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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
DNEL value:
41.2 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
20.7 mg/m³
Explanation for the modification of the dose descriptor starting point:

Based on repeated dose inhalation studies (28 -d, 90 -days, and 2 -years) in rats a lowest NOAEC of 41.2 mg/m³  for 6h per day on 5 days per week was determined in a subchronic study.

Correction factor 1.33 (daily exposure 8h per day), 1.5 (inhalation light activity);

Conversion of the inhalatory rat NOAEC (starting point) into in a corrected inhalatory NOAEC (modified starting point):

- assumptions (for workers): 8h exposure/day; inhalation absorption rat = inhalation absorption human

corrected NOAEC = NOAEC, inhal * (6 h/d) / (8 h/d) * (6.7 m3 (8h) / 10 m3 (8h)) = 41.2 mg/m3 * 0.75 * 0.67 =20.7 mg/m3

DNEL = corr. NOAEC * assessment factors: 1 (interspecies), 5 (intraspecies), 2 (exposure duration), 1 (dose response) , 1 (quality of database) overall : 10

DNEL = 20.7 mg/m3 / 10 = 2.1 mg/m3

AF for dose response relationship:
1
Justification:
Starting point is a NOAEC. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov 2012).
AF for differences in duration of exposure:
2
Justification:
according to ECHA Guidance on information requirements and chemical safety assessment Chapter R.8 assessment factor of 2 for duration extrapolation sub-chronic to chronic taken into consideration
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA Guidance an allometric scaling factor is not applicable when setting an inhalation DNEL based on an inhalation animal study (see Appendix R.8-2 of TGD (ECHA, Nov. 2012)), therefore AF 1 is chosen.
AF for other interspecies differences:
1
Justification:
Rodents like the rat are in general more sensitive compared to humans as the rat`s ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.
AF for intraspecies differences:
5
Justification:
According to ECHA Guidance an default factor for Intraspecies differences (factor 5) is chosen
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD (ECHA, Nov. 2012).
AF for remaining uncertainties:
1
Justification:
No further assessment factors are considered necessary.
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:
2.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
10
Dose descriptor:
NOAEC
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:
0.167 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Derivation of DNELacute

Tetrahydronaphthalene was of low toxicity in experimental animals upon oral or dermal application at high dose levels, LD50 were 2850 and 16800 mg/kg bw.

No adverse effects were noted upon inhalation of saturated vapour of tetrahydronaphthalene, LC50 exceeded 1800 mg/m³.

Qualitative assessment regarding skin irritation properties

Tetrahydronaphthalene induced irritation in a rabbit skin: In an experimental study in rabbits according to OECD TG 404 (1981) 0.5 mL of undiluted tetrahydronaphthalene applied for 4 hours to the shaved back skin. While the current test guideline requires only semi-occlusive dressing the test item was kept under occlusive dressing and induced moderate skin irritation. Therefore, tetrahydronaphthalene is classified as skin irritant (Xi, R38,Irritant, Irritatint to skin; GHS: Skin Irritant class 2, H315 Causes skin irritation). Direct skin contact has to be avoided, protective gloves have to worn.

 

Derivation of DNELlong term

 

Oral/dermal exposure.

In a 28-day oral toxicity study the NOAEL was determined at50 mg/kg bw/dwith effects on body weight and spleen at 150 mg/kg.

Similarly, reduced body weight was noted in dams in a rat teratogenicity study upon oral administration of 135 mg/ tetrahydronaphthalene/kg bw/d. The oral NOAEL was 45 mg/kg bw day. This effect of maternal toxicity is also covered by the derived long term DNEL (dermal).

 

The NOAEL from the 28 day oral toxicity study is used to derive the DNEL for systemic effects after repeated dermal exposure for workers:

Derivation of DNEL for repeated dermal exposure for workers from NOAEL of the 28 day rat oral toxicity study:

 

(derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this chapter):

 

For workers:

assumptions:

- absorptionrat= absorptionhumanand oral absorption = dermal absorption

(Toxicokinetic studies with experimental animals (rats) indicated that oral absorption was complete. As a worst case consideration dermal absorption is considered as 100%.)

- Frequency: “daily” (=frequency of exposure of rat (7d/wk) >frequency of exposure of worker (5d/wk)) . As worst case consideration frequency is considered to be equal because experimental frequency covers workers frequency

 

corrected NOAELoral; rep.dose   = rat NOAELoral; rep. dose* (exp. cond.rat/ exp. cond.human)

= rat NOAELoral; rep. dose* (frequencyrat/ frequencyworker) * (ABSrat/ ABShuman)

= 50 mg/kg bw day * 1 * 1

= 50 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

 

Description

 Factor

Interspecies: factor for allometric scaling (systemic)  

4

Interspecies: remaining differences (systemic)

2.5

Intraspecies (systemic)  

5

Exposure duration (systemic;subacute to chronic) 

6

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

300

 

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

 

DNELdermal; rep. dose=corrected NOAELoral; rep.dose/ overall AF

=50 mg/kg bw day / 300

DNELdermal; rep. dose= 0.167 mg/kg bw day

Inhalation exposure

A series of 28-day, 90-day or 2 year inhalation studies with rats and mice within the US NTP program was conducted. The lowest systemic NOAEC was observed at 7.5 ppm (41.2 mg/m³) for mice in the 90-day study with uterus atrophy noted at 82.4 mg/m³ and higher doses. Information about severity was not reported for this dose. This effect was not observed at identical doses in the 90 day study with rats and hence it may assumed that this effect is rather a mice specific effect. Furthermore the uterus atrophy in mice were not observed at identical doses in the chronic 2 year inhalation study conducted with mice leading to the conclusion that this effect seems to be reversible under conditions of chronic exposure in mice.

For local effects the NOAEC was noted in rats (90days) at 7.5 ppm (41.2 mg/m³)with olfactory atrophy at higher dose levels. This NOAEC is used to derive a DNEL that covers local and systemic effects after long term exposure for workers.

 

 

Derivation of DNEL for repeated inhalation exposure for workers from NOAEC of 90 day rat inhalative study(according to section R 8.4.2 b) figure R 8-2 of TGD)

 

For workers:

assumptions:

-duration of exposure of rat (6h/d) ≠ duration of exposure of workers (8h/d)

-frequency of exposure of rat (5d/week) = frequency of exposure of workers (5d/week)

-inhalation absorption rat = inhalation absorption human

(Toxicokinetic studies with experimental animals (rats) indicated that oral absorption was complete. As a worst case consideration dermal absorption is considered as 100%. Absorption via the inhalation route is considered as 100% by default)

 

corrected NOAECinhalation; long-term = rat NOAECinhalation; rep.dose* (exp. cond.rat/ exp. cond.human)

= rat NOAECinhalation; rep.dose* (6h/d / 8 h/d) * 6.7 m3(8h)/10 m3(8h)

= 41.2 mg/m3 * 0.75 * 0.67

= 20.7 mg/m3

 

 

Selected assessment factors (according to Table R 8-6 of the TGD): 

 

Description

 Factor

Interspecies: factor for allometric scaling (systemic)  

1****

Interspecies: remaining differences (systemic)

1***

Intraspecies (systemic)  

5

Exposure duration (subchronic to chronic; systemic) 

2

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

10

 

* Starting point is a NOAEC. Thus standard assessment factor 1 is used as described in chapterR 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used asdescribed in chapter R 8.4.3.1 of TGD

***A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences which are not releated to differences in basal metabolic rate, but justified deviations are possible. Regarding exposure by inhalation rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.

**** allometric scaling factor not applicable when setting an inhalation DNEL based on an inhalation animal study according to table R 8-3 of the TGD.

 

 

Calculation of DNELinhal; longterm :

DNELinhal; long term = corrected NOAELinhal; short term / overall AF

DNELinhal; long term = 20.7 mg/m3/ 10

DNELinhal; long term = 2.1 mg/m3

Further effects.

Tetrahydronaphthalene was not genotoxic and there was no structural alert for carcinogenic activity. Incidences of adenoma or carcinoma in the liver of female rats and uterus polyps were increase at 120 ppm ; the NOAEC for neoplastic lesions was 60 ppm (330 mg/m³). Renal tubule adenoma in male rats and nephrotoxicity was not considered, based on the observations in repeated dose studies of hyaline droplet formation it is concluded that the mechanism of induction of these kidney adenoma is specific to male rats and of no relevance to humans cancer risk. These effects are covered by the derived long term inhalation DNEL.

 

 

 

Summary

 

Endpoint

Most relevant quantitative dose descriptor

Overall AF applied

Endpoint specific DNEL

Acute
toxicity

oral

LD502850 mg/kg bw (rat)

-

Not relevant, see text

dermal

LD50> 16800 mg/kg bw

-

Not relevant, see text

inhalation

LC50> 1800 mg/m³

-

Not relevant, see text

Repeated dose toxicity (sub-acute / sub-chronic / chronic)

Local effects inhalation

NOAEC (rat,6h/d) = 41.2 mg/m³
Corrected NOAEC (rat,6h/d) = 20.7 mg/m³

10

2.1 mg/m³

oral

NOAEL = 50 mg/kg bw /d (28 day oral rat study)

600 (general population only 

(see discussion in subsection "General population"

)

Oral route not relevant for worker exposure; for general population: DNEL= 0.083 mg/kg bw/d (see discussion in subsection "General population"

dermal

DNEL calculated from NOAEL = 50 mg/kg bw /d (28 day oral rat study)

300

0.167 mg/kg bw/d

Systemic effects inhalation

NOAEC (rat,6h/d) = 41.2 mg/m³
Corrected NOAEC (rat,6h/d) = 20.7 mg/m³

10

2.1 mg/m³

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Tetrahydronaphthalene is not intended for consumer uses. Therefore no DNEL for the general population are derived.

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:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

Tetrahydronaphthalene is not intended for consumer uses. Therefore no DNEL for the general population are derived.

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:
0.083 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
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

The use of the substance tetrahydronaphthalene is restricted only to industrial and professional applications. Hence there is no need to derive DNEL´s for general population (consumers).

An indirect exposure of man via the environment might occur through ingestion of foodstuff or drinking water. Therefore, a systemic oral long-term DNEL for general population is derived and will be used to assess any possible risk that could result from indirect exposure of man via the environment .

Derivation of DNELlong term

 

Oral/dermal exposure.

In a 28-day oral toxicity study the NOAEL was determined at50 mg/kg bw/dwith effects on body weight and spleen at 150 mg/kg.

Similarly, reduced body weight was noted in dams in a rat teratogenicity study upon oral administration of 135 mg/ tetrahydronaphthalene/kg bw/d. The oral NOAEL was 45 mg/kg bw day. This effect of maternal toxicity is also covered by the derived long term DNEL (oral).

 

The NOAEL from the 28 day oral toxicity study is used to derive the DNEL for systemic effects after repeated indirect oral exposure for general population (consumers) via environment:

Derivation of DNEL for repeated oral exposure for general population (consumers) from NOAEL of the 28 day rat oral toxicity study:

 

(derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this chapter):

 

For consumers:

assumptions:

- absorptionrat= absorptionhumanand oral absorption = dermal absorption

(Toxicokinetic studies with experimental animals (rats) indicated that oral absorption was complete. As a worst case consideration dermal absorption is considered as 100%. )

- Frequency “daily” (=frequency of exposure of rat =frequency of exposure consumer)

 

corrected NOAELoral; rep.dose   = rat NOAELoral; rep. dose* (exp. cond.rat/ exp. cond.human)

= rat NOAELoral; rep. dose* (frequencyrat/ frequencyworker) * (ABSrat/ ABShuman)

= 50 mg/kg bw day * 1 * 1

= 50 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

Description

 Factor

Interspecies: factor for allometric scaling (systemic)  

4

Interspecies: remaining differences (systemic)

2.5

Intraspecies (systemic)  

10

Exposure duration (systemic;subacute to chronic) 

6

Dose-response (systemic)   

1*

Quality of the database (systemic; overall)

1**

overall Assessment Factor (overall AF)  

600

 

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

 

DNELoral; rep. dose=corrected NOAELoral; rep.dose/ overall AF

=50 mg/kg bw day / 600

DNELoral; rep. dose= 0.083 mg/kg bw day

For indirect exposure of man via environment a DNELlong-termis calculated for general population for systemic effects after indirect oral exposure which is 0.083 mg/kg bw/d and an overall assessment factor of 600 was used. DNEL for dermal or inhalation exposure were not calculated for general population because tetrahydronaphthalene is intended for uses in industrial settings only.