Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.3 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):
25
Modified dose descriptor starting point:
NOAEC
Value:
82.7 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Default value (ECHA) for rat versus human
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for workers
AF for the quality of the whole database:
1
Justification:
Scientifically acceptable and sufficient documentd for evaluation
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Modified dose descriptor starting point:
NOAEC

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:
0.94 mg/kg bw/day
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:
NOAEL
Value:
67 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In the subchronic study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 (7/5) is used.

AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA) for rat versus human
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for workers
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for workers
AF for the quality of the whole database:
1
Justification:
Scientifically acceptable and sufficient documentd for evaluation
AF for remaining uncertainties:
1
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

INTRODUCTORY NOTE

Trimethylopropane is a solid at room temperature which does not cause irritational effects to the skin or mucous membranes. Thus the local effects are not the prominent effects which have to be considered with regard to toxicity evaluation of trimethylolpropane. Based on these considerations it is assumed that local effects are covered by the DNELs for the systemic toxicity and no separate DNELs for local effects were derived. Furthermore, the available data have shown that TMP has a low toxicological potential [e.g LD50(oral) >2000 mg/kg bw and a NOAEL(oral, 13w ) of ca. 0.1 % in diet (approx.67 mg/kg bw/day) based on unspecific liver and spleen effects at higher dosages of 0.3% and 1% of TMP in food.]

WORKER

For workers the oral DNELs are not relevant and are therefore not applicable for trimethylolpropane. Only the dermal and the inhalation route are regarded to be relevant in the case of trimethylolpropane.

WORKER DNEL (systemic, long term)

Worker DNEL (systemic, long term, dermal route)

There are no long term toxicity data available using the dermal exposure route . However, there are two reliable sub-chronic studies available which could be taken as starting point. Trimethylolpropane was given to young male and female Wistar rats at 0, 0.03, 0.1, 0.3, 1.0 % in diet (corresponding to 20, 67, 200 or 667 mg/kg bw/d) for three months. On the basis of the presented results (see section 5.6.1.1), the NOAEL is considered 0.1 % in the diet which is equivalent to 67 mg/kg bw/day (de Knecht-van Eekelen, at the request of Bayer AG, 1969 and at the request of Perstorp AB, 1969).

NOAEL: 67 mg/kg bw/day

In the subchronic study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 (7/5) is used.

• For extrapolation of exposure duration: sub-chronic to chronic: 2

• For interspecies differences rat vs human: 4

• For remaining interspecies differences: 2.5

• For intraspecies differences in workers: 5

• For quality of the whole data base: 1

The database provides information on all relevant toxicological endpoints

Overall factor: 100

 DNEL (systemic, long-term, dermal route, Arbeiter) = 67 x 1.4 / 100 = 0.94 mg/kg/day

There is no toxicokinetic study available that provides definite information on dermal absorption. ECHA TG R 8, p.19, 2012 postulated that in general it can be assumed that dermal absorption will not be higher than oral absorption. Therefore no additional default factor should be introduced for the oral to dermal extrapolation. Based on this statement the derived value for oral exposure is taken as surrogate for the DNEL (systemic, longterm, dermal application)

Worker DNEL (systemic, long term, inhalation route)

There is no long term study available using the inhalation exposure route. In addition, there is no toxicokinetic study available which provides definite information on inhalation absorption. From results of acute toxicity studies using the inhalation route it can be assumed that inhalation absorption might be limited. However, due to the lack of toxicokinetic data the DNEL systemic longterm, oral route is taken as starting point without addition of a further default value to correct for inhalation absorption.

NOAEL: 67 mg/kg bw/day

Long-term inhalation route – systemic effects (worker) using extrapolation factors:

Correction of the starting point according ECHA Guidance Chapter R.8:

Corrected inhalation NOAEC = Oral NOAEL (67 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 7/5 x 0.5

=> NOAEC worker = 82.7 mg/m³

In the subchronic study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 (7/5) is used.

•For extrapolation of exposure duration: sub-chronic to chronic: 2

•For interspecies differences rat vs human: 1 (the AF of 4 is already included in the route to route extrapolation.)

•For remaining interspecies differences: 2.5

•For intraspecies differences in workers: 5

•For quality of the whole data base: 1

Overall factor: 25

  DNEL (systemic, long-term, inhalation route, Arbeiter) 3.3 mg/m³

Reproductive toxicity:

In the OECD TG 443 treatment related effects are observed at the high dose (ca. 1000 mg/kg) and the single occurrence of hydrocephaly and small eye in one pup at 740 ppm and partly closed eye in one pup at 2200 ppm might be a change finding but a test-item-related effect could not be fully excluded.

Effects observed in the OECD TG 414 and OECD TG 443 are taken into account by classification of the compound with Repr. Tox. Cat 2. The systemic DNEL covers developmental and fertility effects, since the NOAEL for systemic toxicity used for DNEL derivation is lower than the NOAEL of 100 mg/kg observed for developmental toxicity (OECD TG 414) and treatment related effects are observed in the OECD TG 443 only at the highest dose, 6600 ppm (ca. 1000 mg/kg).

Even if the observations in the OECD TG 443 at 2200 ppm and 740 ppm would not be chance findings, the corresponding DNEL would be higher than the DNEL for general toxicity.

Starting point reproductive toxicity DNEL:

74 mg/kg/bw in female rats (OECD TG 443 study, lowest dose tested)

 

As an example, derivation dermal DNEL, Worker, systemic long-time:

In the chronic study rats were dosed daily, whereas workers are exposed 5 days a week. Therefore a correction factor of 1.4 (7/5) is used.

• For extrapolation of exposure duration: chronic EOGRT study: 1

• For interspecies differences rat vs human: 4

• For remaining interspecies differences: 2.5

• For intraspecies differences in workers: 5

• For dose-response modifications of LOAEL to NOAEL: 2; the observations at 2200 and 740 ppm might be chance findings; so the study did not define a NOAEL for developmental toxicity, but also no LOAEL was defined. Here we have something between NOAEL and LOAEL and we consider an assessment factor of 2 is appropriate to account for the uncertainty but no higher factor based on the absence of a dose response and the possibility of a chance finding.

• For quality of the whole data base: 1

The database provides information on all relevant toxicological endpoints

Overall factor: 100

       DNEL (systemic, long-term, dermal route, Worker) = 74 x 1.4 / 100 = 1.04 mg/kg/day; since this value is above the systemic DNEL developmental toxicity is covered by the systemic DNEL.

WORKER DNEL (systemic, short term)

DNEL (systemic, short term, dermal route)

A DNEL short term is relevant for single events that occur for exposure periods ranging from a few minutes up to 24 hours. Therefore dermal acute exposure has to be considered. The respective results from acute dermal experiments in rabbits (1000, 2150, 4640, and 10000 mg/kg bw, 24 hour application time), however, show that dermal treatment was tolerated without any signs of intoxication or mortality.

The acute dermal LD50 is > 10000 mg/kg bw. A classification for acute dermal toxicity is not proposed and therefore no hazard is identified for acute dermal toxicity (systemic).

DNEL (systemic, short term, inhalation route)

In the key study for inhalation (Bayer 1965) rats were whole body exposed to concentrations up to 850 mg/m³ for four hours. No deaths and no clinical signs were reported neither during exposure nor during the 14 day post exposure observation period.

The exact LC50 was not determined, but is assumed much higher. This assumption is supported by the acute oral LD50 which is ca. 14700 mg/kg bw and the acute dermal LD50 which is greater than 10000 mg/kg bw. A classification for acute inhalation toxicity is not proposed. Therefore no hazard is identified for acute inhalation toxicity (systemic).

Trimethylolpropane is not irritating/corrosive to skin and eyes. Therefore for local effects no hazard is identified.

Critical DNEL

The critical DNELs are:

WORKER DNEL (systemic, long term, dermal): 0.94 mg/kg bw/day

WORKER DNEL (systemic, long term, inhalation): 3.3 mg/m³

WORKER DNEL (systemic, short term, dermal): no hazard identified

WORKER DNEL (systemic, long term, inhalation): no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 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
Value:
29 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Default value (ECHA) for rat versus human
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for general population
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Justification:
Scientifically acceptable and sufficient documentd for evaluation
AF for remaining uncertainties:
1
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:
0.34 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
67 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA) for rat versus human
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA)
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Justification:
Scientifically acceptable and sufficient documentd for evaluation
AF for remaining uncertainties:
1
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:
0.34 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
200
Modified dose descriptor starting point:
NOAEL
Value:
67 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Default value (ECHA) for sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA) for rat versus human
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA).
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Justification:
Scientifically acceptable and sufficient documentd for evaluation
AF for remaining uncertainties:
1
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

INTRODUCTORY NOTE

Trimethylopropane is a solid at room temperature which does not cause irritational effects to the skin or mucous membranes. Thus the local effects are not the prominent effects which have to be considered with regard to toxicity evaluation of trimethylolpropane. Based on these considerations it is assumed that local effects are covered by the DNELs for the systemic toxicity and no separate DNELs for local effects were derived. Furthermore, the available data have shown that TMP has a low toxicological potential [e.g LD50(oral) >2000 mg/kg bw and a NOAEL(oral, 13w ) of ca. 0.1 % in diet (approx.67 mg/kg bw/day) based on unspecific liver and spleen effects at higher dosages of 0.3% and 1% of TMP in food.]

GENERAL PUBLIC

For the general public, the oral DNELs as well as the dermal and the inhalation routes of exposure are regarded to be relevant in the case of trimethylolpropane.

GENERAL PUBLIC DNEL (systemic, long term)

DNEL (systemic, long term, oral route)

Trimethylolpropane was given to young male and female Wistar rats at 0, 0.03, 0.1, 0.3, 1.0 % in diet (corresponding to 20, 67, 200 or 667 mg/kg bw/d) for three months. On the basis of the presented results (see section 5.6.11), the NOAEL is considered 0.1 % in the diet which is equivalent with 67 mg/kg bw/day (de Knecht-van Eekelen, at the request of Bayer AG, 1969 and at the request of Perstorp AB, 1969).

NOAEL: 67 mg/kg bw/day

•For extrapolation of exposure duration: sub-chronic to chronic: 2

•For interspecies differences rat vs human: 4

•For remaining interspecies differences: 2.5

•For intraspecies differences in general public: 10

•For quality of the whole data base: 1

The database provides information on all relevant toxicological endpoints

Overall factor: 200

General Public DNEL (systemic, long term, oral): 0.34 mg/kg bw/day

DNEL (systemic, long term, dermal route)

There are no long term toxicity data available using the dermal exposure route.

There is no toxicokinetic study available that provides definite information on dermal absorption. However, there are two reliable sub-chronic studies available which could be taken as starting point ECHA TG R 8, p.19, 2012 postulated that in general it can be assumed that dermal absorption will not be higher than oral absorption. Therefore no additional default factor should be introduced for the oral to dermal extrapolation. Based on this statement the derived value for oral exposure is taken as surrogate for the DNEL (systemic, long-term, dermal application)

General Public DNEL (systemic, longterm, dermal route): 0.34 mg/kg bw/day

General Public DNEL (systemic, long term, inhalation route)

There is no long term study available using the inhalation exposure route. In addition, there is no toxicokinetic study available which provides definite information on inhalation absorption. From results of acute toxicity studies using the inhalation route it can be assumed that inhalation absorption might be limited. However, due to the lack of toxicokinetic data the DNEL systemic long-term, oral route is taken as starting point without addition of a further default value to correct for inhalation absorption.

NOAEL: 67 mg/kg bw/day

Corrected inhalation NOAEC = Oral NOAEL (67 mg/kg) x 1/1.15 m³/kg x 0.5

=> NOAEC general population = 29 mg/m³

• For extrapolation of exposure duration: sub-chronic to chronic: 2

• For interspecies differences rat vs human: 1 (the AF of 4 is already included in the route to route extrapolation.)

• For remaining interspecies differences: 2.5

• For intraspecies differences in workers: 10

• For quality of the whole data base: 1

Overall factor: 50

 DNEL (systemic, long-term, inhalation route, Bevölkerung) 0.58 mg/m³

DNEL (Reproductive toxicity):

The effects observed in the OECD TG 414 and OECD TG 443 are taken into account by classification of the compound with cat 2 reprotoxicity. The systemic DNEL cover developmental and fertility effects, since the NOAEL for systemic toxicity used for DNEL derivation is lower than the NOAEL observed for developmental toxicity (OECD TG 414) and the observations reported in a single F2 offspring at the low dose (OECD TG 443) is biologically uncertain. Consequently a test item effect at the low dose “cannot be excluded” and this observation is considered for classification but not for risk assessment.

In the OECD TG 443 treatment related effects are observed at the high dose (ca. 1000 mg/kg) and the single occurrence of hydrocephaly and small eye in one pup at 740 ppm and partly closed eye in one pup at 2200 ppm might be a change finding but a test-item-related effect could not be fully excluded.

Effects observed in the OECD TG 414 and OECD TG 443 are taken into account by classification of the compound with Repr. Tox. Cat 2. The systemic DNEL covers developmental and fertility effects, since the NOAEL for systemic toxicity used for DNEL derivation is lower than the NOAEL of 100 mg/kg observed for developmental toxicity (OECD TG 414) and treatment related effects are observed in the OECD TG 443 only at the highest dose, 6600 ppm (ca. 1000 mg/kg).

Even if the observations in the OECD TG 443 at 2200 ppm and 740 ppm would not be chance findings, the corresponding DNEL would be higher than the DNEL for general toxicity.

Starting point reproductive toxicity DNEL:

74 mg/kg/bw in female rats (OECD TG 443 study, lowest dose tested).

GENERAL PUBLIC DNEL (systemic, short term)

DNEL (systemic, short term, oral route)

A DNEL (systemic, short term) should be derived if an acute toxicity hazard has been identified and if there is potential for high peak exposure. Therefore also oral acute exposure has to be considered.

In the key study for acute oral toxicity single oral doses (1000 -21500 mg/kg bw) were applied to rats. LD50 ca. 14500 mg/kg bw; (Celanese Corp 1956).

The acute oral LD50 is ca. 14500 mg/kg bw. A classification for acute oral toxicity is not proposed and therefore no hazard is identified for acute oral toxicity (systemic).

DNEL (systemic, short term, dermal route)

A DNEL short term is relevant for single events that occur for exposure periods ranging from a few minutes up to 24 hours. Therefore dermal acute exposure has to be considered. The respective results from acute dermal experiments in rabbits (1000, 2150, 4640, and 10000 mg/kg bw, 24 hour application time), however, show that dermal treatment was tolerated without any signs of intoxication or mortality.

The acute dermal LD50 is > 10000 mg/kg bw. A classification for acute dermal toxicity is not proposed and therefore no hazard is identified for acute dermal toxicity (systemic).

DNEL (systemic, short term, inhalation route)

In the key study for inhalation (Bayer 1965) rats were whole body exposed to concentrations up to 850 mg/m³ for four hours. No deaths and no clinical signs were reported neither during exposure nor during the 14 day post exposure observation period.

The exact LC50 was not determined, but is assumed much higher. This assumption is supported by the acute oral LD50 which is ca. 14700 mg/kg bw and the acute dermal LD50 which is greater than 10000 mg/kg bw. A classification for acute inhalation toxicity is not proposed. Therefore no hazard is identified for acute inhalation toxicity (systemic).

Trimethylolpropane is not irritating/corrosive to skin and eyes. Therefore for local effects no hazard is identified.

Critical DNEL

The critical DNELs are

GENERAL PUBLIC DNEL (systemic, long term, oral): 0.34 mg/kg bw/day

GENERAL PUBLIC DNEL (systemic, long term, dermal): 0.34 mg/kg bw/day

GENERAL PUBLIC DNEL (systemic, long term, inhalation): 0.58 mg/m³

GENERAL PUBLIC DNEL (systemic, short term, oral): no hazard identified

GENERAL PUBLIC DNEL (systemic, short term, dermal): no hazard identified

GENERAL PUBLIC DNEL (systemic, short term, inhalation): no hazard identified