Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
BMDL10
8 960 µg/kg bw/day
Study duration:
subchronic
Species:
mouse

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
15 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1.5 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed

Additional information

For an assessment of repeated dose toxicity read across to the two main constituents of the substance 2,2'-iminodiethanol (DEA; CAS No 111-42-2) and 2,2-bis(4-hydroxyphenyl)propane (BPA; CAS No 80-05-7) is performed. These account for approx. 55 % of the substance (BPA ca. 15 %, DEA ca. 40 %), and information on their repeated dose toxicity is thus relevant for the assessment of the substance. Two reaction products of DEA, formaldehyde and BPA (i.e. Mannich Bases) account for further 39 % of the substance (Mannich Base 1 ca. 26 %, Mannich Base 2 [two isomers] ca. 13 %). The Mannich Bases are structurally similar to BPA, but are larger molecules (i.e. BPA with one or two diethanolaminomethyl-substituents attached to the aromatic ring). Due to the higher molecular weights of the Mannich Bases (345 g/mol and 462 g/mol for Mannich Base 1 and 2, respectively) a lower absorption is expected compared to the lower molecular weight-substances DEA and BPA (105 g/mol and 228 g/mol, respectively). A QSAR analysis (OECD toolbox, version 3.3.0.132) revealed for the Mannich Bases no specific finding except a predicted estrogen receptor binding based on the BPA core-structure. Therefore, based on the available evidence it is not expected that the Mannich Bases determine the overall toxicological picture of the substance and the toxicological properties of the two main constituents DEA and BPA instead are decisive for the toxicological profile of the substance.

In conclusion, the required repeated dose toxicity studies for the respective tonnage (i.e. Short-term (28 days) and Sub-chronic (90 days) repeated dose toxicity at 100-1000 tonnes/a) is not needed since read-across to reliable sub-chronic (90 days) and chronic (2 years) toxicity data of the main constituents (BPA and DEA) can be performed and by that repeated dose toxicity of the substance can be sufficiently assessed. The so concluded thresholds are based on worst case assessment, since DEA (ca. 40 %) and BPA (ca. 15 %) are only constituents of the substance and for the overall assessment in case of differences the lower respective NOAEL/LOAEL from the two constituents is used. Further repeated dose testing with the substance itself was omitted, since it is very unlikely that this would result in a lower NOAEL and thus a lower DNEL. Without a change of the NOAEL and DNEL further testing would have no influence on the protective measures.

 

For BPA and DEA summaries on the repeated dose toxicity exist based on peer-reviewed chemical risk assessments, e.g. EU Risk Assessment Report and OECD SIDS Initial Assessment Report, respectively. These are taken into account in the following.

 

Concerning BPA the 2003 EU RAR concluded with respect to repeated dose toxicity: "No useful information on the effects of repeated exposure to BPA in humans is available, but experimental studies in rats, mice, and dogs are available. In rat inhalation studies, the principal effect of repeated exposure was the same as observed following a single exposure: slight upper respiratory tract epithelium inflammation, with a NOAEC of 10 mg/m³ and a LOAEC of 50 mg/m³. Dietary studies in rats have reported reductions in reproductive organ weights and testicular toxicity at 235 mg/kg and a NOAEL of 74 mg/kg was established in a two-year study based on marginal effects on body weight gain at the next dose level of 148 mg/kg. In mice, the LOAELs of 120 mg/kg in males for multinuclear giant hepatocytes and 650 mg/kg in females for a reduction in body weight gain of unknown magnitude were identified in a two-year study. There are no animal data available for repeated dermal exposure."

The 2008 updated EU RAR concluded: "Oral studies in rats and mice have shown that the repeated dose toxicity of BPA involve[s] effects on bodyweight gain, liver and kidney. A NOAEL of 50 mg/kg/day has been identified in a recent 2-generation study in mice for these effects. This NOAEL rather than the original NOAEL of 120 mg/kg/day for liver effects from the published report is taken forward to the risk characterisation."

In 2014 SCOEL concluded in its recommendation on BPA: "To establish a recommended occupational exposure limit (OEL), SCOEL began by considering the available data relating to inhalation exposure. In rats exposed daily to airborne BPA for 13 weeks there was a NOAEC of 10 mg/m³, with mild olfactory epithelium inflammation at 50 and 150 mg/m³. There was no evidence of systemic toxicity in this study (Nitschke 1988).”

Meanwhile EFSA calculated a BMDL10 of 8960 µg/kg bw per day for changes in the mean relative kidney weight based on the 2 -generation study in mice (EFSA Scientific Opinion, EFSA Journal 2015, 13 (1), 3978). This BMDL10 is the most recent relevant threshold for BPA and thus replaces the NOAEL of 50 mg/kg and day as point of departure for risk characterisation.

 

Repeated dose toxicity of the second constituent DEA is discussed in the following: For inhalation toxicity of DEA two subchronic (90 days) studies in rats are available. Since the earlier study failed to reveal a NOAEC due to local irritant effects of the respiratory tract up to the lowest dose of 15 mg/m³ a second 90-day study was conducted, which investigated predominantly effects of the respiratory tract at doses of 0, 1.5, 3, and 8 mg/m³. At the end of the exposure period slight signs of irritation at the upper respiratory tract were histopathologically evident in 9/10 animals of both sexes in the high-dose group, and in 3/10 males of the mid-dose group; all findings completely reversible at the end of the 3-month recovery period. The latter study revealed a NOAEC at 1.5 mg/m³ for local effects (cp. MAK documentation for Diethanolamin, 2007; http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb11142e4314/pdf). Systemic effects were found to be “comparable between inhalation and oral exposure route with NOAECs considerably above those of respiratory tract effects” (Gamer et.al., Food Chem. Toxicol 46, 2173-2183, 2008).

For oral and dermal exposure subchronic (90 days) studies in rats and mice are available (NTP TR 478; Melnick et al., Journal of Applied Toxicology, 14, 1-9 and 11-19, 1994). For the dermal exposure route chronic studies in rats and mice are also available (NTP TR 478). In these studies the kidneys in rats and the liver in mice were consistently identified as the most sensitive target organs (cp. MAK documentation for Diethanolamine, 2007; http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb11142e4314/pdf). The lowest NOAEL after repeated oral exposure at 630 ppm (eq. to approx. 48 mg/kg for male rats) is based on test-substance related kidney effects in rats at the next higher dose (approx. 1250 ppm; eq to approx. 97 mg/kg for male rats). These thresholds are already acknowledged in a recent evaluation of ECHA, published on the ECHA website (ECHA decision on substance evaluation pursuant to article 46(1) of Regulation (EC) No 1907/2006 for 2,2'-iminodiethanol - CAS No 111-42-2 (EC No 203-868-0; http://echa.europa.eu/documents/10162/d34b5848-6b8e-4944-8ce7-4d0200ea43d7). Chronic and subchronic dermal toxicity studies in rats and mice reveal additionally local effects at the site of application with a lowest LOAEL at 8 mg/cm² after chronic application to rats. In all dermal studies “the substance was applied non-occlusively in 95 % ethanol as a vehicle. Therefore, ingestion by licking must also be assumed” (MAK documentation for Diethanolamin, 2000; http://onlinelibrary.wiley.com/doi/10.1002/3527600418.mb11142e3014/pdf). For this reason the NOAELs after repeated oral exposure is given preference over the NOAELs after repeated dermal exposure for setting the point of departure for the DNEL-derivation for systemic effects.

With regard to mode of action-considerations "various mechanistic in vitro and in vivo studies identified that DEA induced choline depletion is the key event in the toxic mode of action" (OECD, 2007). Cholin-deficiency is thought to play a role in the development of liver diseases, artherosclerosis and possibly neurological disorders (Zeisel & da Costa, Nutr. Rev., 67(11), 615 -623, 2009), but the mechanisms behind are still under investigation.

 

In conclusion, a comparison of the oral NOAELs of the substance's constituents BPA and DEA reveal quite similar thresholds (NOAEL BPA 50 mg/kg vs. NOAEL DEA 48 mg/kg), thus the recently published BPA-BMDL10 of 8.96 mg/kg is considered adequate for risk assessment of systemic effects of both substances. On the contrary, DEA is more relevant for toxicity after repeated inhalation, since the DEA-NOAEC (1.5 mg/m³) for local irritant effects to the respiratory tract is below the local and systemic BPA-NOAEC (10 mg/m³), and also below the DEA-NOAEC for systemic effects (15 mg/m³). Conclusively, 1.5 mg/m³ is a NOAEC for both local and systemic effects after repeated inhalation exposure to DEA and BPA. DEA also drives the magnitude of effects for local effects to the skin, but this is addressed by the endpoint skin irritation/corrosion.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A two-generation study with the read across substance BPA (CAS No 80-05-7) as the study with the most relevant point of departure for the derivation of a systemic DNEL is selected. According to a recent EFSA Scientific Opinion (EFSA Journal 2015, 13 (1), 3978) a BMDL10 of 8960 µg/kg bw per day was calculated for the read across substance based on this two-generation study and further used to delineate a temporary TDI (Tolerable Daily Intake).

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Based on read across to DEA (CAS No 111-42-2) the selected study is relevant for establishing a NOAEC systemic. A study of the second read across substance BPA (CAS No 80-05-7) revealed no systemic toxicity (cp. SCOEL, SUM/113, 2014) and is therefore not selected here. However, the lower NOAEC based on local effects of the read across substance DEA is taken as point of departure for derivation of an inhalation DNEL.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The study with the lowest NOAEC for local effects after repeated inhalation toxicity (in this case for the read across substance DEA; CAS No 111-42-2) is selected.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
No study is selected here, since with respect to these studies uncertainties exist that prevent reliable threshold derivation (ingestion by licking must be assumed, cp. MAK documentation for Diethanolamine, 2000; local skin damage may have confounded the threshold for systemic effects after repeated dermal toxicity). For risk assessment of this endpoint route to route extrapolation (oral to dermal) is applied.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
No study is selected here, since with respect to these studies uncertainties exist that prevent reliable threshold derivation (ingestion by licking must be assumed; cp. MAK documentation for Diethanolamine, 2000). For risk assessment of the local effects after dermal exposure a qualitative approach is chosen (Allocation to the appropriate hazard band; ECHA Guidance, Part E, 2012).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008, Annex I, 3.9.3., classification as STOT RE 2 is appropriate, if a component of a mixture in concentrations > 10 % is classified as STOT RE 2. Since 2,2'-iminodiethanol (DEA, CAS No 111-42-2) is contained in the substance at approx. 40 %, classification as STOT RE 2 is warranted.

Categories Display