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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:
9.79 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other:
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
176.3 mg/m³
Explanation for the modification of the dose descriptor starting point:

Based on a 10-day repeated dose inhalation rat study, whereby a structural analogue of 2,3,6-trimethylphenol, Battelle Memorial Institute 1991) was given for 6 hours /day, a no-observable effect level (NOEC) of 200 mg/m³ was determined. Due to the corrosive (R34) properties of the structural analogue of 2,3,6 triphmethylphenol, this value is rather conservative compared to the irritating (R38) properties of 2,3,6 -trimethylphenol and was estimated as overpredictive for risk assessment of 2,3,6 -trimethylphenol. Therefore, the endpoint specific DNEL for inhalation repeated-dose toxicity for workers was calculated using the rat oral subacute repeated dose studies (reported above), using a route to route extrapolation.

The conversion of the rat oral NOAEL of 100 mg/kg bw/day to a corrected inhalatory human NOAEL was based on the different respiratory volume of the rat (0.38 m³/kg/day and the different rate during light activity at work (10 m³) and standard conditions (6.7 m³).

Corrected NOAEL = 100 mg/kg * 1/0.38 m³/kg/day * 6.7 m³ (8h) / 10 m³ (8h) = 176.3 mg/m³/day.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9.79 mg/m³
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:
2.778 mg/kg bw/day
DNEL related information
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

For the determination of the dermal DNEL, the NOAEL of 100 mg/kg bw/day of the same rat oral subacute repeated dose study (BASF 1996) was used.

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:
high hazard (no threshold derived)

Additional information - workers

Short-term exposure and local effects:

Acute/short-term DNELS were not determined as according to 67/548/EEC no relevant acute toxic effects occurred after oral, inhalative and dermal administration to rats.

Local irritating effects were observed on skin and eye irritation/corrosion and sensitization in the murine local lymph node assay were observed.

2,3,6-Trimethylphenol caused severely irritating effects to the eye based on the finding of staphyloma and on the severity / irreversibility of the observations. Erythema of grade 2 to 3 was reported for 1/2 rabbits after application of 2,3,6-Trimethylphenol to the skin for 1, 5, or 15 minutes. Erythema of grade 2 and necrosis was observed in both animals after application for 20 h; the findings were not reversible within 8 days.

According to REACh Guidance document R.8, DNELs for irritation/corrosion can only be derived if dose-response information is available. There is no information available achieving the requirements.

 

Therefore the following DNEL(s) for local effects and short term exposure were not determined:

- Dermal DNEL for acute / short-term exposure - systemic effects

- Inhalation DNEL for acute / short-term exposure - systemic effects

- Dermal DNEL for acute / short-term exposure - local effects

- Inhalation DNEL for acute / short-term exposure - local effects

- Dermal DNEL for long-term exposure - local effects

 

Long-term exposure - systemic and local effects

Based on the integration of all available data for 2,3,6-Trimethylphenol (Cas No. 2416-94-6) the endpoint-specific Derived-No-Effect-Level (DNEL) for oral repeated-dose toxicity, considered a No-(Adverse)-Effect-Level has been calculated. Since there is no human exposure to the general population, a DNEL was only determined for worker exposure in an industrial setting.

For 2,3,6-Trimethylphenol and analogues following long-term exposure different mammalian toxicity data were available.

 

In the oral subacute toxicity gavage study of Ohara et al. (1999) with 2,3,6-Trimethylphenol (CAS No. 2416-94-6, purity 99.67%) a NOAEL of 100 mg/kg/day and a LOAEL of 300 mg/kg bw/day day based on reduced body weight gain and food consumption for male and female rats was determined. Target organs were kidney, hematopoietic system, liver and foerestomach.

In the 28-day oral rat study with 2,3,6-Trimethylphenol (Cas No. 2416-94-6, BASF 1996) a NOAEL of 55 mg/kg body weight/day and due to a decrease in hematocrit in females a LOAEL of 273 mg/kg body weight/day was determined. Target organ in the 28-day repeated-dose study were the hematopoietic system (spleen, bone marrow, red blood cells).

In a modified combined repeated dose toxicity study with the reproductive/ developmental toxicity screening test of structural analogue of 2,3,6-Trimethylphenol administered via oral gavage to rats, for parental and offspring toxicity as well as for parental fertility / reproductive and developmental toxicity a NOAEL of ≥ 200 mg/kg body weight /day was observed.

In the developmental study using the structural analogue of 2,3,6-trimethylphenol, a NOAEL of 180 mg/kg body weight/day was determined for developmental toxicity. Based on the NOEL of 60 mg/kg body weight /day for maternal toxicity due to reduced maternal body weights during gestation (- 5.8 %) and reduced weight gain (-22.6 %) over the entire treatment period (day 6 to 16), a NOAEL for maternal toxicity of 180 mg/kg body weight /day was determined.

Regarding the dose-response relationship of the studies, the LOAEL is considered as the more appropriate starting point for the DNEL calculation, and an extrapolation of the LOAEL to the appropriate NOAEL was made. Taking into account the dose spacing in the experiment (from 55 to 273 mg/kg body weight / day) and the extent and severity of the effect seen at the LOAEL, based on defaults typically suggested for such an assessment factor ranging from 1–10 (ECHA R8 Guidance document 2008) or rather set to 3 (ECETOC 2003) an appropriate assessment factor of around 3 was used and the NOAEL was assessed as 100 mg/kg body weight / day as corrected starting point.

Additionally, since, bolus gavage dosing is expected as worst case compared to feeding the study of Ohara et al. (1999) supports a NOAEL of 100 mg/kg/day for male and female rats.

 

- Dermal DNEL for long-term exposure - systemic effects

For the determination of the dermal DNEL, the NOAEL of 100 mg/kg bw/day of the same rat oral subacute repeated dose study (BASF 1996) was used.

The absorption difference was assessed to 50 % comparing the dermal to the oral route. Accordingly, for dermal exposure the corrected starting point was calculated as 200 mg/kg body weight / day. Using the overall assessment factor of 72, including assessment factors for interspecies extrapolation of 4 (allometric scaling rat to human), intraspecies extrapolation of 3 for worker according to ECETOC 2003, exposure duration of 6 (sub-acute to chronic) and for remaining factors, dose response and quality of database of 1, respectively, the DNEL (Worker) for dermal exposure was calculated as follows: 200 mg/kg/day/ (4*3*6*1*1*1) = 2.778 mg/kg body weight /day.

 

- Inhalation DNEL for short-term exposure - systemic effects

Based on a 10-day repeated dose inhalation rat study, whereby a structural analogue of 2,3,6-trimethylphenol, Battelle Memorial Institute 1991) was given for 6 hours /day, a no-observable effect level (NOEC) of 200 mg/m³ was determined. Due to the corrosive (R34) properties of the structural analogue of 2,3,6 triphmethylphenol, this value is rather conservative compared to the irritating (R38) properties of 2,3,6 -trimethylphenol and was estimated as overpredictive for risk assessment of 2,3,6 -trimethylphenol. Therefore, the endpoint specific DNEL for inhalation repeated-dose toxicity for workers was calculated using the rat oral subacute repeated dose studies (reported above), using a route to route extrapolation.

The conversion of the rat oral NOAEL of 100 mg/kg bw/day to a corrected inhalatory human NOAEL was based on the different respiratory volume of the rat (0.38 m³/kg/day and the different rate during light activity at work (10 m³) and standard conditions (6.7 m³).

Corrected NOAEL = 100 mg/kg * 1/0.38 m³/kg/day * 6.7 m³ (8h) / 10 m³ (8h) = 176.3 mg/m³/day. Using the overall assessment factor of 18, including assessment factors for intraspecies extrapolation of 3 for worker according to ECETOC 2003, exposure duration of 6 (sub-acute to chronic) and for remaining factors, dose response and quality of database of 1, respectively, the DNEL (Worker) for inhalative exposure was calculated as follows: 176.3 mg/m³/ (3*6*1*1*1) = 9.79 mg/m³.

 

 

 

 

General Population - Hazard via inhalation route

Systemic effects

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

Local effects

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

General Population - Hazard via dermal route

Systemic effects

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

Local effects

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

General Population - Hazard via oral route

Systemic effects

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

General Population - Hazard for the eyes

Local effects

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

Additional information - General Population

For general population no DNEL was calculated, since 2,3,6 -trimethylphenol is only used in closed systems and there is no exposure for the general population.