Registration Dossier

Diss Factsheets

Administrative data

Workers - 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:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
148.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available for 1-(dimethylamino)propan-2-ol (CAS 108-16-7). Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the oral NOAEL of 120 mg/kg bw/day, obtained in the Key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 0.38 m³/kg/8h

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default)

- experimental exposure time = 7 days/week

- exposure time worker = 5 days/week

--> modified dose descriptor (corrected inhalatory NOAEC) = 120 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (50%/100%) * (7 exposure days/week; rat/5 exposure days/week; worker) = 148.1 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance: Starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance: The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance: No additional factor needed for extrapolation from oral to inhalation route.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance: The recommended default AF for other interspecies differences is applied.
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance: The recommended default AF for workers is applied.
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance: The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance: Default factor. The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/m³
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:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. No oral absorption data are available for dimepranol either, therefore an absorption of 50% is assumed for the oral route. Regarding dermal absorption,dimepranol 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 dimepranol (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

Dimepranol is classified for acute oral, and dermal 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

Dimepranol is classified for Skin Corrosion Cat. 1B (H314: Causes severe skin burns and eye damage) and Eye Damage Cat. 1 (H318: Causes serious eye damage) (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 characterization 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

The study considered for DNEL derivation of dimepranol is a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422) in Wistar rats. Ten male and ten female Wistar rats per group were given dimepranol at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0), 40 mg/kg bw/d (test group 1), 120 mg/kg bw/d (test group 2) and 375 mg/kg bw/d (test group 3) in the course of a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test performed according to OECD TG 422 and GLP. Deionized water served as vehicle, control animals were dosed daily with the vehicle only. The duration of treatment covered a 2-week premating period and mating in both sexes (mating pairs were from the same test group) as well as entire gestation and lactation period in females up to one day prior to the day of schedule sacrifice of the animals. Regarding clinical examinations, obvious signs of general systemic toxicity were observed in female animals of test group 3 (375 mg/kg bw/d) during the premating period when treated at 375 mg/kg bw/d. Food consumption was significantly reduced and body weight loss occurred during the first week of treatment. Respiration sounds were observed in 2 male and 2 female animals of the same test group. Male animal No. 31 of test group 3 showed respiration sounds between study days 28 to 31. These changes were assessed to be related to treatment and adverse. Furthermore, one female animal of test group 3 was found dead on study day 5. Because no explanation for the premature death of this individual could be given after pathological examinations and no other animal died ahead of schedule, its occurrence was assessed to be spontaneous in nature and not related to treatment. However, having the results of the range-finding study in mind together with the occurrence of the mentioned findings and the premature death of one animal during the first days of application, a reduction of the dose level seemed to be necessary. Thus, it was reduced to 240 mg/kg bw/d from study day 10 onwards. Concerning clinical pathology, no treatment-related, adverse effects were observed up to a dose level of the compound of 375 and 240 mg/kg bw/d. Regarding pathology, no treatment-related findings were identified. All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment. Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration by gavage of the test substance to male and female Wistar rats revealed signs of systemic toxicity at a dose level of 375 mg/kg bw/d taking clinical findings in male and female animals into account. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 120 mg/kg bw/d for male for female Wistar rats.

 

Mutagenicity

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

 

Reproduction toxicity

Under the conditions of a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422, GLP), the oral administration of the test item by gavage to Wistar rats did not cause adverse effects on fertility and reproduction and did not cause signs of developmental toxicity up to the highest tested dose. Therefore, dimepranol is not classified for toxicity to reproduction or developmental toxicity. Based on this, no separate risk characterisation for is needed.

 

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 long-term toxicity, regarding systemic effects, a NOAEL of 120 mg/kg bw/day was observed in a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test (OECD TG 422). This NOAEL is used in the derivation of the DNELs. An absorption of 50% is assumed for the oral route.

 

Inhalation:Exposure to aerosols or droplets of an inhalable size cannot be excluded. Long-term inhalation toxicity data is not available and therefore route-to-route extrapolation is performed. An absorption of 100% is assumed for the inhalation route.

 

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

 

Tab. 1: DNEL derivation for long-term –inhalation, systemic effects (based on sub-acute combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test):

Description

Value

Remanrk

Step 1) Relevant dose-descriptor

NOAEL: 120 mg/kg bw/day

Based on clinical signs (respiration sounds), bod weight loss and reduced food consumption.

Step 2) Modification of starting point

100% / 50%

Ratio of oral to inhalation absorption (default value, as proposed in the REACH guidance (R.8.4.2))

 

0.38 m3/kg bw

An 8 h respiratory volume of 0.38 m3/kg bw for rats was used for conversion into NOAEL upon inhalation exposure.

 

6.7 m3/10 m3

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

 

7 d/wk (rat) / 5 d/wk (worker)

Correction for exposure time driven differences of in laboratory animals compared to workers.

Modified dose descriptor

148.1 mg/m3

 

Step 3) Assessment factors

 

 

Dose-response

1

Starting point for the DNEL calculation is a NOAEL, therefore no additional factor is used.

Duration of exposure (subacute)

6

The recommended AF for the extrapolation from sub-acute to chronic exposure is applied.

Interspecies differences (Allometric scaling)

-

No additional factor needed for extrapolation from oral to inhalation route.

Other interspecies differences

2.5

The recommended default AF for other interspecies differences is applied.

Intraspecies differences

5

The recommended default AF for workers is applied.

AF Quality of database

1

The quality of the whole data base is considered to be sufficient and uncritical.

Remaining uncertainties

1

The approach used for DNEL derivation is conservative. No further assessment factors are required.

DNEL

2.0 mg/m3

Calculation: NOEAL * (1/0.38) * (50/100) * (6.7/10) * (7/5) / (1*6*2.5*5*1)

Overall Assessment factor

75

 

 

Long-term - inhalation, local effects:No data are available based on which a DNEL for local effects can be derived. There are also no data to suggest that the substance may cause local effects by inhalation exposure.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Since there are no consumer uses of 1-(dimethylamino)propan-2-ol (CAS 108-16-7) and, therefore, relevant exposure of the general population can be ruled out, DNEL derivation for the general population is not required.

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

Since there are no consumer uses of 1-(dimethylamino)propan-2-ol (CAS 108-16-7), and therefore, relevant exposure of the general population can be ruled out, DNEL derivation for the general population is not required.