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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
500
Dose descriptor starting point:
NOAEL
Value:
65 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
455 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation assuming 100% absorption for both exposure routes (oral and inhalation).

NAEC (8 h) = 65 x (70/10) = 455 mg/m3

AF for differences in duration of exposure:
1
Justification:
No assessment factor for the time duration since a 2 years study was used.
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA R8 guidance default assessment factor for rats.
AF for other interspecies differences:
2.5
Justification:
ECHA R8 guidance default assessment factor.
AF for intraspecies differences:
5
Justification:
ECHA R8 guidance default assessment factor.
AF for the quality of the whole database:
1
Justification:
Data with reliability 2 under klimisch rating
AF for remaining uncertainties:
10
Justification:
For severity of the effect (malignant tumours)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
85 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
37.5
Dose descriptor starting point:
NOAEC
Value:
1 500 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
1 005 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the DNEL derivation the first step is to modify the starting point Rat NOAEC (8h) into NOAEC worker (8h), according to ECHA guidance on information requirements and chemical safety assessment R8.

Rat NOAEC (8h) = 1.5 mg/L (1500 mg/m3)

--> inhalation NOAEC worker (8h) = 1500 mg/m3 x (sRVhuman/wRV)

sRVhuman: standard respiratory volume for human:6.7 m3

wRV: worker respiratory volume for 8 hours:10m3

--> NAEC worker (8h) = 1500 x (6.7/10) = 1005 mg/m3

AF for interspecies differences (allometric scaling):
1
Justification:
Not needed if the study used for the derivation of the DNEL is an inhalation study.
AF for other interspecies differences:
2.5
Justification:
ECHA R8 guidance default assessment factor.
AF for intraspecies differences:
5
Justification:
ECHA R8 guidance default assessment factor.
AF for the quality of the whole database:
3
Justification:
The quality of the study is poor in details.
Justification:
The Haber law was used in oder to derive a DNEL for 15 mn of exposure.

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Route of original study:
Dermal
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
125 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is needed.

AF for interspecies differences (allometric scaling):
4
Justification:
ECHA R8 guidance default assessment factor for rats.
AF for other interspecies differences:
2.5
Justification:
ECHA R8 guidance default assessment factor.
AF for intraspecies differences:
5
Justification:
ECHA R8 guidance default assessment factor.
AF for the quality of the whole database:
1
Justification:
Study with reliability 2 under Klimisch rating.

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

DNEL for WORKERS

 

1. Acute / short-term exposure - systemic effects

 

1.1 For oral route:

The oral route is not relevant to workers. But the data should be used for extrapolation route to route.

 

1.2 For inhalation route:

Determination of the DNEL (15mn) for Human from rat inhalation study:

In one study (Flickinger, 1976) with validity 2, 6 female Wistar rats per group were exposed to aerolizated solutions of catechol at nominal doses from 1.5, 2 and 2.8 mg/L for 8 hours.

The LC0 was > 2.8 mg/L. At this dose, no mortality occurred, but effects were noted on central nervous system and loss of tail and toes. Similar tail loss occurred in 2/6 rats subjected to 2.0 mg/L aerosol. The loss of distal portions of the tail and accompanying loss of digits at doses of 2.8 and 2.0 mg/l was dose related. No clinic signs and/or similar tail loss occurred in the 6 rats exposed to 1.5 mg/L.

Regarding these data it is possible to define the Rat NOAEC (8h) = 1.5 mg/L and LOAEC (8h) = 2 mg/L.

For the DNEL derivation the first step is to modify the starting point Rat NOAEC (8h) into NOAEC worker (8h), according to ECHA guidance on information requirements and chemical safety assessment R8.

Rat NOAEC (8h) = 1.5 mg/L

--> inhalation NOAEC worker (8h) = 1.5 mg/L x (sRVhuman/wRV)

sRVhuman: standard respiratory volume for human:6.7 m3

wRV: worker respiratory volume for 8 hours:10m3

--> NAEC worker (8h) = 1.5 x (6.7/10) = 1.005 mg/L

Assessment factors (AS) :

Intraspecies differences: 5 (default value for workers)

Interspecies differences: 2.5 (to consider the phamacodymany variation), the factor of 4 (allometric scaling) for pahrmacodynamy is not necessary for inhalation route (R8 guide of ECHA).

Quality of whole database: 3 (the quality of the study is poor in details, and the test substance had been tested in aerosol which is not the current state of Human exposure form exposure, in doubt of difference in the effect an assessment factor is considered).

DNEL (8h) = NAEC / AS = 1.005 / (5 x 2.5 x 3) = 0.0268 mg/L = 26.8 mg/m3

 

Conversion of the DNEL for 8 hours to DNEL for 15 minutes using Haber low: Haber law Cnx t = k with n=3 for extrapolation from longer to shorter duration:

(26.8)3x8 x 60= k = 9239439,36

DNEL (15 min) =39239439,36/15 = 85.08 mg/m3

 

Worker-DNEL acute for inhalation route-systemic (15 min) = 85.08 mg/m3= 85 mg/m3

 

1.3 For dermal route:

In an acute dermal toxicity study (Rhône-Poulenc, 1973), CD male and female rats (5/sex/group) were exposed to Catechol by dermal route for a maximum of 24 hours to their back, at doses of 125, 875 and 1125 mg/kg bw. Animals then were observed for 15 days.

0/10 died at 125 mg/kg and no clinical signs, and 10/10 died at 875 and 1125 mg/kg, the rats presented tremors 5 minutes after dermal application, and died within 30 minutes after clonic convulsions.

Dermal LD50 Combined = 600 mg/kg bw.

Rat NOAEL combined = 125 mg/kg bw 

This value is considered as starting point

 

The following assessment factors were applied:

-      Interspecies differences: 4 (default value for rats allometric scaling for pharmacokinetic) x 2.5 (default value for rats for pharmacodynamy)

-      Intraspecies differences: 5 (default value for workers)

-      Quality of whole database: 1 (reliability 2 study)

 

Worker-DNEL acute for dermal route-systemic= 125 / (4 x 2.5 x 5)=2.5 mg/kg bw

 

2. Acute / short-term exposure - local effects

2.1 Irritation and corrosion

2.1.1 Skin irritation

One key study was selected to evaluate the effect for this endpoint: 

In a primary dermal irritation study (Flickinger, 1976), 6 albino rabbits were exposed by dermal route to 0.5 mg of Catechol for 24 hours to bellies. No indication was done concerning dressing. Skin of animals was abraded or intact. Animals then were observed for 14 days. Irritation was scored by the method of Draize.

 

The contact of catechol produced slight to moderate erythema (score 2.2) and slight oedema (score 1.2) after 24 hours on intact skin.

The irritation was less marked 72 h after exposure (erythema: 1.7 and oedema: 1.0).

In this study, Catechol is irritating to the skin based on Draize scoring. According to classification criteria of EC regulation 1272/2008 and current EC regulation in Annex VI 3.1., the catechol is classified as irritant for the skin category 2 (H315: Causes skin irritation)

 

No DNEL can be derived.

A qualitative approach for risk assessment and management is therefore required because Catechol was classified as irritant for the skin (chapter R8, appendix R8 -9).

2.1.2 Eye irritation

Only one study was available and was selected as key study and had reliability 2. The summary of this key study is the following:

In a primary eye irritation study (Flickinger, 1976), 0.1 mg of Catechol was instilled into the conjunctive sac of one eye of 6 male albino rabbits. Animals then were observed for 14 days. Irritation was scored by the method of Draize.

Upon application, the conjunctivae became moderately erythematous and oedematous, and moderate exudate and corneal opacity were produced. Signs of marked discomfort were evident. 

The total evaluation varied from 103 to 78 at 24 to 72 hours.

Based on these results, Catechol is highly irritating to eyes, in this study. In the current EC regulation in Annex VI 3.1., the catechol is classified as irritant for the eye category 2 (H319: Causes serious eye irritation.)

No DNEL can be derived.

A qualitative approach for risk assessment and management is therefore required because Catechol was classified as irritant for the eye (chapter R8, appendix R8 -9).

2.1.3 Respiratory tract irritation

Physico chemistry data available and validated according to Klimish scale for Catechol indicated that:

- At ambient temperature and pressure, catechol is an organic solid substance, appearing under the form of beige-brown flakes with a weak odour of phenol. Its density range: 1.341 to 1.371 (at 15 to20°C) (Handbook, 2001)

- Particle size distribution of Catechol flakes was characterized through sieving. The majority of flakes were in the range of 1000 to 5000 µm (and higher).

Very little quantity of flakes below 100 µm was present (<1.05%). (CRTL, 2010).

Due to particle size, Catechol was not susceptible to be inhaled. Irritancy effect on upper respiratory tract should be possible regarding the irritant properties of catechol for skin and eye irritation.

2.2 Sensitizer

Two studies with reliability 2 were available and a "Weight of Evidence " (WoE) approach was applied.

In one study (Rao, 1981) the sensitization of Catechol was tested by aSplit adjuvant test. In the other study (Baer, 1967), Catechol was tested with n-alkylcatechol in a Freund's complete adjuvant test.

In both studies Catechol showed positive response, but Split Adjuvant test indicated a positive response in 22% of the animals that is not sufficient for a classification as sensitizer.

The weight of evidence approach and the result of Freund's complete adjuvant test where majority of the animals injected became sensitized lead to the conclusion that Catechol is a potential skin sensitizer.

 

According to classification criteria of EC regulation 1272/2008 the catechol should be classified as skin sensitizer category 1B (H317: May cause an allergic skin reaction).

No DNEL can be calculated from these 2 studies because the method did not permit to determine concentrations for threshold.

Therefore, since catechol is classified as skin sensitizer, a qualitative approach to risk assessment and management is required (chapter R8, appendix R8 -9).

3. Long term exposure

Regarding repeated toxicity only one study with reliability 1 was selected as key study.

The purpose of this study (Harlan, 2009), was to determine dose levels of Catechol suitable for use in a subsequent combined repeated dose toxicity screening test in the rat.

The test item was administered orally by gavage once daily at dose levels of 30, 90 and 180 mg/kg/b.w./day to 3 males and 3 females. Males were treated over a 14-day pre-pairing period and during the pairing period and up to one day before necropsy (for a total of at least 28 days of treatment). Females were treated throughout the pre-pairing, pairing and gestation period up to day 13 post coitum.

One male at dose level of 180 mg/kg/day was found dead at the beginning of the pairing period. Since no macroscopical findings were noted and the clinical sign was tremor as the other animals, it was not clear if the causes of this death were due to the treatment with Catechol.

Treatment with the test item at 90 and 180 mg/kg/day caused tremor in males and females during the pre-pairing period. At 180 mg/kg/day, this effect was prolonged in one male during the pairing period and in all females until the beginning of the gestation period. At 180 mg/kg, food consumption and body weight gain were decreased in males at the onset of the treatment.

The relevant reproduction data such as number of corpora lutea, pre- and postimplantation loss were not affected by the treatment with the test item.

The general NOEL was considered to be 30 mg/kg/day.

Based on the results of this dose range-finding study, dose levels of 30, 80 and 160 mg/kg/day were considered applicable for the subsequent dose toxicity study with reproduction/ developmental toxicity screening test.

The following results were obtained:

In parent animals, in males and females, body weight and body weight gain were not considered to be affected by the treatment with the test item.

At 160 mg/kg/day, liver weights were statistically significantly increased in males and females. This was considered to be of metabolic nature since only hepatocellular hypertrophy and no liver injury was recorded during the histopathological examination.

At 80 and 160 mg/kg/day, incidence and severity of squamous hyperplasia in the stomach were increased in animals of both sexes. This lesion represents a localized stomach reaction to a repeatedly gavages irritant test material.

Based on the findings noted at histopathological examination the general NOAEL (No Observed Adverse Effect Level) was considered to be 30 mg/kg/day, due to the squamous hyperplasia in the stomach.

Other available studies, by different route of application had reliability 3, and were not taken into account for assessment.

 

The starting point is to transform the Rat NOAEL oral into NAEC worker inhalation (8h), using an oral-to-inhalation route extrapolation:

- assuming 100% absorption for both exposure routes,

- taking into account an interspecies assessment factor of 4 for pharmacokinetic variation, and the factor of 2.5 for pharmacodynamy:

NAEC worker (8 h) = 30/ (4x 2.5) = 3 mg/kg bw

- the bodyweight of 70 kg for humans and a respiratory volume of 10 m3/person over 8 hours for workers under light activity,

NAEC worker (8 h) = 3 x (70/10) = 21 mg/m3

 

The following assessment factors were applied for the DNEL calculation:

-     Intraspecies differences: 5 (default value for workers)

-     Quality of whole database: 1 (reliability 1 study)

- Extrapolation subacute to chronic : 6 (default value for workers)

 

DNEL = NAEC / AS = 21 / 5 x 6 = 0.7 mg/m3

 

Worker-DNEL for inhalation route-systemic= 0.7 mg/m3

The DNEL value was derived according to main toxic effect which is a local effect in rat (squamous hyperplasia in the stomach). This effect was an oral local effect and the concentration may not be reliable for systemic effect, so the extrapolation to inhalation route could be questionable. However, regarding previous data available, in particular acute effect, it is possible to use the data from oral route to extrapolate to inhalation route.

 

The squamous hyperplasia in the stomach observed in rat in this subacute toxicity study, correspond to premium effects that could lead after long repeated exposure to carcinogenic effect, regarding data available in the 38 carcinogen studies available. 28 studies were considered as validity 2 according to Klimish scale and 3 considered as key studies.

 

In the study of Hagiwara (2001), the dose-dependence of Catechol glandular stomach carcinogenesis was investigated in male F344 rats. Groups of 30 male rats were fed Catechol at dietary levels of 0, 0.1, 0.2, 0.4 and 0.8 % (0, 33, 65, 141 and 318 mg/kg/day) for up to 104 weeks. Five rats of each group were killed at 34 weeks and the remaining animals were sacrificed at the termination, all undergoing histopathological examination. Moderate retardation of body weight increase was observed in the 0.8% group, but no adverse effects were found in terms of survival. Submucosal hyperplasias and adenomas of the pyloric glands developed in the 0.4 and 0.8% groups, only very minor changes being noted in the 0.1 and 0.2% groups at week 34. Incidences of adenocarcinoma development in the pylorus were 4% and 8% in 0.4% and 0.8% groups respectively, and 0 inthe 0.1% and 0.2% groups, at the termination. Adenomas and submucosal hyperplasias were found in nearly all animals fed 0.2% Catechol or more, the incidences of those in 0.1% group being 0 and 56% at 34 and 104 weeks respectively. Serum gastrin levels were significantly increased in the 0.2, 0.4 and 0.8% groups at 34 weeks, and in all tested groups at the termination, at extents comparable with the induction of proliferative lesions in the pylorus. The results thus demonstrated that dietary levels of 0.4% and 0.8% Catechol long-term induce adenocarcinomas in the pyloric glands, while 0.1 and 0.2% cause begnin proliferative lesions, all accompanied by increase in serum gastrin levels (hyperplasia from 0.1% and adenomas from 0.2).

According to this study and the other carcinogenic studies, catechol induces malignant tumours at high dose and benign tumours at mid dose. Based on all the available studies a threshold can be define for malignant tumours and for benign tumours. In rats, malignant tumours appear mainly at 0.8% and also at 0.4%. Adenomas were observed from 0.2%.

Based on Hagiwara et al., 2001 study, several DNELs can be derived: one for hyperplasia of the stomach, the other one for benign tumours (adenomas) and the third one for malignant tumours.

DNEL for hyperplasia observed in the stomach:

LOAEL Rat = 0.1 % or 33 mg/kg bw (hyperplasia). Similar value that for systemic effect in repeated dose toxicity study.

The starting point is to transform the Rat LOAEL oral into LAEC worker inhalation (8h), using an oral-to-inhalation route extrapolation:

- assuming 100% absorption for both exposure routes,

- taking into account an interspecies assessment factor of 4 (allometric scaling) for pharmacokinetic variation, and the factor of 2.5 for pharmacodynamy:

- the bodyweight of 70 kg for humans and a respiratory volume of 10 m3/person over 8 hours for workers under light activity,

LAEC worker (8 h) = 33/ (4x2.5) x (70/10) = 23.1 mg/m3

 

The following assessment factors were applied for the DNEL calculation:

-     Intraspecies differences: 5 (default value for workers)

-     Quality of whole database: 1 (reliability 1 study)

- issued related to severity and dose-response: 3 ( use LOAEL as starting point)

DNEL(8h) = LAEC / AS = 23.1 / 5 x 3 =1.54 mg/m3

 

Worker-DNEL for inhalation route-hyperplasia = 1.5 mg/m3

 

DNEL for benign tumours observed in the stomach:

NOAEL Rat = 0.1 % or 33 mg/kg bw (adenomas).

The starting point is to transform the Rat NOAEL oral into NAEC worker inhalation (8h), using an oral-to-inhalation route extrapolation:

- assuming 100% absorption for both exposure routes,

- taking into account an interspecies assessment factor of 4 (allometric scaling) for pharmacokinetic variation, and the factor of 2.5 for pharmacodynamy:

- the bodyweight of 70 kg for humans and a respiratory volume of 10 m3/person over 8 hours for workers under light activity,

NAEC worker (8 h) = 33/ (4x2.5) x (70/10) = 23.1 mg/m3

 

The following assessment factors were applied for the DNEL calculation:

-     Intraspecies differences: 5 (default value for workers)

-     Quality of whole database: 1 (reliability 1 study)

-  severity of effect: 3 (adenomas)

DNEL (8h) = NAEC / AS = 23.1 / 5 x 3 =1.54 mg/m3

 

Worker-DNEL for inhalation route-benign tumours = 1.5 mg/m3

DNEL for malignant tumours observed in the stomach:

NOAEL Rat = 0.2 % or 65 mg/kg bw (adenocarcinomas).

The starting point is to transform the Rat NOAEL oral into NAEC worker inhalation (8h), using an oral-to-inhalation route extrapolation:

- assuming 100% absorption for both exposure routes,

- taking into account an interspecies assessment factor of 4 (allometric scaling) for pharmacokinetic variation, and the factor of 2.5 for pharmacodynamy:

- the bodyweight of 70 kg for humans and a respiratory volume of 10 m3/person over 8 hours for workers under light activity,

NAEC worker (8 h) = 65 / (4x2.5) x (70/10) = 45.5 mg/m3

 

The following assessment factors were applied for the DNEL calculation:

-     Intraspecies differences: 5 (default value for workers)

-     Quality of whole database: 1 (reliability 1 study)

- Severity: 10 (malignant tumours - adenocarcinomas)

DNEL(8h) = NAEC / AS = 45.5 / 5 x 10 =0.9 mg/m3

 

Worker-DNEL for inhalation route-Malignant tumours = 0.9 mg/m3

The DNEL set for malignant tumours is the lowest one derived from the study Hagiwara et al, 2001 performed in rats. A DNEL was also derived based on Hirose, 1990 - 1993 study for adenomas noted in mice. The DNEL derived was higher than 0.9 mg/m3. Since the same effect (hyperplasia) was observed from the carcinogenic study and from the OECD 422 study. The carcinogenic effect study was retain for the derivation of the DEL, since this study is more robust.

Therefore, regarding this specific toxic effect and results obtained in carcinogenic studies and subacute toxicity study, it is reasonable to consider that the:

 

 Worker-DNEL for inhalation route-carcinogenicity is 0.9 mg/m3.

 

 

 

 

4. Reprotoxicity

 

One study was considered as validity 1 and key study, it is a combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Han Wistar Rat (OECD 422) of R. Ceccatelli (2009).

Catechol was administered by gavage at 0, 30, 80, 160 mg/kg body weight/day to male rats for at least 28 days and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.

Reproduction and Breeding regarding mean precoital time, conception rate, fertility and gestation indexes were not affected by the treatment with the test item. Same conclusion for implantation rate and post-implantation loss.

The treatment with the test item did not reveal any effects on the completeness of stages or cell

populations of the testes in males rats.

The mean number of pups at first litter check and on day 4 post partum was not affected by the

treatment with the test item. The sex ratio was also not affected.

Pup weight development was not affected by the treatment with the test item. At necropsy of pups, no test item-related findings were noted.

The NOEL for reproduction/developmental toxicity was considered to be 160 mg/kg/day, the highest dose tested without observed effect.

In absence of effect regarding reproduction performance, it was not possible to determine the starting point to derive a DNEL for this endpoint.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
medium hazard (no threshold derived)
DNEL related information
Modified dose descriptor starting point:
NOAEL

Local effects

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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information
Modified dose descriptor starting point:
NOAEL

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

General population are not exposed to catechol. There is no exposure of consumers to catechol since there is no consumer’s usage. Furthermore, as catechol is readily biodegrable and there is no indication for bioaccumulation potential of the substance, no secondary poisoning is expected.