Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.69 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
500 ng/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Occupational exposure to tetrahydro-2-isobutyl-4-methyl-2H-pyran occurs mainly by dermal route, whereas inhalation exposure is less likely due to the low vapour pressure (110 Pa at 20°C). However, a long-term systemic inhalation DNEL has been derived via route-to-route extrapolation. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1 and are thus not shown in the calculations presented below.

Selection of the relevant dose descriptor (starting point): 
The key study for repeated dose toxicity and toxicity to reproduction has been chosen as suitable starting point for the derivation of the respective DNELs.

 

In this key study, i.e. a combined repeated dose toxicity and reproduction/developmental toxicity screening study according to OECD TG 422 and GLP, tetrahydro-2-isobutyl-4-methyl-2H-pyran was administered daily to groups of 10 male and 10 female Wistar rats by gavage at doses of 50, 150 and 500 mg/kg bw/d in corn oil (BASF 2018; 85R0080/13R165).

 

As the only test substance related findings, signs of a bad taste of tetrahydro-2-isobutyl-4-methyl-2H-pyran and/or local affection of the upper respiratory and/or digestive tract such as temporary salivation and animal “ploughed nose first into bedding” were noted in a dose-dependent fashion. As they were transient and appeared only shortly after dosing they were not considered as signs of systemic toxicity.

An observed increase in mean liver weights in males and females of the 500 mg/kg bw/d treated group was considered to be related to minimal centrilobular hepatocellular hypertrophy, encountered microscopically. This hepatocellular hypertrophy is believed to represent the morphologic hallmark of a low level of enzyme induction and is as such considered an adaptive non-adverse response.

 

A small decrease in pup body weights of the high-dose group was observed, but not noteworthy enough to be considered adverse, as it showed a tendency to recover during the course of lactation until PND 13. Neither a test substance-related influence on body weight change nor any corroborative effects on pup well-being or survival were noted.

 

Accordingly, the no observed adverse effect level (NOAEL) for general systemic toxicity, fertility and reproductive performance and for developmental toxicity in the offspring was set at 500 mg/kg bw/d tetrahydro-2-isobutyl-4-methyl-2H-pyran, representing the highest dose tested.

 

In the associated range-finding study in Wistar rats, exposure to the limit dose (1000 mg/kg bw/d) resulted in clinical signs (exhibited salivation, piloerection and unsteady gait), increased water consumption, reduced food consumption, reduced body weights, increased liver and kidney weights.

However, in a screening study on testes toxicity in male Wistar rats, no signs of general systemic toxicity besides salivation were observed after exposure to the limit dose (1000 mg/kg bw/d).

Route to route extrapolation:

Based on its physicochemical properties, such as high logPow (4.4 - 5.2 at 25 °C) and moderate water solubility (130 mg/L at 20 °C), tetrahydro-2-isobutyl-4-methyl-2H-pyran is not expected to be highly but moderately bioavailable via the dermal route. No dermal penetration data are available to define the rate of dermal penetration of tetrahydro-2-isobutyl-4-methyl-2H-pyran. Concerning the absorption via the oral route, the uptake of this rather lipophilic substance with moderate water solubility may occur by micellular solubilization. The oral repeated dose toxicity study showed systemic effects such as hepatic enzyme induction, that can be based on systemically available), tetrahydro-2-isobutyl-4-methyl-2H-pyran. Overall, a higher oral than dermal absorption rate is assumed, however, due to the lack of experimental data, no difference between oral and the dermal route are considered for the route-to-route extrapolation as a worst-case assumption.

On the basis of the low vapour pressure and a high boiling point (181.9 °C at 1013 hPa), the exposure with tetrahydro-2-isobutyl-4-methyl-2H-pyran via inhalation as a vapour is low. In the absence of route-specific information to assess the route-to-route extrapolation between oral and the inhalation route, a twofold higher inhalative than oral uptake has been considered as a worst-case assumption, i.e. 50% oral and 100% inhalation absorption. 

 

 

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

Modification into a correct starting point: 

 

Modification of starting point:

50%/100%

 

 

 

 

0.38 m3/kg bw

 

 

 

 

6.7 m3/10 m3

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

 

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

 

NOAEC corrected = 500*(1/0.38)*(50/100)*(6.7/10) = 440.8 mg/m3

 


Use of assessment factors: 30 

 

Allometric scaling

1

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

Remaining differences

1

Substance specific assessment factor:

No adverse systemic effects of tetrahydro-2-isobutyl-4-methyl-2H-pyran were observed in the key study for repeated dose toxicity/toxicity to reproduction. Transient signs of a bad taste and/or local affection, adaptive liver enzyme induction and transient decreases in pup body weights were observed only.

On the basis of the non-adverse and transient findings in the key study, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling (not relevant, see above).

Thus, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Assessment factor for intraspecies differences according to R8 ECHA 2008

Exposure duration

6

Data from study with subacute exposure was taken into account

.

In conclusion, long term systemic inhalation DNEL, workers = 14.69 mg/m³  

 

Acute/short term, systemic inhalation DNEL

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic inhalation effects.

Acute/short term and long term, local inhalation DNEL

No data on respiratory irritation or repeated inhalation toxicity is available. Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified as irritating to eyes but as a skin irritant, indicating a limited irritative potential on mucus membranes. As no quantitative data are available, no DNELs for local effects after acute or long-term inhalation exposure have been derived. Inhalative occupational exposure to tetrahydro-2-isobutyl-4-methyl-2H-pyran is limited due to its low vapour pressure and workplace measures in place to reduce inhalative exposure. Furthermore, inhalative exposure of tetrahydro-2-isobutyl-4-methyl-2H-pyran to the general population is limited due to its low use concentrations. Thus, respiratory irritation is not considered relevant due to the given exposure situation.

 

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

Modification of starting point:

100%/100%

 

 

Ratio of oral (rat) to dermal (human) absorption according to R8 ECHA 2008.

 

NOAEL corrected = 500*(100/100) = 500 mg/kg bw/d

 

Use of assessment factors: 120

Allometric scaling

4

Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008

Remaining differences

1

Substance specific assessment factor:

No adverse systemic effects of tetrahydro-2-isobutyl-4-methyl-2H-pyran were observed in the key study for repeated dose toxicity/toxicity to reproduction. Transient signs of a bad taste and/or local affection, adaptive liver enzyme induction and transient decreases in pup body weights were observed only.

On the basis of the non-adverse and transient findings in the key study, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Thus, no additional AF for remaining differences is considered mandatory.

Intraspecies

5

Assessment factor for intraspecies differences according to R8 ECHA 2008

Exposure duration

6

Data from study with subacute exposure was taken into account

 

In conclusion, long term systemic dermal DNEL, workers = 4.17 mg/kg bw/day

Acute/short-term systemic dermal DNEL 

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

 

Acute/short-term and Long term local dermal DNEL

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is classified and labelled for skin irritation but not for eye irritation and skin sensitization according to Regulation (EC) No 1272/2008 (CLP). The present data on skin irritation do not allow to derive a robust starting point for the DNEL for local effects after acute and long-term dermal exposure. However, in a supportive skin irritation study in Vienna white rabbits, single application of 25% tetrahydro-2-isobutyl-4-methyl-2H-pyran in Vaseline led to very slight skin irritation reactions (i.e. mean erythema and edema scores were 0.22 and 0, respectively) and 10% did not result in any skin irritation reactions. Thus, sufficient dermal protection (i.e. use of suitable gloves) are implemented when handling undiluted tetrahydro-2-isobutyl-4-methyl-2H-pyran or masterbatch concentrations of tetrahydro-2-isobutyl-4-methyl-2H-pyran above the final use concentration, which are generally far below 10% tetrahydro-2-isobutyl-4-methyl-2H-pyran.  

Worker - Hazard for the eyes

Tetrahydro-2-isobutyl-4-methyl-2H-pyran does not have to be classified as eye irritant according to the EU (CLP) criteria for classification and labelling requirements for dangerous substances and preparations. Therefore, no obligatory requirements to protect for eye irritation are necessary. 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.62 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
60
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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:
2.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.08 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
240
Dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Discussion"

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

In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1 and are thus not shown in the calculations presented below.

Selection of the relevant dose descriptor (starting point): 
The key study for repeated dose toxicity and toxicity to reproduction has been chosen as suitable starting point for the derivation of the respective DNELs.

 

In this key study, i.e. a combined repeated dose toxicity and reproduction/developmental toxicity screening study according to OECD TG 422 and GLP, tetrahydro-2-isobutyl-4-methyl-2H-pyran was administered daily to groups of 10 male and 10 female Wistar rats by gavage at doses of 50, 150 and 500 mg/kg bw/d in corn oil (BASF 2018; 85R0080/13R165).

 

As the only test substance related findings, signs of a bad taste of tetrahydro-2-isobutyl-4-methyl-2H-pyran and/or local affection of the upper respiratory and/or digestive tract such as temporary salivation and animal “ploughed nose first into bedding” were noted in a dose-dependent fashion. As they were transient and appeared only shortly after dosing they were not considered as signs of systemic toxicity.

An observed increase in mean liver weights in males and females of the 500 mg/kg bw/d treated group was considered to be related to minimal centrilobular hepatocellular hypertrophy, encountered microscopically. This hepatocellular hypertrophy is believed to represent the morphologic hallmark of a low level of enzyme induction and is as such considered an adaptive non-adverse response.

 

A small decrease in pup body weights of the high-dose group was observed, but not noteworthy enough to be considered adverse, as it showed a tendency to recover during the course of lactation until PND 13. Neither a test substance-related influence on body weight change nor any corroborative effects on pup well-being or survival were noted.

 

Accordingly, the no observed adverse effect level (NOAEL) for general systemic toxicity, fertility and reproductive performance and for developmental toxicity in the offspring was set at 500 mg/kg bw/d tetrahydro-2-isobutyl-4-methyl-2H-pyran, representing the highest dose tested.

 

In the associated range-finding study in Wistar rats, exposure to the limit dose (1000 mg/kg bw/d) resulted in clinical signs (exhibited salivation, piloerection and unsteady gait), increased water consumption, reduced food consumption, reduced body weights, increased liver and kidney weights.

However, in a screening study on testes toxicity in male Wistar rats, no signs of general systemic toxicity besides salivation were observed after exposure to the limit dose (1000 mg/kg bw/d).

 

Route to route extrapolation:

Based on its physicochemical properties, such as high logPow (4.4 - 5.2 at 25 °C) and moderate water solubility (130 mg/L at 20 °C), tetrahydro-2-isobutyl-4-methyl-2H-pyran is not expected to be highly but moderately bioavailable via the dermal route. No dermal penetration data are available to define the rate of dermal penetration of tetrahydro-2-isobutyl-4-methyl-2H-pyran. Concerning the absorption via the oral route, the uptake of this rather lipophilic substance with moderate water solubility may occur by micellular solubilization. The oral repeated dose toxicity study showed systemic effects such as hepatic enzyme induction, that can be based on systemically available), tetrahydro-2-isobutyl-4-methyl-2H-pyran. Overall, a higher oral than dermal absorption rate is assumed, however, due to the lack of experimental data, no difference between oral and the dermal route are considered for the route-to-route extrapolation as a worst-case assumption.

On the basis of the low vapour pressure and a high boiling point (181.9 °C at 1013 hPa), the exposure with tetrahydro-2-isobutyl-4-methyl-2H-pyran via inhalation as a vapour is low. In the absence of route-specific information to assess the route-to-route extrapolation between oral and the inhalation route, a twofold higher inhalative than oral uptake has been considered as a worst-case assumption, i.e. 50% oral and 100% inhalation absorption. 

 

General population – Hazard via inhalation route

Long term, systemic inhalation DNEL

Modification into a correct starting point: 

 

Modification of starting point:

50%/100%

 

 

 

 

1.15 m3/kg bw

 

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

 

 

Standard respiratory volume of a rat, corrected for 24h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

NOAEC corrected = 500*(1/1.15)*(50/100)= 217.4 mg/m3

 


Use of assessment factors: 60 

 

Allometric scaling

1

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

Remaining differences

1

Substance specific assessment factor:

No adverse systemic effects of tetrahydro-2-isobutyl-4-methyl-2H-pyran were observed in the key study for repeated dose toxicity/toxicity to reproduction. Transient signs of a bad taste and/or local affection, adaptive liver enzyme induction and transient decreases in pup body weights were observed only.

On the basis of the non-adverse and transient findings in the key study, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling (not relevant, see above).

Thus, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Assessment factor for intraspecies differences according to R8 ECHA 2008

Exposure duration

6

Data from study with subacute exposure was taken into account

.

In conclusion, long term systemic inhalation DNEL = 3.62 mg/m³  

 

Acute/short term, systemic inhalation DNEL

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic inhalation effects.

Acute/short term and long term, local inhalation DNEL

No data on respiratory irritation or repeated inhalation toxicity is available. Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified as irritating to eyes but as a skin irritant, indicating a limited irritative potential on mucus membranes. As no quantitative data are available, no DNELs for local effects after acute or long-term inhalation exposure have been derived. Inhalative occupational exposure to tetrahydro-2-isobutyl-4-methyl-2H-pyran is limited due to its low vapour pressure and workplace measures in place to reduce inhalative exposure. Furthermore, inhalative exposure of tetrahydro-2-isobutyl-4-methyl-2H-pyran to the general population is limited due to its low use concentrations. Thus, respiratory irritation is not considered relevant due to the given exposure situation.

 

General population - Hazard via dermal route

Long term, systemic dermal DNEL

 

Modification of starting point:

100%/100%

 

 

Ratio of oral (rat) to dermal (human) absorption according to R8 ECHA 2008.

 

NOAEL corrected = 500*(100/100) = 500 mg/kg bw/d

 

Use of assessment factors: 240

Allometric scaling

4

Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008

Remaining differences

1

Substance specific assessment factor:

No adverse systemic effects of tetrahydro-2-isobutyl-4-methyl-2H-pyran were observed in the key study for repeated dose toxicity/toxicity to reproduction. Transient signs of a bad taste and/or local affection, adaptive liver enzyme induction and transient decreases in pup body weights were observed only.

On the basis of the non-adverse and transient findings in the key study, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Thus, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Assessment factor for intraspecies differences according to R8 ECHA 2008

Exposure duration

6

Data from study with subacute exposure was taken into account

 

In conclusion, long term systemic dermal DNEL = 2.08 mg/kg bw/day

Acute/short-term systemic dermal DNEL 

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is classified and labelled for skin irritation but not for eye irritation and skin sensitization according to Regulation (EC) No 1272/2008 (CLP). The present data on skin irritation do not allow to derive a robust starting point for the DNEL for local effects after acute and long-term dermal exposure. However, in a supportive skin irritation study in Vienna white rabbits, single application of 25% tetrahydro-2-isobutyl-4-methyl-2H-pyran in Vaseline led to very slight skin irritation reactions (i.e. mean erythema and edema scores were 0.22 and 0, respectively) and 10% did not result in any skin irritation reactions. Thus, sufficient dermal protection (i.e. use of suitable gloves) are implemented when handling undiluted tetrahydro-2-isobutyl-4-methyl-2H-pyran or masterbatch concentrations of tetrahydro-2-isobutyl-4-methyl-2H-pyran above the final use concentration, which are generally far below 10% tetrahydro-2-isobutyl-4-methyl-2H-pyran.  

 

General population - Hazard via oral route

Long term, systemic oral DNEL

NOAEL = 500 mg/kg bw/d

 

Use of assessment factors: 240

Allometric scaling

4

Assessment factor for allometric scaling (rat to human) according to R8 ECHA 2008

Remaining differences

1

Substance specific assessment factor:

No adverse systemic effects of tetrahydro-2-isobutyl-4-methyl-2H-pyran were observed in the key study for repeated dose toxicity/toxicity to reproduction. Transient signs of a bad taste and/or local affection, adaptive liver enzyme induction and transient decreases in pup body weights were observed only.

On the basis of the non-adverse and transient findings in the key study, no toxicodynamic and/or additional toxicokinetic differences between test animals and humans is to be expected besides aspects already covered by allometric scaling.

Thus, no additional AF for remaining differences is considered mandatory.

Intraspecies

10

Assessment factor for intraspecies differences according to R8 ECHA 2008

Exposure duration

6

Data from study with subacute exposure was taken into account

 

In conclusion, long term systemic oral DNEL= 2.08 mg/kg bw/day

Acute/short-term systemic oral DNEL 

Tetrahydro-2-isobutyl-4-methyl-2H-pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute toxicity. Thus, no DNEL for systemic effects after acute oral exposure is required. Furthermore, the DNEL derived for systemic effects after long term oral exposure is considered sufficiently conservative to cover potential acute systemic oral effects.

 

General population - Hazard for the eyes

Tetrahydro-2-isobutyl-4-methyl-2H-pyran does not have to be classified as eye irritant according to the EU (CLP) criteria for classification and labelling requirements for dangerous substances and preparations. Therefore, no obligatory requirements to protect for eye irritation are necessary.