3-dimethylaminopropan-1-ol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

8.18 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):

20

Modified dose descriptor starting point:

NOAEC

Value:

163.6 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction for MW (103.2 /89.1) between dimethylaminopropanol and DMAE. A factor of 0.75 (6h/8h) was applied to correct for the differences in the experimental and worker exposure conditions. Finally, a correction factor for activity driven differences of respiratory volumes in workers compared to workers in rest of 0.67 was used (6.7 m3/10m3).

AF for differences in duration of exposure:

2

Justification:

Extrapolation to chronic exposure based on a sub-chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of inhalation exposure

AF for intraspecies differences:

5

Justification:

Default assessment factor

AF for the quality of the whole database:

2

Justification:

Assessment factor for read-across

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.09 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor:

NOAEC

AF for differences in duration of exposure:

1

Justification:

No assessment factor has to be applied for local effects

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of inhalation exposure

AF for intraspecies differences:

5

Justification:

Default assessment factor

AF for the quality of the whole database:

2

Justification:

Assessment factor for read-across

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 0.5 in case of inhalation-to-oral extrapolation (i.e. 100% absorption for the inhalation route and 50% absorption for the oral route). This approach will be taken forward to DNEL derivation. Regarding dermal absorption, dimethylaminopropanol is corrosive to the skin (if necessary, the figure for dermal absorption would be equal to oral absorption). In case the exposure assessment shows that exposure occurs to non-corrosive concentrations of dimethylaminopropanol (which can be determined using the information on mixtures/preparations reported in Regulation (EC) 1272/2008), a dermal DNEL for these non-corrosive concentrations has to be derived.

 

Acute toxicity

Dimethylaminopropanol has to be classified for acute oral toxicity. However, a short-term DNEL is deemed unnecessary because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.

 

Irritation

Dimethylaminopropanol is classified as corrosive to skin and eyes (C, R34). The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion. 

 

Sensitization

No data on sensitization are available. The study does not need to be conducted as the substance is classified for corrosivity.

 

Repeated dose toxicity

No repeated dose toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used for read-across. The data from the inhalation repeated dose toxicity study with DMAE (Klonne et al., 1987) is taken to derive the DNEL of Dimethylaminopropanol, using the inhalation rat NOAEC of 76 ppm (281.1 mg/m³) for systemic and the NOEC of 24 ppm (87.5 mg/m3) for local effects respectively. In the two-week inhalation study, rats exposed to higher concentrations of DMAE vapour (98, 288 and 586 ppm) during an 11 -day period exhibited severe signs of respiratory and ocular irritation (except the 98 ppm group). All animals of the 586 ppm group and 4 of 15 male rats of the 288 ppm group died. Body weight values for the 288 ppm group were reduced to about 75% of pre-exposure values, while the 98 ppm group gained 35% less weight than controls. Statistically significant differences in clinical pathology parameters (288 ppm group) and in organ weight values (288 and 98 ppm groups) probably resulted from the decreased food consumption and not from specific target organ toxicity. In the groups evaluated histologically (the 98 and 288 ppm groups) the eye and nasal mucosa were the primary target organs.

In the 13-week sub-chronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks (Klonne et al., 1987). No animals died during the study. The body weight gains for both sexes of the 76 ppm group were statistically significantly lower than control values for most of the latter half of the 13-week exposure time. The body weight gain values for the 76 ppm group returned to control values during the recovery period and were therefore considered non-advers. There were no exposure-related of body weight gain for rats exposed to 8 or 24 ppm of DMEA. There were no exposure-related effects on the neurobehavioral, food and water consumption, hematologic, serum chemistry, or urinalysis evaluations, on organ weights, or on the gross appearance of organs. Exposure-related nasal lesions were observed histologically at the termination of exposures in both sexes of the 76 ppm group, but were generally not observed in rats of the 24 ppm group. The lesions were limited to the anterior nasal cavity and included squamous metaplasia, microcysts and mucous cell hyperplasia of the respiratory epithelium, mild rhinitis and atrophy of the dorsal olfactory epithelium. The incidence and severity of these lesions were decreased at the end of the recovery period, indicating some degree of repair. Additionally, 4/10 males had laryngitis and two of these rats also had tracheitis. No similar lesions were found in female rats. Vacuolization of the corneal epithelium was observed in 3/10 female rats of the 76 ppm group at the termination of exposures but not at the end of the recovery period. Corneal opacity occurred in the 24 and 76 ppm groups at the end of the daily exposure, beginning approximately 2-3 weeks after initiation of exposures. The opacity regressed during the night-time nonexposure hours. There was also a moderate incidence (approximately 25%) of audible respiration in rats of the 76 ppm group.

 

Mutagenicity

Dimethylaminopropanol is assessed as being non-mutagenic. Based on this, no separate risk characterisation for mutagenicity is needed.

 

Reproduction toxicity

No reproduction and developmental toxicity study is available for Dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used for read-across. In the Modified Developmental Toxicity Screening Study in Wistar rats with DMAE (BASF, 2008), the test material was administered to time-pregnant female rats orally by gavage from gestation day (GD) 6 through GD 19 (prenatal study part) or GD 6 through postnatal day (PND) 3 (postnatal study part) at dose levels 300 and 600 mg/kg bw/day. In the prenatal part of study, the clinical signs by dams included salivation, respiratory sounds, statistically significant reduced food consumption as well as reduced mean body weight and body weight change. One animal was found dead and another was sacrificed moribund on GD 14. Gross patology revealed increased liver weight compared to the control group (100%) and post-implantation loss compared to the control group and the historical control data (11.8% vs. 5.2% in control). In 8 out of 10 animals, stomach erosion/ulcera were observed. No substance related findings were observed in fetuses. Viability of pups was affected more severe (see below). In the postnatal part of study, 7 animals out of 8 delivered their pups. Live birth index was 91% (control 100%). The stomach erosion/ulcera were also the common observation. In the 300 mg/kg bw dose group, post implantation losses and increased resorption occured in the range of strong ulcera in the stomach. No test substance-related findings in fetuses and pups were observed. No DNEL has to be derived for developmental and reproductive toxicity. For further details also refer to IUCLID chapter 7.8.

 

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.

 

Oral: For the general population oral exposurecannot be excluded. Long-term oral toxicity data is not available and therefore route-to-route extrapolation is performed. An absorption of 50% is assumed for the oral route.

 

Inhalation: For long-term toxicity, regarding systemic effects, a NOAEC of 76 ppm (281.1 mg/m³) was observed in a in the 13-week sub-chronic study.

For long-term toxicity, regarding local effects, a NOAEC of 24 ppm (87.5 mg/m³) was observed accordingly. These NO(A)ECs were used for the derivation of the respective DNELs.

Dermal: As dimethylaminopropanol is a corrosive substance, dermal exposure is not expected. Therefore, a dermal DNEL has not been derived.

Long-term – dermal, systemic effects 

No dermal DNELs have been derived as Dimethylaminopropanol is corrosive to the skin and no quantitative data is available. Therefore, applicable RMM should be used for safe use.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 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):

40

Modified dose descriptor starting point:

NOAEC

Value:

81.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

Correction for MW (103.2 /89.1) between dimethylaminopropanol and DMAE. A factor of 0.25 (6h/24h) was applied to correct for the differences in the experimental and general population exposure conditions.

AF for differences in duration of exposure:

2

Justification:

Extrapolation to chronic exposure based on a sub-chronic toxicity study

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of inhalation exposure

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

2

Justification:

Assessment factor for read-across

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.27 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor:

NOAEC

AF for differences in duration of exposure:

1

Justification:

No assessment factor has to be applied for local effects

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling has to be applied in case of inhalation exposure

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

2

Justification:

Assessment factor for read-across

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.7 mg/kg bw/day

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):

160

Modified dose descriptor starting point:

NOAEL

Value:

116.5 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A 24 h respiratory volume of 1.15 m3/kg bw for rats was used for conversion into NOAEL upon inhalation exposure

AF for differences in duration of exposure:

2

Justification:

Extrapolation to chronic exposure based on a sub-chronic toxicity study

AF for interspecies differences (allometric scaling):

4

Justification:

Default assessment factor

AF for intraspecies differences:

10

Justification:

Default assessment factor

AF for the quality of the whole database:

2

Justification:

Assessment factor for read-across

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

 

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 0.5 in case of inhalation-to-oral extrapolation (i.e. 100% absorption for the inhalation route and 50% absorption for the oral route). This approach will be taken forward to DNEL derivation. Regarding dermal absorption,dimethylaminopropanol is corrosive to the skin (if necessary, the figure for dermal absorption would be equal to oral absorption).In case the exposure assessment shows that exposure occurs to non-corrosive concentrations of dimethylaminopropanol (which can be determined using the information on mixtures/preparations reported in Regulation (EC) 1272/2008), a dermal DNEL for these non-corrosive concentrations has to be derived.

 

Acute toxicity

Dimethylaminopropanol has to be classified for acute oral toxicity. However, a short-term DNEL is deemed unnecessary because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.

 

Irritation

Dimethylaminopropanol is classified as corrosive to skin and eyes (C, R34). The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and eye corrosion. 

 

Sensitization

No data on sensitization are available. The study does not need to be conducted as the substance is classified for corrosivity.

 

Repeated dose toxicity

No repeated dose toxicity study is available for dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used for read-across. The data from the inhalation repeated dose toxicity study with DMAE (Klonne et al., 1987) is taken to derive the DNEL of Dimethylaminopropanol, using the inhalation rat NOAEC of 76 ppm (281.1 mg/m³) for systemic and the NOEC of 24 ppm (87.5 mg/m3) for local effects respectively. In the two-week inhalation study, rats exposed to higher concentrations of DMAE vapour (98, 288 and 586 ppm) during an 11 -day period exhibited severe signs of respiratory and ocular irritation (except the 98 ppm group). All animals of the 586 ppm group and 4 of 15 male rats of the 288 ppm group died. Body weight values for the 288 ppm group were reduced to about 75% of pre-exposure values, while the 98 ppm group gained 35% less weight than controls. Statistically significant differences in clinical pathology parameters (288 ppm group) and in organ weight values (288 and 98 ppm groups) probably resulted from the decreased food consumption and not from specific target organ toxicity. In the groups evaluated histologically (the 98 and 288 ppm groups) the eye and nasal mucosa were the primary target organs.

In the 13-week sub-chronic study, F-344 rats were exposed to 0, 8, 24, or 76 ppm DMEA for 6 hr/day, 5 days/week for 13 weeks (Klonne et al., 1987). No animals died during the study. The body weight gains for both sexes of the 76 ppm group were statistically significantly lower than control values for most of the latter half of the 13-week exposure time. The body weight gain values for the 76 ppm group returned to control values during the recovery period and were therefore considered non-advers. There were no exposure-related of body weight gain for rats exposed to 8 or 24 ppm of DMEA. There were no exposure-related effects on the neurobehavioral, food and water consumption, hematologic, serum chemistry, or urinalysis evaluations, on organ weights, or on the gross appearance of organs. Exposure-related nasal lesions were observed histologically at the termination of exposures in both sexes of the 76 ppm group, but were generally not observed in rats of the 24 ppm group. The lesions were limited to the anterior nasal cavity and included squamous metaplasia, microcysts and mucous cell hyperplasia of the respiratory epithelium, mild rhinitis and atrophy of the dorsal olfactory epithelium. The incidence and severity of these lesions were decreased at the end of the recovery period, indicating some degree of repair. Additionally, 4/10 males had laryngitis and two of these rats also had tracheitis. No similar lesions were found in female rats. Vacuolization of the corneal epithelium was observed in 3/10 female rats of the 76 ppm group at the termination of exposures but not at the end of the recovery period. Corneal opacity occurred in the 24 and 76 ppm groups at the end of the daily exposure, beginning approximately 2-3 weeks after initiation of exposures. The opacity regressed during the night-time nonexposure hours. There was also a moderate incidence (approximately 25%) of audible respiration in rats of the 76 ppm group.

 

Mutagenicity

Dimethylaminopropanol is assessed as being non-mutagenic. Based on this, no separate risk characterisation for mutagenicity is needed.

 

Reproduction toxicity

No reproduction and developmental toxicity study is available for Dimethylaminopropanol. Dimethylethanolamine (DMAE, CAS 108-01-0) is a structural analogue of dimethylaminopropanol and was used for read-across. In the Modified Developmental Toxicity Screening Study in Wistar rats with DMAE (BASF, 2008), the test material was administered to time-pregnant female rats orally by gavage from gestation day (GD) 6 through GD 19 (prenatal study part) or GD 6 through postnatal day (PND) 3 (postnatal study part) at dose levels 300 and 600 mg/kg bw/day. In the prenatal part of study, the clinical signs by dams included salivation, respiratory sounds, statistically significant reduced food consumption as well as reduced mean body weight and body weight change. One animal was found dead and another was sacrificed moribund on GD 14. Gross patology revealed increased liver weight compared to the control group (100%) and post-implantation loss compared to the control group and the historical control data (11.8% vs. 5.2% in control). In 8 out of 10 animals, stomach erosion/ulcera were observed. No substance related findings were observed in fetuses. Viability of pups was affected more severe (see below). In the postnatal part of study, 7 animals out of 8 delivered their pups. Live birth index was 91% (control 100%). The stomach erosion/ulcera were also the common observation. In the 300 mg/kg bw dose group, post implantation losses and increased resorption occured in the range of strong ulcera in the stomach. No test substance-related findings in fetuses and pups were observed.No DNEL has to be derived for developmental and reproductive toxicity. For further details also refer to IUCLID chapter 7.8.

  

DNEL derivation

For short-term toxicity, no DNEL needs to be derived for all routes of exposure, because the long-term DNELs are considered to ensure sufficient protection to prevent peak exposure.

 

Oral: For the general population oral exposurecannot be excluded. Long-term oral toxicity data is not available and therefore route-to-route extrapolation is performed. An absorption of 50% is assumed for the oral route.

Inhalation: For long-term toxicity, regarding systemic effects, a NOAEC of 76 ppm (281.1 mg/m³) was observed in a in the 13-week sub-chronic study.

For long-term toxicity, regarding local effects, a NOAEC of 24 ppm (87.5 mg/m³) was observed accordingly. These NO(A)ECs were used for the derivation of the respective DNELs.

 

Dermal: As dimethylaminopropanol is a corrosive substance, dermal exposure is not expected. Therefore, a dermal DNEL has not been derived.

Long-term –inhalation, systemic effects (based on sub-chronic inhalation toxicity study with rats with DMAE)

 

Long-term - inhalation, local effects (based on sub-chronic inhalation toxicity study with rats with DMAE) 

Long-term – dermal, systemic effects 

No dermal DNELs have been derived as Dimethylaminopropanol is corrosive to the skin and no quantitative data is available. Therefore, applicable RMM should be used for safe use.

Long-term – oral, systemic effects (based on sub-chronic inhalation toxicity study with rats with DMAE)