor 1) as they are based on a 2-generation study.

Interspecies differences:

An allometiric scaling factor from rats to humans of 4 and an additional factor of 2.5 is applied for remaining uncertainties in the interspecies extrapolation. These factors are consistent with the default factors recommended in ECHA (2008).

Intraspecies factor:

For consumers and humans indirectly exposed via the environment a conservative default intraspecies factor of 10 is applied in accordance with ECHA, 2008.

Total assessment factor for reproductive and developmental toxicity for consumers and humans indirectly exposed via the environment:

4 x 2.5 x 10 = 100