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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
117 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
117 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.6 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.6 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

Due to the strong irritant/corrosive properties of Thymol DNELs have to be established for systemic and local effects, respectively

Two studies for repeated dose are avalilable:

Repeated dose toxicity

Basis for delineation of the DNEL (systemic effects):

Feeding study

Study: Repeated dose study

rat, male, female,

Subchronic oral feed study for 19 weeks

rat: 0 (control), 1000 or 10000 ppm males + females

rat: 0 (control), approx. 67 or 667 mg/kg bw/d – males and females

NOEL = 10000 ppm (ca. 667 mg/kg bw/day) - (male + female rats)

Effects, NOAEL

10000 ppm: no effects

1000 ppm: no macroscopic findings

At the termination of the experiment the rats were sacrificed.

Viscera were examined macroscopically and histopathologically

Reference:

Hagen EC et al. (1967)

Food flavourings and compounds of related structure.

II. Subacute and chronic toxicity

Fd Cosmet. Toxicol. Vol. 5, pp. 141-157

Basis for delineation of the DNEL (local effects):

Gavage study

Reference

Study: OECD combined Repeat dose and Reproductive/Developmental toxicity screening test

rat, male, female,

aministration period:

males, 43 days

females, from 14 days before mating to day 3 of lactation

rat: 0 (control), 8, 40, 200 mg/kg bw/d – males and females

Effects, NOAEL

NOEL = 8 mg/kg bw/day (male + female rats)

effects:

In the 40 mg/kg group, histophatological changes in the forestomach (mucosal hyperplasia, inflammatory cell infiltration and edema) were observed in the forestomach in both sexes and in the thymus in female rats. There were no significant differences in food consumption or organ weights amoung the groups. No effects ascribable to the compound were found on hematological or blood chemical examination for both sexes.

The NOEL for repeat dose toxicity local is considered to be 8 mg/kg/day for both sexes

Reference:

Toxicity testing reports of environmental chemicals

Vol. 4 1996

Ministery of Health & Welfare, Japan

The gavage study (OECD combined Repeat dose and Reproductive/Developmental toxicity screening test) revealed local effects on the forestomach due to the corrosive properties of thymol which were not seen in the 19 weeks oral feed study, where the test substance is incorporated in the feed matrix.

Therefore for systemic effects the oral feed study was used and for local effects the gavage study, respectively.

1a.) Long-term toxicity – systemic effects (workers)

Long-term oral or dermal route-systemic effects (worker):

NOEL (rat) from the subchronic feeding study: 667 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 40

Worker DNEL long-term for oral or dermal route-systemic: 16.6 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010)

Long-term inhalation route-systemic effects (workers):

NOEL (rat) from the subchronic feeding study: 667 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (667 mg/kg) x 1/0.38 m³/kg x 6.7 m³/10m³ x 1.0

=> NOEC worker = 1176.0 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 10

Worker DNEL long-term for inhalation exposure: 117.6 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

1b.) Long-term toxicity – local effects (workers)

Long-term oral route-local effects (worker):

NOEL (rat) from the OECD 422 oral gavage toxicity study: 8 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in workers: 5

For extrapolation of exposure duration: 1 **

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 20

Worker DNEL long-term for oral route-local: 0.40 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010)

** No time extrapolation is applied since the dominant effect is local irritation; Thymol is labeled as a corrosive compound R34. It is anticipated the at the severity of the local irritation might increase over time but the threshold for irritation is independent of the exposure time.

Long-term dermal route-local effects (worker):

There are no studies available to define a threshold for local toxicity after dermal application. Consequently, for local effects the derivation of a long-term DNEL(local) for dermal toxicity is not possible due to the corrosive effects of thymol.

DNEL (long-term, local) for inhalation

In the REACH TGD the DNEL calculation for compounds without fully valid long term inhalation study is usually based on oral studies. This extrapolation covers the systemic effects of the compound. For non-irritating compounds it can be assumed that the potential local effects will be covered by the derived systemic DNEL. For compounds with irritating or corrosive properties the derived systemic DNEL might not cover potential local effects.

A toxicological TF within the German VCI discussed the derivation of DNEL for local irritating compound with a limited database. The experts developed upper boundary values for irritating and/or corrosive compounds based on available data. In particular the expert TF evaluated the German MAK-values published in the TRGS900 in 2009. For irritating compounds labelled with R36 or R38 but without relevant inhalation toxicity data available the TF developed a generic upper boundary value of 10 mg/m3; for compounds with corrosive properties (R34 or R35) a respective value of 1 mg/m3 is developed.

Since Thymol is labelled with R34 an upper boundary value of 1 mg/m³ is proposed as a long-term inhalation DNEL for local effects.

2a.) Short-term toxicity – systemic effects (workers)

Since the primary effect of Thymol is local irritation no short-term DNEL are derived for the systemic toxicity.

2b.) Short-term toxicity – local effects (workers)

For local effects the derivation of a short-term DNEL is not appropriate due to the corrosive effects of thymol. We propose to take the above mentioned long-term DNEL value also for short-term exposure.

Conclusion (systemic effects):

Worker DNEL long-term for oral or dermal route-systemic: 16.6 mg/kg bw/day

Worker DNEL long-term for inhalation exposure: 117.6 mg/m³

Worker DNELshort-term for oral or dermal route-systemic: 16.6 mg/kg bw/day

Worker DNEL short-term for inhalation exposure: 117.6 mg/m³

Conclusion (local effects):

Worker DNEL long-term for inhalation exposure: 1.0 mg/m³

Worker DNEL short-term for inhalation exposure: 1.0 mg/m³

Worker DNEL long-term for oral route: 0.4 mg/kg bw/day

Worker DNELshort-term for oral route: 0.4 mg/kg bw/day

3.) Reproductive Toxicity – systemic effects (workers)

In the OECD combined repeat dose and reproductive/developmental toxicity screening test the compound exerted no effects on reproductive parameters such as the estrous cycle, mating index, fertility index, gestation lenght, number of corpora lutea or implantations, the implantation index, gestation index, delivery index, parturition or maternal behaviour. Birth weight and body weight gain tended to be low in the 200 mg/kg group neonates. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates.

The NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day for parental males and females, and 200 mg/kg/day for offspring.

As the NOEL for reproductive/developmental toxicty is higher than the NOEL for repeated dose toxicity (8 mg/kg bw/day), the derivation of a separate DNEL for reproductive/developmental toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Local effects have no direct impact on reproductive/developmental toxicity at relevant exposure conditions and the derivation of DNELs for these endpoints is not appropriate.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

Thymol, tested according to OECD Guideline 404, is corrosive to the skin.

Thymol, tested according to OECD Guideline 405, is strong irritating to the eye.

According Annex I to directive 67/548/EEC thymol is classified as C; R34

5. Sensitization

Thymol is not sensitizing to the skin of guinea pigs.

Based on the irritant/corrosive effects (corrosive to the skin, strong irritating to the eye) the systemic effects not applies to local effects:

Conclusion:

Route of exposure DNEL;        local effect DNEL;       systemic effect

Oral (long and short term)              0.4 mg/kg                16.6 mg/kg

Dermal (long and short term)       No threshold;

Classification R34           16.6 mg/kg

Inhalation (short and long term)       1 mg/m³                  117 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
29 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.3 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Due to the strong irritant/corrosive properties of Thymol DNELs have to be established for systemic and local effects, respectively

Two studies for repeated dose are avalilable:

Repeated dose toxicity

Basis for delineation of the DNEL (systemic effects):

Feeding study

Study: Repeated dose study

rat, male, female,

Subchronic oral feed study for 19 weeks

rat: 0 (control), 1000 or 10000 ppm males + females

rat: 0 (control), approx. 67 or 667 mg/kg bw/d – males and females

Effects, NOAEL

NOEL = 10000 ppm (ca. 667 mg/kg bw/day)

(male + female rats)

effects:

10000 ppm: no effects

1000 ppm: no macroscopic findings

At the termination of the experiment the rats were sacrificed.

Viscera were examined macroscopically and histopathologically

Reference:

Hagen EC et al. (1967)

Food flavourings and compounds of related structure.

II. Subacute and chronic toxicity

Fd Cosmet. Toxicol. Vol. 5, pp. 141-157

Basis for delineation of the DNEL (local effects):

Gavage study

Study: OECD combined Repeat dose and Reproductive/Developmental toxicity screening teststudy

rat, male, female,

aministration period:

males, 43 days

females, from 14 days before mating to day 3 of lactation

rat: 0 (control), 8, 40, 200 mg/kg bw/d – males and females

Effects, NOAEL

NOEL = 8 mg/kg bw/day (male + female rats)

effects:

In the 40 mg/kg group, histophatological changes in the forestomach (mucosal hyperplasia, inflammatory cell infiltration and edema) were observed in the forestomach in both sexes and in the thymus in female rats. There were no significant differences in food consumption or organ weights amoung the groups. No effects ascribable to the compound were found on hematological or blood chemical examination for both sexes.

The NOEL for repeat dose toxicity local is considered to be 8 mg/kg/day for both sexes

Reference:

Toxicity testing reports of environmental chemicals

Vol. 4 1996

Ministery of Health & Welfare, Japan

The gavage study (OECD combined Repeat dose and Reproductive/Developmental toxicity screening test) revealed local effects on the forestomach due to the corrosive properties of thymol which were not seen in the 19 weeks oral feed study, where the test substance is incorporated in the feed matrix.

Therefore for systemic effects the oral feed study was used and for local effects the gavage study, respectively.

1a.) Long-term toxicity – systemic effects (general population)

Long-term oral or dermal route-systemic effects (general population):

NOEL (rat) from the subchronic feeding study: 667 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 80

Worker DNEL long-term for oral or dermal route-systemic: 8.3 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010)

Long-term inhalation route-systemic effects (general population):

NOEL (rat) from the subchronic feeding study: 667 mg/kg bw/day

Correction of the starting point according TGD Figure R.8-3:

Corrected inhalatory NOEC = Oral NOEL (667 mg/kg) x 1/1.15 m³/kg x 1.0

=> NOEC general population = 580.0 mg/m³

For interspecies differences rat vs. human: 1 (according TGD Table

R.8-4. already covered by correction of starting point)

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration subchronic to chronic: 2

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 20

Worker DNEL long-term for inhalation exposure: 29.0 mg/m³

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010).

1b.) Long-term toxicity – local effects (general population)

Long-term oral route-local effects (general population):

NOEL (rat) from the OECD 422 oral gavage toxicity study: 8 mg/kg bw/day

Penetration oral compared to dermal (both assumed 100%) 1

For interspecies differences rat vs. human: 4

For remaining interspecies differences: 1*

For intraspecies differences in general population: 10

For extrapolation of exposure duration: 1 **

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 40

Worker DNEL long-term for oral route-local: 0.20 mg/kg bw/day

* In an evaluation by ECETOC 2003 and 2010 it is considered that routine application of the factor of 2.5 is scientifically unjustified as a default factor. This view is supported by data generated by the ERASM project (Batke et al, 2010)

** No time extrapolation is applied since the dominant effect is local irritation; Thymol is labeled as a corrosive compound R34. It is anticipated the at the severity of the local irritation might increase over time but the threshold for irritation is independent of the exposure time.

For local effects the derivation of a long-term DNEL for dermal toxicity is not appropriate due to the corrosive effects of thymol.

Since Thymol is labelled with R34 an upper boundary value of 1 mg/m³ is proposed as a long-term inhalation DNEL for local effects in workers. see justification for worker.

Since the upper boundary value concept was developed for the occupation setting an additional safety factor of 2 might be applied to protect the general population.

We propose to use an upper boundary value of 0.5 mg/m³ as a DNEL for long-term local effects after inhalation for the general population.

2a.) Short-term toxicity – systemic effects (general population)

Since the primary effect of Thymol is local irritation no short-term DNEL are derived for the systemic toxicity.

2b.) Short-term toxicity – local effects (general population)

For local effects the derivation of a short-term DNEL for dermal toxicity is not appropriate due to the corrosive effects of thymol. We propose to take the above mentioned long-term DNEL value also for short-term exposure.

Conclusion (systemic effects):

general population DNEL long-term for oral or dermal route-systemic: 8.3 mg/kg bw/day

general population DNEL long-term for inhalation exposure: 29.0 mg/m³

general population DNELshort-term for oral or dermal route-systemic: 8.3 mg/kg bw/day

general population DNEL short-term for inhalation exposure: 29.0 mg/m³

Conclusion (local effects):

general population DNEL long-term for inhalation exposure: 0.5 mg/m³

general population DNEL short-term for inhalation exposure: 0.5 mg/m³

general population DNEL long-term for oral route: 0.2 mg/kg bw/day

general population DNELshort-term for oral route: 0.2 mg/kg bw/day

3.) Reproductive Toxicity – systemic effects (workers)

In the OECD combined repeat dose and reproductive/developmental toxicity screening test the compound exerted no effects on reproductive parameters such as the estrous cycle, mating index, fertility index, gestation lenght, number of corpora lutea or implantations, the implantation index, gestation index, delivery index, parturition or maternal behaviour. Birth weight and body weight gain tended to be low in the 200 mg/kg group neonates. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates.

The NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day for parental males and females, and 40 mg/kg/day for offspring.

As the NOEL for reproductive/developmental toxicty is higher than the NOEL for repeated dose toxicity (8 mg/kg bw/day), the derivation of a separate DNEL for reproductive/developmental toxicity is not necessary, because the DNEL for repeated dose toxicity covers both endpoints.

Local effects have no direct impact on reproductive/developmental toxicity at relevant exposure conditions and the derivation of DNELs for these endpoints is not appropriate.

4. Long-term and short-term dermal or inhalation route - local effects (worker)

Thymol, tested according to OECD Guideline 404, is corrosive to the skin.

Thymol, tested according to OECD Guideline 405, is strong irritating to the eye.

According Annex I to directive 67/548/EEC thymol is classified as C; R34

5. Sensitization

Thymol is not sensitizing to the skin of guinea pigs.

Based on the irritant/corrosive effects (corrosive to the skin, strong irritating to the eye) the systemic effects not applies to local effects:

Conclusion:

Route of exposure DNEL;       local effect DNEL;       systemic effect

Oral (long and short term)              0.2 mg/kg                 8.3 mg/kg

Dermal (long and short term)        No threshold;

Classification R34             8.3 mg/kg

Inhalation (short and long term)       0.5 mg/m³                 29 mg/m³