Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low 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 for workers. But the data should be used for extrapolation route to route.

1.2 For inhalation route:

Only one study on rat (Makaruk, 1980) was available. In this study, only one dose was tested which is the saturated vapour concentration. It gave a result of LC50 above 41.7 mg/m3 after 4 hours exposure for rats and 2 hours for mouse with no other details. It was in validity 3 according to Klimish scale, and no purpose flag was selected.

This study was not taken into account for the derivation of the DNEL value.

No DNEL could be derived and it is not relevant to use acute oral toxicity study because of the discrepancy in duration of exposure.

1.3 For dermal route:

In an acute dermal toxicity study (Hazleton, 1991), groups of 5 -7 weeks old Sprague-Dawley rats (male / female) were dermally exposed to Vanillin for 24 hours to approximately 10% area of the body at doses of 2000 mg/kg bw. Animals then were observed for 14 days.

 In the preliminary study, 2 males and 2 females per group were treated under the same conditions as those employed in the main study, at the dose levels of 1000 and 2000 mg/kg. No deaths were seen at all dose level tested.

 

Dermal LD50 Combined > 2000mg/kg bw. No clinical sign, except yellowish coloration of the skin and no mortality occurred at this dose.

 

According to classification criteria of EC regulation 1272/2008, Vanillin should not be classified for acute dermal toxicity based on the LD50 in male and female rats.

 

No DNEL can be calculated because no effects were seen after dermal acute exposure to Vanillin.

2. local effects

2.1 Irritation and corrosion

2.1.1 Skin irritation

Three studies were available but two only were of validity 1 or 2. One of them performed on rat was selected as key study (Hazleton 1991, validity 1), and another one performed on rabbit (Birck 1976, validity 2) as supporting study.

The two selected studies gave the same results:not irritating to the skin. Summaries of these studies are the following:

In an acute dermal toxicity study (Hazleton, 1991), young adult Sprague-Dawley rats (5/sex) were dermally exposed to 2000 mg/kg bw of Vanilline Cristallisée (purity unknown) in water for 24 hours to 10% body surface area. Test sites were covered with a semi-occlusive dressing for 24 hours. Animals then were observed for 14 days. Irritation was scored by the method of EU guideline. In this study, cristallised Vanillin is not a dermal irritant based on the absence of skin reaction. Only a yellowish colour was observed from day 2 to 14.

In a primary dermal irritation study (Birck, 1976),New Zealandwhite rabbits (6 animals) were dermally exposed to0.5 gof vanillin (purity unknown) for 24 hours. In this study, vanillin was not a dermal irritant.

It is not relevant to derive a DNEL for the skin irritation.

2.1.2 Eye irritation

Five studiesin vitroandin vivowere available on Vanillin. Twoin vivoselected studies and thein vitroHCE test gave the same result:irritating to the eyes. Summaries of these studies are the following:

In a primary eye irritation study (CIT, 2007) 100 mg of Vanillin (pure product) was instilled into the conjunctival sac of right eye of a young adult New Zealand White rabbit (3 males). Animals then were observed for 8 days (period of reversibility).  Irritation was scored according to the OECD and EU guidelines.  

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 1.7 and 2.0 for chemosis, 2.0, 2.0 and 2.0 for redness of the conjunctiva, 0.7, 0.7 and 0.3 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity. In this study, Vanillin is irritating to the eye.

 

In a primary eye irritation study [Birck, 1976], 0.1 mL of vanillin (purity unknown) undiluted was instilled into the conjunctivae sac of New Zealand White rabbits (6 animals) for 24 hours. Animals then were observed for 7 days.  Irritation was scored by the method of Kay and Calandra, and in this study, vanillin is an eye irritant.

According toclassification criteria of EC regulation 1272/2008 Vanillin should be classified as irritant for the eyes.

No DNEL can be derived, but aqualitative approach to risk assessment and management is required because Vanillin should be classified as irritant for eyes (chapter R8, appendix R8 -9).

2.1.3 Respiratory tract irritation

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

- The substance is a solid powder with a density of1.06g/cm3 (CLAYTON, 1993)

- The particle size distribution indicated that vanillin powders were characterized through laser diffraction analysis and by sieving for flakes. D10 were 100.7 µm and 121.2 µm respectively for the two powders tested. As concerning the flakes: no flakes above 5000 µm and no particles below 100 µm were collected. The finest particles collected were in the range 100 to 200 µm (0.2 %), 91% of weight was above 1000 µm. (CRTL 2010).

No DNEL can be derived for respiratory tract irritation of Vanillin powder dust but aqualitative approach to risk assessment and management is required for worker protection to dust.

2.2 Sensitizer

Several animal studies were available for skin sensitization with Vanillin. Four were of Validity 2; One of them, a maximization test, was selected as key study and had reliability 2 (Hazleton, 1992), two others were a LLNA and a MEST tests and were selected as supporting studies with reliability 2 (Basketter, 2001; Gad, 1986), the fourth was a buehler test (Wang, 1987).

All the results lead to same conclusion, no effect on sensitization with Vanillin.

Three Human data with validity 2 confirmed the results obtained in animal studies. These studies were Patch tests on Humans (Hausen, 2001; Francalanci, 2000; Wang, 1987).

All the results available indicated that Vanillin is not a sensitizer.According toclassification criteria of EC regulation 1272/2008 Vanillin should not be classified for sensitisation.

In the absence of effects, no DNELcould be derived.

3. Long term exposure

8 studies by oral route on rats and mice were available from 16 weeks to 2 years of treatment. Only one of them (Monsanto, 1955) was selected as key study and was with validity 2. Other available studies were with validity from 2 to 4.

In most of these studies, no effects were observed (body weight, clinical signs, organ weight, histopathology. . .).

In the key study, a subchronic toxicity (26 weeks) study (Mosanto, 1955) vanillin (purity unknown) was administered to male Carworth Farms rats, 10/dose, in diet at dose levels of 0, 1000, 5000,10000ppm.
No effect related to vanillin was observed.
The NOEL is
10000ppm (equivalent to ca. 650 mg/kg bw/d).

One study by dermal route and two studies by inhalation route were available. They were validity 3, poorly described and were not taken into account for assessment.

All the results available indicated that Vanillin had no effect in oral subchronic toxicity studies, and the NOEL= 650 mg/kg bw which was the highest dose tested (Monsanto, 1955). This NOEL could not be used as starting point for DNEL derivation due to the absence of effects. No DNEL could be derived.

4. Carcinogenicity

Seven studies are available, 4 had validity 3 and 3 validity 4. All available studies were not conducted according to recognized guidelines. In most of time the period of treatment was shorter than 2 years (from 8 days to 40 weeks), or only the tumor protective effects had been evaluated. These studies were not well described but in a "Weight of Evidence" approach, all results presented no carcinogenic effects with Vanillin.

 

In the absence of carcinogenic effect, no DNEL or DMEL could be derived.

5. Reprotoxicity

Only few data are available.

No specific data are available on toxicity to reproduction, but the data available on repeated dose toxicity studies indicated no effects on reproductive organs.

 

Three teratogenicity studies were available on different species (mouse, chicken, rat). Two of them were considered as validity 3 according to Klimish scale. Two studies were considered as validity 3, because of the poor detail information on material and methods and results, furthermore they did not follow the recognised OECD guidelines. However, the results were similar and indicated no teratogen effects. The study on rat (Vollmuth, 1990) is also poorly described but had been evaluated by EFSA (European Food Safety Authority) and hence was considered as validity 2.

10 female rats per group were exposed one week before mating until 4 days post partum to 0, 125, 250, 500 mg/kg bw/day of Vanillin. Maternal toxicity had been reported with only few details: death, clinical signs and change in body weight and feed consumption. The NOAEL maternal was consider to be 250 mg/kg bw. No effect on pups were reported and the NOEL for teratogenicity was the highest dose tested 500 mg/kg bw.

The “weight of evidence” approach permit to consider that Vanillin had no teratogen properties.

 

In the absence of effect no DNEL could be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

For explanation for no DNEL derivation, please see the discussion above developed for workers.

Vanillin is classified irritant for eyes (Eye irrit Cat. 2, H319: causes serious eye irritation under CLP criteria) and upper tract irritation after dust exposure is expected.

General population would not be exposed directly to the substance as such; the substance is always diluted and present in different types of products such as cosmetic and food. By this way, the eye and respiratory tract irritant hazard would be reduced, and no specific recommendation to protect general population would be proposed. Therefore for the chemical risk assessment, no quantitative nor qualitative approach would be done.