2-vinylpyridine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.76 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

10

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.28 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

Additional information - workers

The Derived No Effect Levels (DNELs) for 2-vinylpyridine (2VP) have been determined in accordance with the requirement of registration for REACH as a Tier 1 substance.  The basis for this determination is the Technical Guidance on Information requirements and chemical safety assessment, Guidance for information requirements and the chemical safety assessment, Chapter R.8, 2008, by the European Chemical Agency (ECHA), supplemented with the ECETOC guidance on Assessment Factors for Risk Assessment (2003) and the Guidelines on Route-to-Route Extrapolation of Toxicity Data when Assessing Health Risks of Chemicals, by the Intergovernmental Group on Health Risks from Chemicals (IGHRC, 2006). Published papers have also been consulted.

 

As noted in ECHA, 2008, derivation of DNELs is chemical specific and mode-of-action specific. In most cases, not all DNELs are required to be established (R.8.1.2.4). Some DNELs may also be qualitative, such as those for irritation and sensitization (R.8.7.2, Appendix R.8-9).

  

MODE OF ACTION:

 

For 2-VP, the mode-of-action is a threshold toxicant. This determination is based on the findings that, in repeated dose oral toxicity studies, systemic toxicity has a NOAEL. Furthermore, the weight of evidence is that 2-VP is not mutagenic nor is it predicted to be carcinogenic, characteristics which are associated with non-threshold modes of action. Hence, a non-threshold mechanism for 2VP is not considered.

 

 PORTAL OF ENTRY EFFECTS:

 

2-VP demonstrates portal-of-entry effects.  It is known to be corrosive to skin, and to cause serious damageseverely irritating[MLB1] to[m2] the eye. Upon repeated oral gavage for 28 day or for 90 days, irritation of the stomach occurred, with severity correlated with increasing dosage.

 

The corrosive properties of 2-VP impact the derivation of DNELs.  According to the IGHRC, 2006 and Rennen, et al, 2007, this substance may not meet all the criteria for validity for route-to-route extrapolation, and hence, extrapolation from oral- to-inhalation and from oral-to- dermal toxicity applies only to systemic toxicity.  ECHA (TGD, 2008, R.8.4.2) likewise supports the IGHRC, 2006 guidance limiting the situations when route-to-route estimations are made. Even the extrapolation to systemic effects is questionable, as the local irritation may have impacted long-term growth rates of test animals. The IGHRC, 2006 criteria are presented in the following Table 1, along with the behavior of 2-VP relevant to meeting these criteria.

TABLE 1. Requirements for Valid Route-to-Route Extrapolation of No-Effect Levels

No.	Criterion	2-VP meets criterion?
1	The available toxicity data are considered adequate and reliable	Yes.
2	Critical effects for the routes under consideration are systemic, and absorption and expression of toxicity are not influenced by possible local effects.	Critical effect: Decreased weight gain (Vlaovic 1984). Yes. Local effect: corrosion in non-glandular stomach: No.
3	The considered toxic effect is independent of the route of exposure	Systemic: Decreased weight gain: Yes. Local: stomach irritation: No.
4	The absorption efficiency is the same between routes or the difference is known and can be quantified.	No info available, but defaults are available
5	The half-life of the chemical is long.	Unknown
6	Hepatic first-pass effects are minimal, and the substance is not broken down to a substantial extent in the stomach or upper GI tract.	Unknown first-pass effects, substantial activity in the non-glandular stomach
7	No significant biotransformation occurs by intestinal microflora or pulmonary macrophages.	Unknown
8	The chemical is relatively soluble in body fluids	Yes. (is water-soluble)

 

From IGHRC, 2006, and Rennen, et al., 2004

  

A valid 90-day oral study of 2VP in rats (Vlaovic, 1984) is available to derive route-to-route extrapolated NOAELs for the inhalation route. In addition, a second 90-day study of 2VP has been located, and this employs the inhalation route. However, this study by Dukhovnaya, 1964, is not judged to be reliable (Klimisch 4), as very little detail is provided to compare the methodology with currently accepted OECD standards.   It is noteworthy that there was no evidence of irritation of the lung or upper airways in the exposed rats at the high dose of 5 mg/m³, suggesting that higher air concentrations may be tolerated. 

 

The key findings from experimental studies which will be used in the development of DNELs are summarized in Table 2.

Table 2: Summary Table for Key Effects Per Toxicology Endpoint

 

 

 

Endpoint	Dose Descriptor		Associated Effect	Remarks
	Local Effect	Systemic Effect
Acute Toxicity (oral)				Long-term DNELs will be modified
Acute Toxicity (dermal)				Long-term DNELs will be modified
Irritation/corrosivity	0.5 ml undiluted liquid		Skin Irritation	All rabbits displayed skin necrosis 48 h after a 1 h exposure
Sensitisation	No data		Sensitisation	Sensitising in 8 of 10 animals
Repeated Dose Toxicity (oral)	LOAEL = 20 mg/kg bw/d	NOAEL = 20 mg/kg bw/d	Local: Irritation and inflammation of glandular stomach. Systemic: increased relative organ weights and liver enzyme levels	A minimal local irritation effect was found at the low dose of 20 mg/kg bw/d.
Mutagenicity				Not mutagenic
Carcinogenicity				Modeling predicts not carcinogenic
Reproductive Toxicity				Modeling predicts not a reproductive toxin

 

   DOSE DESCRIPTORS AND DERIVED NO EFFECT LEVELS (DNELs): WORKERS

 

 

While there are concerns about the legitimacy of route-to-route extrapolations, selected DNELs have been developed, as required for risk assessment.  The first set of DNELs is calculated for the worker.

 

 

REPEATED DOSE TOXICITY EFFECTS: 

 

 

The observed systemic effect is increased absolute and relative organ weights and liver enzyme alterations in the oral gavage study of Vlaovic, 1984 (Klimisch 1). The systemic NOAEL is 20 mg/kg/d.   While oral exposure to a worker is unlikely, this calculation also represents the systemic DNEL from dermal exposure.  There is no modifier to the dose descriptor, and there are 5 assessment factors whose values are as follows: (from 2008 ECHA technical guidance document R.8, or from ECETOC Technical Report No. 86, 2003, on Derivation of Assessment Factors for Human Health Risk Assessment):

 

Table 3: Assessment Factors Used in this Risk Assessment

 

Assessment Factor	Category	Description	Value
AF1	Interspecies	Allometric Scaling (rat to human, pharmacokinetic)	4
AF2	Interspecies	Remainder 2.5 to total 10 (pharmacodynamic); not recommended by ECETOC*	1
AF3	Intraspecies	Individual variability in response	5
AF4	Duration	Subchronic to chronic study	2
AF5	Full Data Set	All critical data gaps are filled	1

 *ECETOC, 2003. Derivation of Assessment Factors for Human Health Risk Assessment, Technical Report No.86. Brussels, BE.

 The overall assessment factor for workers is 40, which is divided into the NOAEL of 20 mg/kg bw/day, for a final value of 0.50 mg/kg bw/day. (The assessment factor for intraspecies variability for the general public is 10, making the overall AF for consumers 80.)

 

Table 4: Derivation of DNEL for systemic effects of oral/dermal exposure to 2 VP

 

Source	NOAEL (mg/kg bw/d)	Modifiers for Dose Descriptor	Final Dose Descriptor (mg/kg bw/d)	AF1 Allometric Scaling (rat to human)	AF2 Remainder	AF3 Intraspecies	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	Overall AF	Final DNEL (mg/kg bw/d)
Vlaovic 1984	20	1	20	4	1	5	2	1	40	0.50

 

 

Local Effect 1: Considering oral exposure, Vlaovic, 1984, noted local irritation and inflammation in the non-glandular stomach at the lowest dose tested (20 mg/kg bw/d). This became progressively more severe with administration of higher doses. Similar stomach irritation was also noted in the 28-day oral toxicity study in rats at 50 mg/kg bw/day, but not at 12.5 mg/kg bw/day (Oba, et.al, 1997). This is interpreted as a local irritation effect on the forestomach as a result of gavage administration of a corrosive substance. This factor may also be a critical etiology in the decreased weight gain of the animals at the higher doses.  In the absence of this local effect, the NOAEL and the associated systemic DNEL may behigher[m1] .[MLB2] 

 

The calculation for the local DNEL for oral exposure is provided below. The LOAEL is not modified, but an extra assessment factor is added to lower the value of the LOAEL to an estimated NOAEL (factor of 3).   No allometric scaling factor is appropriate, as the direct corrosive effect of 2VP is not a consequence of pharmacokinetic or pharmacodynamic variables; there is no indication to apply an additional assessment factor for local metabolism as suggested in Table R.8-6. Nor is the duration-based assessment factor applicable. Thus, the value of the overall AF is 15, resulting in an oral DNEL for local effects of 1.33 mg/kg bw/day.

 

Table 5: Derivation of DNEL for local effects of oral/dermal exposure to 2 VP

 

 

Source	LOAEL (mg/kg bw/d)	Modifiers for Dose Descriptor	Final Dose Descriptor (mg/kg bw/d)	AF1 Allometric Scaling (rat to human)	AF2 Remainder	AF3 Intra-species	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	AF 6 LOAEL to NOAEL	Overall AF	Final DNEL (mg/kg bw/d)
Vlaovic 1984	20	1	20	1	1	5	1	1	3	15	1.33

 

  A DNEL is required to be derived for systemic inhalation risks from long-term exposure. There is no subchronic study in animals of sufficient validity which will provide insight on this topic, nor is one proposed, due to the corrosive nature of 2VP. The introduction to Annex VIII of the REACH legislation specifically states “In vivo testing with corrosive substances at concentrations/dose levels causing corrosivity shall be avoided.”

 

An inhalatory DNEL for systemic effects may be estimated from the 90-day oral study of Vlaovic, 1984, using route-to-route extrapolation techniques. The systemic NOAEL of 20 mg/kg bw/day must be modified to estimate the equivalent inhalation dose. As gastrointestinal absorption is about half as efficient as absorption in the lung, the corresponding inhalatory concentration is 50% of that of the administered GI dose. Secondly, the mass of chemical absorbed per day is converted to the amount provided in the respiratory volume of the rat in an 8 hour dosing period.  The absorbed dose must be divided by the respiration rate in the rat (0.38 m3/kg bw). Finally, the newly derived concentration must be modified by a factor associated with a respiratory rate involving light activity (compared to the standard rate at rest; 6.7 m3 resting/10 m3 active). The NOAEL from the oral study is thus modified to a dose descriptor of 17.6 mg/m3.   No allometric scaling factor is applied (R.8, pp 32 and 68); the overall AF is 10. The DNEL is 1.76 mg/m3.

 

 Table 6: Derivation of DNEL for systemic effects of inhalation exposure to 2 VP

  

Source	NOAEL (mg/kg bw/d)	Modifier 1 Absorption	Modifier 2 Resp Volume	Modifer 3 Activity	Final Dose Descriptor (mg/m3/d)	AF2 Remainder	AF3 Intra-species	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	Overall AF	Final DNEL (mg/m3)
Vlaovic 1984	20	2	0.38	0.67	17.6	1	5	2	1	10	1.76

 

 

Local Effect 2: 2VP, as a corrosive substance, is likely to cause severe irritation effects to lung tissue upon inhalation exposure.  It is of interest that this effect was not reported under pathology findings by Dukhovnaya, 1964 in a 4-hour exposure period for 90-days in rats at levels up to 5 mg/m3.  This suggests that higher concentrations might be tolerated by experimental animals.

 

Both IGHRC and ECHA indicate that route-to-route extrapolation of effect levels is not appropriate for local toxic effects (R.8.4.2, p 24).

 

The classification of 2VP includes H071, Corrosive to the respiratory tract. This classification insures that workers will be advised about potential risks to the respiratory tract and recommendations will be made for engineering controls and protective equipment. This DNEL is assessed qualitatively.

ACUTE TOXICITY EFFECTS: WORKERS

 

Acute local dermal effects are assessed qualitatively. While 2VP is corrosive to the skin and induces serious damage to eyes, there are no available NOAELs from which to derive DNELs. The REACH regulation discourages testing of animals using corrosive substances (introduction to Annex VIII).

 

DNELs for acute effects are recommended to be derived if an acute toxicity hazard (leading to classification and labeling) has been identifiedandthere is a potential for high peak exposure (R.8. 1.2.5, p. 16). 2VP is classified for acute effects (Acute Toxicity-Dermal 3, Skin corrosion/irritation 1B, Serious eye damage/eye irritation 1, and Skin Sensitisation 1). Concerning exposure of 2VP, in the scenarios reported by users, there may be opportunities for short intermittent dermal or inhalation exposure in the workplace, such as during sampling or transferring material. Oral exposure is unlikely.  

 

According to the ECHA Guidance, Appendix R 8.8, there is no accepted methodology for determining acute dermal exposures, and protection is generally accommodated by more conservative long-term systemic DNELs” (p. 106).

 

One simple and well-established method used to estimate an acute threshold limit value (TLV) is multiplication of the long-term DNEL by a factor of 3 (Guidance R.8, Appendix R.8.8, p. 110, 2008). For the worker handling 2VP, the oral/dermal systemic DNEL from repeat dose studies is 0.50 mg/kg/day, and for inhalation exposure, is 1.76 mg/m3. 

 

The acute DNEL for 2VP for dermal/oral exposure is thus calculated to be 1.50 mg/kg/day, or 105 mg/day for a 70 kg worker.  The acute DNEL for inhalation, equivalent to a 15-min TLV, is calculated to be 5.28 mg/m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.44 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

20

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.32 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

irritation (respiratory tract)

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Local effects

Long term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

no-threshold effect and/or no dose-response information available

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.75 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

3

Additional information - General Population

DNELs are also derived for the consumer in the general population, although consumer exposure of this industrial chemical monomer is highly unlikely.  The method of calculation of the systemic DNEL for potential oral and dermal exposure by the general population is similar to that for the worker. The same NOAELs are used as those in the calculation for workers (See Table 2). 

 

As in previous calculations, the systemic NOAEL (20 mg/kg bw/d) does not require dose descriptor modification for oral/dermal exposures. The NOAEL is, however, divided by a larger overall assessment factor (80), to reflect the larger potential intraspecies variability response in the general population compared to the healthy worker population. The final DNEL for 2VP is 0.25 mg/kg bw/day.

 

 Table 9: Derivation of DNEL for systemic effects of oral/dermal exposure to 2 VP

  

Source	NOAEL (mg/kg bw/d)	Modifiers for Dose Descriptor	Final Dose Descriptor (mg/kg bw/d)	AF1 Allometric Scaling (rat to human)	AF2 Remainder	AF3 Intraspecies	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	Overall AF	Final DNEL (mg/kg bw/d)
Vlaovic 1984	20	1	20	4	1	10	2	1	80	0.25

 

 

The calculations for a DNEL for local effects of 2VP are shown below, with the larger assessment factor for individual sensitivity applied. The final DNEL is 0.67 mg/kg bw/day.

 

Table 10: Derivation of DNEL for local effects of oral/dermal exposure to 2 VP

  

Source	LOAEL (mg/kg bw/d)	Modifiers for Dose Descriptor	Final Dose Descriptor (mg/kg bw/d)	AF1 Allometric Scaling (rat to human)	AF2 Remainder	AF3 Intra-species	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	AF 6 LOAEL to NOAEL	Overall AF	Final DNEL (mg/kg bw/d)
Vlaovic 1984	20	1	20	1	1	10	1	1	3	30	0.67

 

 

Calculation of an inhalatory DNEL for the general public differs from that of the worker, who is assumed to be actively working for a period of 8 hours. The general public will have a default exposure duration of 24 hours, and the respiration rate is assumed to be based on resting exchange volumes. The systemic NOAEL is divided by 2 for the GI:lung absorption factor, and 1.15 for the respiratory volume factor for 24 hours. This results in a modified dose descriptor of 8.70 mg/m3.  Allometric scaling is not applicable. The overall AF is 20, resulting in a DNEL of 0.44 mg/m3.

  

Table 11: Derivation of DNEL for systemic effects of inhalatory exposure to 2 VP

  

Source	NOAEL (mg/kg bw/d)	Modifier 1 Absorption	Modifer 2 Resp Volume	Final Dose Descriptor (mg/m3/d)	AF2 Remainder	AF3 Intra-species	AF4 Duration (subchronic to chronic)	AF5 Full Data Set	Overall AF	Final DNEL (mg/m3/d)
Vlaovic 1984	20	2	1.15	8.70	1	10	2	1	20	0.44

 

 

Route-to-route extrapolation of local effect levels is not appropriate for 2 VP.  DNELs are not calculated.

  

ACUTE TOXICITY EFFECTS: GENERAL POPULATION

  

As with workers, tripling of the long-term DNEL is the method used for estimating the acute DNELs for consumers. The oral/dermal systemic DNEL for 2VP from repeat dose studies is 0.25 mg/kg/day, and for inhalation exposure, is 0.44 mg/m3. 

 

The acute DNEL for dermal/oral exposure to 2VP is thus calculated to be 0.75 mg/kg/day, or 52.5 mg/day for a 70 kg adult.  The acute DNEL for inhalation, equivalent to 15-min TLV, is calculated to be 1.32 mg/m3.