Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.18 mg/m³
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.12 mg/kg bw/day
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:
medium hazard (no threshold derived)

Additional information - workers

Adaptation of testing requirements and establishment of long term systemic DNELs

Experimental data on repeated dose and reproductive toxicity which are normally required for a substance of the 100-1000 t/y band have been waived in accordance with Annex XI, section 3.2 (b) of Regulation (EC) No 1907/2006 (REACH) since the substance is manufactured and used solely in industrial settings under strictly controlled conditions which result in negligible worker exposure. The purpose of the information given below together with the data presented in chapter 9 and 10 of the CSR was to provide the justification for this waiving following the recommendations given in the ECHA Guidance on IR & CSA chapter R.5 on the adaptation of information requirements (2011) and to establish scientifically justified and conservative DNEL values for long term systemic worker exposure.

 

Introduction

In accordance with REACH Annex XI Section 3.2 b the standard testing regime set out in REACH Sections 8.6 and 8.7 of Annex VIII and with Annex IX (testing on repeated dose toxicity and reproductive toxicity) may be omitted, when the substance is manufactured and used under strictly controlled conditions throughout the life cycle. In this context studies on repeated dose toxicity and reproduction toxicity can be adapted based on exposure scenarios and the corresponding exposure assessment. The purpose of the data presented below (chapter 9 and 10 of the CSR) was to provide the justification for this waiving following the recommendations given in the ECHA Guidance on IR & CSA chapter R.5 on the adaptation of information requirements (2011).

Adaptation of testing requirements

The waiving of the repeated dose and developmental toxicity (OECD 414) study follows the principles described in the ECHA Guidance on IR & CSA chapter R.5 on the adaptation of information requirements (2011). It is based on i) the assessment of worker exposure for all exposure scenarios which occur at manufacturing and downstream use sites, ii) derivation of the threshold of toxicological concern (TTC) relevant for Crotonic acid and DNEL establishment and iii) calculation of the Risk Characterization Ratios (RCRs) by comparison of the obtained exposure values with the derived DNELs in order to demonstrate that the estimated worker exposure is not relevant with regard to human health.

i) Worker exposure assessment

Toxicological relevant worker exposure to the substance is not expected as the substance is produced and used under strictly controlled conditions. Worker exposure for all scenarios resulting in possible contact with the substance was estimated using EasyTRA. Exposure estimations were limited to systemic effects via the dermal and inhalation route since Crotonic acid is neither classified for skin irritation nor for skin sensitization according to CLP (1227/2008/EC) and thus, the derivation of the local DNEL is not required. In addition, air measurements were performed during the transfer of Crotonic acid into 25 kg bags (Infraserv GmbH & Co, 2013). This work activity is expected to cause the highest exposure levels at the manufacturing site. The measurements revealed an average dust concentration within 8 hours below the limit of quantification of 0.09 mg/m³ and thus confirmed the appropriateness of the EasyTRA estimation (0.07 mg/m³) for this exposure scenario.

 

ii) Derivation of the threshold of toxicological concern (TTC) relevant for Crotonic acid

The TTC concept is a science-based risk characterization approach establishing human exposure threshold values for chemicals (TTC values) with limited experimental toxicity data. Human exposure below the TTC has a very low probability to cause adverse effects to human health. The scientific acceptability of the concept has been confirmed recently by SCCS (2012) and EFSA (2012). Also, the ECHA Guidance on IR & CSR Chapter R.7a acknowledged the usefulness of the concept (2012).

The TTC assessment scheme for chronic exposure (EFSA, 2012) is applicable to Crotonic acid since it is not a member of an exclusion category (high potency carcinogens (cohort of concern: aflatoxin-like compounds, N-nitroso compounds, azoxy compounds, benzidines, hydrazines), inorganic substances, metals and organometallics, proteins, steroids, substances known/predicted to bioaccumulate, nanomaterials, radioactive substances, mixtures). Therefore, a stepwise assessment was conducted proceeding from consideration of the low TTC value for genotoxic compounds (0.0025 µg/kg bw/day) towards higher TTC values for neurotoxic compounds (0.3 µg/kg bw/day) and ending with TTC values for compounds displaying general systemic toxicity (1.5 µg/kg bw/day for Cramer classes III and II or 30 µg/kg bw/day for Cramer class I).

Genotoxicity

The mutagenic potential of Crotonic acid was assessed in reliable standard in vitro tests covering the three relevant genetic endpoints gene mutation, structural chromosome aberration and numerical chromosome aberration (Ames test: Hoechst AG, 1996 and SCF, 2002; chromosomal aberration test: Toxi-Coop Zrt. (e), 2012; HPRT test: Toxi-Coop Zrt. (d), 2012). All tests were negative, i.e. provided no indication for a mutagenic and/or clastogenic/aneugenic potential of Crotonic acid. Therefore, the genotoxicity threshold of 0.0025 µg/kg bw/day (TTC value) was not identified as a relevant limit value when considering exposure to Crotonic acid.

Neurotoxicity

The available toxicity tests do not indicate a neurotoxic potential of Crotonic acid. Furthermore, Crotonic acid does not contain a structural alert for neurotoxicity. Thus, Crotonic acid does not raise a concern regarding neurotoxicity. On this basis, the generic neurotoxicity threshold of 0.3 µg/kg bw/day (TTC value) was not considered to represent the appropriate limit value for Crotonic acid.

Cramer classification

Using the (Q)SAR tool Toxtree v‑2.5.0 the toxicological hazard of Crotonic acid (when administered orally) was predicted from its molecular structure. Application of both the “Cramer rules” decision tree and the “Cramer rules, with extensions” decision tree resulted in the assignment of a low toxicity hazard (Cramer class I) for Crotonic acid. The corresponding threshold of 30 µg/kg bw/day (TTC value) was thus identified as the appropriate limit value for Crotonic acid.

DNEL derivation

Applying route-to-route extrapolation assuming a comparable oral and inhalation absorption and a 4-fold lower dermal absorption (for justification see toxicokinetic chapter) the oral TTC of 30 µg/kg bw/day corresponds to an inhalation DNEL of 0.18 mg/m³ (assuming a respiratory volume of 10 m³/8 h and a body weight of 60 kg) and a dermal DNEL of 0.12 mg/kg bw/d. These DNEL values were used for the worker risk assessment (see below and chapter 10 of the CSR).

The structurally very similar compound Acrylic acid (CAS 79-10-7) has been toxicologically extensively examined. It is neither classified for repeated dose toxicity (STOT RE) nor reproductive toxicity (fertility and development). The NOAEL for subchronic toxicity of 83 mg/kg bw/d was obtained in a combined subchronic and reproductive toxicity study for Fisher 344 rats (DePass et al., 1981) when the substance was administered in drinking water. Based on this NOAEL a long term systemic oral DNEL of 0.83 mg/kg bw/d can be derived applying the standard assessment factors according to the ECHA guidance on IR & CSA chapter R.8 (2012) (i.e. 2 for difference in exposure duration (subchronic to chronic), 4 for allometric scaling, 2.5 for other interspecies differences and 5 for intraspecies differences within the group of workers). The TTC of 30 µg/kg bw/d which represents the long term systemic oral DNEL for Crotonic acid is 28fold lower than the respective DNEL of 0.83 mg/kg bw/d for Acrylic acid. This demonstrates that the DNEL values derived for Crotonic acid on the basis of the TTC value of 30 µg/kg bw/d is a conservative approach.

 

iii) Calculation of the Risk Characterization Ratios (RCRs)

The Risk Characterization Ratios (RCRs) were obtained by comparison of the worker exposure values to the DNELof 0.18 mg/m³ and 0.12 mg/kg bw/d for inhalation and dermal exposure, respectively(see chapter 10 of the CSR). As the available workplace measurements and the estimated worker exposures were below the DNEL, the resulting RCRs for all of the assessed exposure scenarios were below 1.

 

Conclusion

Crotonic acid is manufactured and used at industrial sites under strictly controlled conditions. The exposure assessment of all scenarios, where a contact of the worker with the substance might occur, revealed that worker exposure to Crotonic acid will not exceed the DNEL value of 0.18 mg/m³ (inhalation route) and 0.12 mg/kg bw/d (dermal route) derived according to the TTC concept. Moreover, the structural analogue Acrylic acid does not display a health concern regarding repeated dose and reproductive toxicity. Therefore, it can be scientifically reliably concluded that Crotonic acid does not cause adverse health effects.

Consequently, the adaptation of the standard testing requirements is justified and the performance of a repeated dose toxicity and developmental toxicity study is not needed and moreover, should not be done considering animal welfare reasons.

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

The substance is manufactured and used at industrial sites under strictly controlled conditions. Further, it is not included in articles or used in consumer products. Therefore, DNELs for general population do not need to be derived.