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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.937 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:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370.263 mg/m³
Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst-case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to-inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

 

To convert the oral NOAEL into inhalatory NOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8 h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8 h exposure period).

 

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC = [NOAEL] X (1/SRVrat x ABS(oral-rat)/ABS(inh-human) x sRVhuman/wRV

= [300 mg/kg bw/day] X  [1/0.38 m3/kg bw/day] X [1/2] X [6.7 m3/10m3]. = 264.474 mg/m3

Correction for differences experimental/human exposure conditions

= 264.474 x Differences experimental and human exposure conditions: 1.4 (= 7 days/week / 5 days/week)

= 264.474 x 1.4

Thus, the corrected dose descriptor for inhalation is 370.263 mg/m3 for workers.

 

Full DNEL derivation:

Step 1: Selection of relevant dose descriptor for the toxicological endpoint

Toxicological endpoint: Other effect - systemic 

NOAEL - oral route:       300      mg/kg bw/d

Step 2: Modification of the relevant dose descriptor per endpoint to correct starting point

Starting point correction formula:                            

corr inh NOAEC = oral NOAEL x 1/sRVan x Diff. exp. cond. x (ABSoral,an/ABSinh,hu) x sRVhu/wRV                              

Relevant human exposure route:             inhalation           

ABSoral,an/ABSinh,hu  0.5         

Experimental animal:     rat         

Standard respiratory volume, animal (sRVan)     0.38       m3/kg bw/8 h

Standard respiratory volume, human (sRVhu)    6.7         m3 / person

Worker respiratory volume (wRV)           10          m3 / person

Differences experimental/human exposure conditions   1.4         

Corrected dose descriptor                           

corr inh NOAEC:              370.263      mg/m3

Step 3: Selection of assessment factors                 

Interspecies, AS1             

Interspecies, remaining differences 2.5         

AF1: Interspecies, total 2.5         

AF2: Intraspecies 5             

AF3: Exposure duration 6             

AF4: Dose response-relationship 1             

AF5: Quality of the whole data base 1             

Overall AF (= AF1xAF2xAF3xAF4xAF5) = 75          

DNEL Results                     

worker-DNEL long-term for inhalation route-systemic-other effect:         4.937 mg/m3

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is expected to be well tolerated via the acute inhalation toxicity route with no expected LC50 of < 5.0 mg/L air. Therefore, no DNEL appears required. Under EU CLP Regulation (EC) 1272/2008, this substance is classified for skin corrosion: category 1A: H314 and eye damage: category 1: H318, therefore qualitative assessment will be performed for local dermal effects and eye effects in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (v 3.0, May 2016) and/or ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.4 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):
300
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For systemic hazard assessment via the dermal route of exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral NOAEL is used as the starting point for the dermal NOAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012)) but modified to account for differences in experimental (oral) versus human exposure conditions (dermal).

 

Full DNEL derivation:

Step 1: Selection of relevant dose descriptor for the toxicological endpoint

Toxicological endpoint: Other effect - systemic 

NOAEL - oral route:       300      mg/kg bw/d

Step 2: Modification of the relevant dose descriptor per endpoint to correct starting point

Starting point correction formula:                            

corr derm NOAEL = oral NOAEL x Diff. exp. cond. x (ABSoral,an/ABSderm,hu)                      

Relevant human exposure route:             dermal 

ABSoral,an/ABSdermal,hu          1             

Experimental animal:     rat         

Differences experimental/human exposure conditions   1.4         

Corrected dose descriptor                           

corr dermal NOAEL:       420      mg/kg bw/d

Step 3: Selection of assessment factors 

Interspecies, AS4

Interspecies, remaining differences 2.5

AF1: Interspecies, total 10

AF2: Intraspecies 5

AF3: Exposure duration 6

AF4: Dose response-relationship 1

AF5: Quality of the whole data base 1

Overall AF (= AF1xAF2xAF3xAF4xAF5) = 300

DNEL Results

worker-DNEL long-term for dermal route-systemic-other effect: 1.400      mg/kg bw/d

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
Default factor for worker. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is expected to be well tolerated systemically via the short term acute dermal toxicity route with no indications that the substance would possess a LD50 of < 2000 mg/kg bw/day from similar substances acute oral toxicity. Therefore, no DNEL appears required. Under EU CLP Regulation (EC) 1272/2008, this substance is classified for skin corrosion: category 1A: H314 and eye damage: category 1: H318, therefore qualitative assessment will be performed for local dermal effects and eye effects in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (v 3.0, May 2016) and/or ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Repeated dose toxicity : target : Reaction products of 2-hydroxyethyl methacrylate and diphosphorous pentoxide and water : Oral (gavage): NOAEL (rat,systemic toxicity): male/female = 300 mg/kg bw/day, 2021

Read-Across: source data : Reaction products of 2-hydroxyethyl methacrylate and diphosphorus pentaoxide : Oral (gavage): NOAEL (rat,systemic toxicity): male/female = 300 mg/kg bw/day, OECD TG 422, 2016

Oral gavage in propylene glycol, vehicle : doses: 0, 100, 300 and 1000 mg/kg bw/day

 

Key Study : OECD TG 422, 2016 : Read-Across SOURCE ( Reaction products of 2-hydroxyethyl methacrylate and diphosphorus pentaoxide ) : The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in Wistar rats, including a screen for reproductive/developmental effects was conducted by oral gavage administration. Males were dosed for 28 days (14 days pre-mating and 14 days mating/post-mating), and females for 14 days pre-mating, during the mating period, through gestation and until the day before the necropsy (at least 4 days post-partum dosing). Three groups each comprising at least 12 male and 12 female rats received the test substance at doses of 0, 100, 300 or 1000 mg/kg bw/day. Parameters measured during the study included signs of morbidity and mortality twice daily, daily or detailed weekly observation of clinical signs, neurological assessment, weekly body weight and food consumption, and clinical pathology evaluation, including haematology, coagulation, clinical chemistry and urinalysis. Neurological assessment including functional observation battery (FOB) and measurements of the landing foot splay, grip strength and motor activity were performed during the last week of the treatment. At termination, necropsy with macroscopic examination was performed. Weights of selected organs were recorded and representative tissues/organs were sampled and preserved in appropriate fixatives. A detailed histological examination was performed on the selected list of retained organs in the control and High dose groups. Daily administration of the test substance at dose levels of 100 mg/kg bw/day or 300 mg/kg bw/day did not result in adverse changes in clinical signs, neurological assessment, body weight, food consumption, haematology, coagulation, clinical chemistry, or urinalysis parameters. Test item related mortality (approximately 15%) was observed in the High dose group (1000 mg/kg bw/day) and clinical adverse effects were present in High dose females. There were no effects on surviving males/females on body weight or clinical pathology. Test item related liver changes were observed in the female High dose group (1000 mg/kg bw/day) with increased weight (approximately 12%) and centrilobular hepatocellular hypertrophy. However, this observation was considered to be an adaptive change and not an adverse effect of treatment. Test item related kidney weight changes were observed in the High dose group (1000 mg/kg bw/day) of both sexes (approximately 10%), but in the absence of any correlating histopathological changes, this was considered to be an adaptive response.Under the study conditions, the rat NOAEL for reproductive and development effects was considered to be 1000 mg/kg bw/day for male/female rats. The rat NOAEL for general systemic toxicity was considered to be 300 mg/kg bw/day for male/female rats.

 

For risk assessment, NOAEL from the most sensitive endpoint was used, i.e. 300 mg/mg bw/day (starting point) from an available read-across study to an analogue source substance. Within the OECD TG 422 (2016): combined repeated oral toxicity and reproduction/developmental toxicity screening test, the following no-observed-adverse-effect level (NOAEL) of 300 mg/kg bw/day for systemic toxicity was utilised.

Since there was no reported significant effects relevant to humans reported at guidance related levels (ORAL ≤ 300 mg/kg bw/day) then there is no requirement to classify STOT-RE.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.741 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):
150
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
111.111 mg/m³
Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal NOAEL. To secure a conservative external NOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external NOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

 

DNEL derivation incorporating ECHA R.8 (2012) and noting ECHA R.15 (2016) :

Note: as first step a conservative consumer exposure duration is presumed (24 hours) see ECHA R.15 (2016)

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalatory NOAEC = oral NOAEL x 1/sRVan x Diff. exp. cond. x (ABSoral,an/ABSinh,hu)

 

= [NOAEL] x [300 mg/kg bw/day] x [1/1.35 m3/kg bw/ 24h] x 1 x [1/2]

Thus, the corrected dose descriptor for inhalation is 111.111 mg/m3 for the general population.

 

Where:

sRVan = 0.45 m3 kg/bw x (24 h/ 8h)

General consumer bodyweight : 60 kg

 

Full DNEL derivation:

Step 1: Selection of relevant dose descriptor for the toxicological endpoint

Toxicological endpoint: Other effect - systemic 

NOAEL - oral route:       300      mg/kg bw/d

Step 2: Modification of the relevant dose descriptor per endpoint to correct starting point

Starting point correction formula:                            

Corrected Inhalator NOAEC = oral NOAEL x 1/sRVan x Diff. exp. cond. x (ABSoral,an/ABSinh,hu)                  

Relevant human exposure route:             inhalation           

ABSoral,an/ABSinh,hu  0.5         

Experimental animal:     rat         

Standard respiratory volume, animal (sRVan)     1.35       m3/kg bw /24 h

Differences experimental/human exposure conditions   1             

Corrected dose descriptor                           

corr inh NOAEC:              111.111      mg/m3

Step 3: Selection of assessment factors                 

Interspecies, AS1

Interspecies, remaining differences 2.5

AF1: Interspecies, total 2.5

AF2: Intraspecies 10

AF3: Exposure duration 6

AF4: Dose response-relationship 1

AF5: Quality of the whole data base 1     

Overall AF (= AF1xAF2xAF3xAF4xAF5) = 150         

DNEL Results

General population-DNEL long-term for inhalation route-systemic-other effect: 0.74074      mg/m3

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
1
Justification:
Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Route of original study:
By inhalation
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is expected to be well tolerated via the acute inhalation toxicity route with no expected LC50 of < 5.0 mg/L air. Therefore, no DNEL appears required. Under EU CLP Regulation (EC) 1272/2008, this substance is classified for skin corrosion: category 1A: H314 and eye damage: category 1: H318, therefore qualitative assessment will be performed for local dermal effects and eye effects in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (v 3.0, May 2016) and/or ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

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:
0.05 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):
600
Dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral NOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for general population. Table R.8-6 ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is well tolerated in an acute dermal toxicity study in HanRcc:WIST (SPF) rats with reported LD50 of > 2000 mg/kg bw/day. No abnormalities or overt toxicity signs reported (OECD 402; Anon 2004). Therefore, no DNEL is required.

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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):
600
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

 

Step 1: Selection of relevant dose descriptor for the toxicological endpoint

Toxicological endpoint: Other effect - systemic 

NOAEL - oral route:       300      mg/kg bw/d

Step 2: Modification of the relevant dose descriptor per endpoint to correct starting point

Starting point correction formula:                            

corr oral NOAEL = oral NOAEL x Diff. exp. cond. x (ABSoral,an/ABSoral,hu)                            

Relevant human exposure route:             oral       

ABSoral,an/ABSoral,hu 1             

Experimental animal:     rat         

Differences experimental/human exposure conditions   1             

Corrected dose descriptor                           

corr oral NOAEL:            300      mg/kg bw/d

Step 3: Selection of assessment factors 

Interspecies, AS4             

Interspecies, remaining differences 2.5 

AF1: Interspecies, total 10

AF2: Intraspecies 10

AF3: Exposure duration 6

AF4: Dose response-relationship 1

AF5: Quality of the whole data base 1

Overall AF (= AF1xAF2xAF3xAF4xAF5) = 600         

DNEL Results

General population-DNEL long-term for oral route-systemic-other effect:             0.500      mg/kg bw/d

AF for dose response relationship:
1
Justification:
The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.
AF for differences in duration of exposure:
6
Justification:
Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.
AF for interspecies differences (allometric scaling):
4
Justification:
Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.
AF for other interspecies differences:
2.5
Justification:
Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.
AF for intraspecies differences:
10
Justification:
Default factor for good/standard quality of the database taken into account completeness, consistency and the standard information requirements for the tonnage band.
AF for the quality of the whole database:
1
Justification:
Default factor for good/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is expected to be well tolerated systemically via the short term acute oral toxicity route with no indications that the substance would possess a LD50 of < 2000 mg/kg bw/day from similar substances acute oral toxicity. Therefore, no DNEL appears required.

Under EU CLP Regulation (EC) 1272/2008, this substance is classified for skin corrosion: category 1A: H314 and eye damage: category 1: H318, therefore qualitative assessment will be performed for local dermal effects and eye effects in accordance with ECHA Guidance on Information Requirements and Chemical Safety Assessment, Part E (v 3.0, May 2016) and/or ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (Version 2.1, November 2012).

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Repeated dose toxicity : target : Reaction products of 2-hydroxyethyl methacrylate and diphosphorous pentoxide and water : Oral (gavage): NOAEL (rat,systemic toxicity): male/female = 300 mg/kg bw/day, 2021

Read-Across: source data : Reaction products of 2-hydroxyethyl methacrylate and diphosphorus pentaoxide : Oral (gavage): NOAEL (rat,systemic toxicity): male/female = 300 mg/kg bw/day, OECD TG 422, 2016

Oral gavage in propylene glycol, vehicle : doses: 0, 100, 300 and 1000 mg/kg bw/day

 

Key Study : OECD TG 422, 2016 : Read-Across SOURCE ( Reaction products of 2-hydroxyethyl methacrylate and diphosphorus pentaoxide ) : The study was performed according the requirements of OECD TG 422 guideline under GLP conditions. Following a previously conducted 14-day sighting study, the systemic toxic potential of the test item in Wistar rats, including a screen for reproductive/developmental effects was conducted by oral gavage administration. Males were dosed for 28 days (14 days pre-mating and 14 days mating/post-mating), and females for 14 days pre-mating, during the mating period, through gestation and until the day before the necropsy (at least 4 days post-partum dosing). Three groups each comprising at least 12 male and 12 female rats received the test substance at doses of 0, 100, 300 or 1000 mg/kg bw/day. Parameters measured during the study included signs of morbidity and mortality twice daily, daily or detailed weekly observation of clinical signs, neurological assessment, weekly body weight and food consumption, and clinical pathology evaluation, including haematology, coagulation, clinical chemistry and urinalysis. Neurological assessment including functional observation battery (FOB) and measurements of the landing foot splay, grip strength and motor activity were performed during the last week of the treatment. At termination, necropsy with macroscopic examination was performed. Weights of selected organs were recorded and representative tissues/organs were sampled and preserved in appropriate fixatives. A detailed histological examination was performed on the selected list of retained organs in the control and High dose groups. Daily administration of the test substance at dose levels of 100 mg/kg bw/day or 300 mg/kg bw/day did not result in adverse changes in clinical signs, neurological assessment, body weight, food consumption, haematology, coagulation, clinical chemistry, or urinalysis parameters. Test item related mortality (approximately 15%) was observed in the High dose group (1000 mg/kg bw/day) and clinical adverse effects were present in High dose females. There were no effects on surviving males/females on body weight or clinical pathology. Test item related liver changes were observed in the female High dose group (1000 mg/kg bw/day) with increased weight (approximately 12%) and centrilobular hepatocellular hypertrophy. However, this observation was considered to be an adaptive change and not an adverse effect of treatment. Test item related kidney weight changes were observed in the High dose group (1000 mg/kg bw/day) of both sexes (approximately 10%), but in the absence of any correlating histopathological changes, this was considered to be an adaptive response.Under the study conditions, the rat NOAEL for reproductive and development effects was considered to be 1000 mg/kg bw/day for male/female rats. The rat NOAEL for general systemic toxicity was considered to be 300 mg/kg bw/day for male/female rats.

 

For risk assessment, NOAEL from the most sensitive endpoint was used, i.e. 300 mg/mg bw/day (starting point) from an available read-across study to an analogue source substance. Within the OECD TG 422 (2016): combined repeated oral toxicity and reproduction/developmental toxicity screening test, the following no-observed-adverse-effect level (NOAEL) of 300 mg/kg bw/day for systemic toxicity was utilised.

 

Since there was no reported significant effects relevant to humans reported at guidance related levels (ORAL ≤ 300 mg/kg bw/day) then there is no requirement to classify STOT-RE.

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