Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
DNEL value:
480 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 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):
300
Modified dose descriptor starting point:
NOAEL
DNEL value:
3 000 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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 inhalation absorption are available. Therefore for the DNEL derivation the default as reported in the REACH guidance will be used, i.e. 100%.

 

Acute toxicity

1,1’-(methylimino)-dipropane-2-ol does not have to be labelled for acute toxicity and therefore derivation of a DNELacute is not necessary.

 

Irritation

1,1’-(methylimino)-dipropane-2-ol is classified for skin corrosion (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 contact.

 

Sensitisation

1,1’-(methylimino)-dipropane-2-ol is not considered a skin sensitiser.

 

Long-term toxicity

The studies which are considered for DNEL derivation of 1,1’-(methylimino)-dipropane-2-ol are the 28 day dermal toxicity study with rats and the 90 day oral toxicity study with dogs conducted with tris-(2-hydroxypropyl)-amine.

1,1’-(methylimino)-dipropane-2-ol and tris-(2-hydroxypropyl)-amine are structurally very similar low molecular weight tertiary amines, which differ only in terms of a methyl group and an isopropanol moiety, respectively. They are low volatile (vapour pressure ≤ 0.015 hPa) organic compounds with similar specific gravity (1,1’-(methylimino)-dipropane-2-ol: 147.22 g/mol and tris-(2-hydroxypropyl)-amine: 191.27 g/mol) and log Pow values between -0.03 for 1,1’-(methylimino)-dipropane-2-ol and -0.02 for tris-(2-hydroxypropyl)-amine. Moreover, the comparison of the available toxicity data for both compounds indicates a similar toxicological profile: the substances are showing low acute toxicity by the oral route (i.e. oral LD50 values for 1,1’-(methylimino)-dipropane-2-ol of 2150 mg/kg bw and beyond 5000 mg/kg bw for tris-(2-hydroxypropyl)-amine. Tris-(2-hydroxypropyl)-amine is irritating to the eyes, whereas 1,1’-(methylimino)-dipropane-2-ol shows corrosive properties.The chemical difference between those two structures apparently do not affect the anticipated toxicity. For a detailed read across justification see also attached assessment report (Reporting Format for the analogue approach of 1,1’-(methylimino)-dipropane-2-ol with comparison to tris-(2-hydroxypropyl)-amine).

 

Tris-(2-hydroxypropyl)-amine was evaluated for potential systemic toxicity following repeated dermal administration. Groups of ten Fischer 344 rats (five/sex/dose) were administered 0 (control), 300, 1000 or 3000 mg tris-(2-hydroxypropyl)-amine/kg bw/day, dermally, 21 times over a 28-day interval. The highest concentration tested was a 75% tris-(2-hydroxypropyl)-aminesolution. Data was collected on the following: clinical appearance and behavior; in-life and terminal body weights; dermal irritation at the dosing site; clinical chemistry and hematological parameters; organ weights; and gross and histopathological appearance of tissues. All rats survived the test period and there were no indications of systemic toxicity observed in treated animals. At the end of the in-life dosing period, very slight erythema and scabs were observed at the dosing site of one male rat administered 1000 mg tris-(2-hydroxypropyl)-amine/kg bw/day and one female rat administered 3000 mg/kg bw/day. Histopathologically, the only effect attributed to treatment of tris-(2-hydroxypropyl)-amine was minimal thickening of the skin, termed epidermal hyperplasia, at the dosing site. This effect was noted in most, but not all, rats dosed with 3000 mg tris-(2-hydroxypropyl)-amine/kg bw/day.

There was no evidence of systemic toxicity in rats administered up to 3000 mg tris-(2-hydroxypropyl)-amine/kg bw/day. Therefore, the NOAEL for systemic toxicity was considered 3000 mg TIPA/kg bw/day, for male and female Fischer 344 rats following dermal administration.

 

Four beagle dogs/sex/dose at approximately 27 weeks of age were given test diets formulated to supply 0, 500, 2,000 or 7,500 ppm tris-(2-hydroxypropyl)-amine. Clinical observations, body weights, and food consumption were determined weekly throughout the study. Cage-site examinations for abnormal behavior and appearance were made at least twice daily. An ophthalmoscopic examination was conducted prior to the start of feeding the test diets, and at the end of the study. Hematology, serum chemistries, and urinalyses were conducted twice prior to the start of the study and after one, two, and three months of feeding. Blood methemoglobin concentrations were determined after two and three months of feeding. After 102 and 104 days of feeding, all dogs were sacrificed and subjected to gross and microscopic pathologic examination (including, but not limited to, gonads and related tissues). Selected organs were weighed.

No dogs died during the study. There were no effects that were considered compound related or biologically significant in any of the parameters measured. The mean daily intake of tris-(2-hydroxypropyl)-amine in the 0, 500, 2,000 and 7,500 ppm groups was 0, 16.8, 71.2, and 272 mg tris-(2-hydroxypropyl)-amine/kg bw/day for males and 0, 19.7, 78.3, and 288 mg/kg bw/day for females. Therefore, the NOAEL was considered 272 mg tris-(2-hydroxypropyl)-amine/kg bw/day for males and 288 mg/kg bw/day for females.

 

Mutagenicity and carcinogenicity

1,1’-(methylimino)-dipropane-2-ol is assessed as being non-mutagenic and not carcinogenic. Based on this, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

 

Reproduction toxicity

No two-generation study is available but acceptable repeated dose studies with tris-(2-hydroxypropyl)-amine are available. Since, the repeated dose studies did not reveal any adverse effects on the gonads or other fertility effects and no teratogenic effects were observed in a prenatal developmental toxicity study (OECD 414) a two-generation study is not expected to provide additional information.

 

Currently, there is no prenatal developmental toxicity study with 1,1’-(methylimino)-dipropane-2-ol available. Nevertheless, a developmental toxicity study via the oral route of exposure (OECD TG 414) was carried out with tris-(2-hydroxypropyl)-amine (CAS 122-20-3) and can be used for cross reading.

1,1’-(methylimino)-dipropane-2-ol and tris-(2-hydroxypropyl)-amine are structurally very similar low molecular weight tertiary amines, which differ only in terms of a methyl group and an isopropanol moiety, respectively. They are low volatile (vapour pressure ≤ 0.015 hPa) organic compounds with similar specific gravity (1,1’-(methylimino)-dipropane-2-ol: 147.22 g/mol and tris-(2-hydroxypropyl)-amine: 191.27 g/mol) and log Pow values between -0.03 for 1,1’-(methylimino)-dipropane-2-oland -0.02 for tris-(2-hydroxypropyl)-amine. Moreover, the comparison of the available toxicity data for both compounds indicates a similar toxicological profile: the substances are showing low acute toxicity by the oral route (i.e. oral LD50values for 1,1’-(methylimino)-dipropane-2-ol of 2150 mg/kg bw and beyond 5000 mg/kg bw for tris-(2-hydroxypropyl)-amine. Tris-(2-hydroxypropyl)-amine is irritating to the eyes, whereas 1,1’-(methylimino)-dipropane-2-ol shows corrosive properties. The chemical difference between those two structures apparently do not affect the anticipated toxicity. For a detailed read across justification see also attached assessment reports (Reporting Format for the analogue approach of 1,1’-(methylimino)-dipropane-2-ol with comparison to tris-(2-hydroxypropyl)-amine.

 

Twenty-five female Wistar rats were administered tris-(2-hydroxypropyl)-amine at 0, 100, 400 or 1000 mg/kg bw/day via oral gavage on gestation days 6 to 15 in an OECD guideline 414 study (BASF AG, 1995). Food consumption, body weights and clinical signs of the dams were recorded. At necropsy on day 20 post coitum, dams were investigated for gross pathology (including weight determination of the unopened uterus), fetuses were removed and sexed, weighed and further investigated for any external, soft tissue and/or skeletal findings. In the highest dose group, decreased food consumption and reduced body weight gain was observed in the dams. No further treatment-related effects were observed in the dams or in the fetuses. Thus, NOAELs of 400 mg/kg bw/day for maternal toxicity and 1000 mg/kg bw/day (the highest dose tested) for teratogenicity were established.

No DNEL has to be derived for developmental toxicity. There are no indications from the available data that dams are more sensitive regarding systemic effects compared to animals exposed in the repeated dose toxicity studies.

 

 

Worker DNELs

 

Long-term – dermal, systemic effects (based on sub-acute dermal toxicity study with rats)

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 3000 mg/kg bw/day

No systemic effects were observed up to the highest dose tested.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

5

Default assessment factor

Remaining differences

2.5

Default assessment factor

Exposure duration

3

Since the material is soluble and is unlikely to accumulate (Log Pow = -0.015) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et al. (2006), Regul Toxicol Pharmacol 46, 202-210). Combination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.

Dose response

1

 

Quality of database

2

 Read across

DNEL

Value

 

3000 / (4 x 5 x 2.5 x 3 x 1 x 2) = 10 mg/kg bw/day

 

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 272 mg/kg bw/day

No adverse effects were observed up to the highest dose tested

Step 2) Modification of starting point

: 0.19

 

 

 

 

 

x 6.7 m3/10 m3

 

 

 

x 50/100

An 8 h respiratory volume of 0.19 m3/kg bw for dogs is used for conversion into a NAEC upon inhalation exposure (calculated according to AIT recommended method (Alexander et al. (2008), Inhal Toxicol 20, 1179-1189), using BASF default bodyweight values).

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

Correction for absorption: 50% absorption after oral administration; 100% absorption is assumed for inhalation.

Modified dose-descriptor

272 x 6.7 x 50 / (0.19 x 10 x 100) = 480 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

5

Default assessment factor

Remaining differences

2.5

Default assessment factor

Exposure duration

2

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

Dose response

1

 

Quality of database

2

 Read across

DNEL

Value

 

480 / (1 x 5 x 2.5 x 2 x 1 x 2) = 9.6 mg/m3

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEC
DNEL value:
239 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 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):
600
Modified dose descriptor starting point:
NOAEL
DNEL value:
3 000 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
1.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
140
Modified dose descriptor starting point:
NOAEL
DNEL value:
272 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General population DNELs

 

Long-term – dermal, systemic effects (based on sub-acute dermal toxicity study with rats) 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 3000 mg/kg bw/day

No systemic effects were observed up to the highest dose tested.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Remaining differences

2.5

Default assessment factor

Exposure duration

3

Since the material is soluble and is unlikely to accumulate (Log Pow = -0.015) the sub-acute to sub-chronic assessment factor is considered 1.5 rather than the default factor 3 (Bitsch et al. (2006), Regul Toxicol Pharmacol 46, 202-210). Combination with the default sub-chronic to chronic factor 2 leads to a correction factor of 3.

Dose response

1

 

Quality of database

2

 Read across

DNEL

Value

 

3000 / (4 x 10 x 2.5 x 3 x 1 x 2) = 5 mg/kg bw/day

 

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 272 mg/kg bw/day

No adverse effects were observed up to the highest dose tested

Step 2) Modification of starting point

: 0.57

 

 

 

 

 

 

x 50/100

An 24 h respiratory volume of 0.57 m3/kg bw for dogs is used for conversion into a NAEC upon inhalation exposure (calculated according to AIT recommended method (Alexander et al. (2008), Inhal Toxicol 20, 1179-1189), using BASF default bodyweight values).

 

Correction for absorption: 50% absorption after oral administration; 100% absorption is assumed for inhalation.

Modified dose-descriptor

272 x 50 / (0.57 x 100) = 239 mg/m3

Step 3) Assessment factors

 

 

Interspecies

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.

Intraspecies

10

Default assessment factor

Remaining differences

2.5

Default assessment factor

Exposure duration

2

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

Dose response

1

 

Quality of database

2

 Read across

DNEL

Value

 

239 / (1 x 10 x 2.5 x 2 x 1 x 2) = 2.4 mg/m3

 

 

Long-term - inhalation, local effects

 

No data are available based on which a DNEL for local effects can be derived.

 

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

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 272 mg/kg bw/day

No adverse effects were observed up to the highest dose tested

Step 2) Modification of starting point

 

 

Step 3) Assessment factors

 

 

Interspecies

1.4

Allometric scaling

Intraspecies

10

Default assessment factor

Remaining differences

2.5

Default assessment factor

Exposure duration

2

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

Dose response

1

 

Quality of database

2

Read across 

DNEL

Value

 

272 / (1.4 x 10 x 2.5 x 2 x 1 x 2) = 1.9 mg/kg bw/day