Abstracts / Toxicology Letters 221S (2013) S59–S256 S205

in Forced Expiratory Volume (FEV1) and increase in Specific Air-way Resistance (SRaw) are more severe, as compared with healthyindividuals. In conclusion, an inter-individual assessment factorof three seems to be sufficiently protective for asthmatics in theabsence of experimental data. The minor difference in sensitivityalong with the more pronounced airway responses make asth-matics an informative group for derivation of guidance values forshort-term exposure in emergency as well as occupational settings.

http://dx.doi.org/10.1016/j.toxlet.2013.05.481

P18-06Assessment of the subchronic anddevelopmental toxicity ofsodium-dimethyl-5-sulphonatoisophthalate(CAS 3965-55-7) in a weight of evidenceapproach

Roth Thomas 1,∗, Udo Jensch 2, Nadine Volz 1

1 SCC GmbH, Bad Kreuznach, Germany, 2 Clariant Produkte(Germany), GmbH, Sulzbach, Germany

The subchronic and developmental toxicity of sodium-dimethyl-5-sulphonatoisophthalate is assessed in a weightof evidence (WoE) approach. Oral repeated dose andreproduction/developmental toxicity of sodium-dimethyl-5-sulphonatoisophthalate were studied in rats in an OECD 407and 421 study. No adverse effects were found, consequently thehighest test dose (1000 mg/kg/d) was derived as NOAEL fromboth studies. Ester-hydrolysis leading to the monomethylesterand finally 5-sulphonatoisophthalic acid was predicted in-silicoas main metabolites. The reliability of the prediction was con-firmed by in vivo kinetic data available for the structural analoguedimethyl terephthalate for which the same metabolic pathway,i.e. ester hydrolysis resulting finally in terephthalic acid wasfound. Isophthalic acid was identified as a further structuralanalogue. All analogues share a toxicological profile comparableto sodium-dimethyl-5-sulphonatoisophthalate (e.g. low acutetoxicity, no sensitization or genotoxic potential). In accordancewith findings in available subchronic and developmental toxicitystudies they are neither classified for repeated dose (STOT) nor fordevelopmental toxicity. The primary toxicity was the formationof renal crystals and caliculi after repeated administration ofhigh doses which were composed of the Ca-salt of the respectivephthalic acid derivate. Due to the higher solubility caused bythe additional sulfonate-group present in sodium-dimethyl-5-sulphonatoisophthalate a similar effect is only expected above thelimit dose of 1000 mg/kg/d.

In summary, the above WoE enables the scientifically soundconclusion that sodium-dimethyl-5-sulphonatoisophthalate doesnot cause adverse effects with regard to subchronic or developmen-tal toxicity at dose levels relevant for classification. Thus, furtheranimal testing to address these endpoints is not justified.

http://dx.doi.org/10.1016/j.toxlet.2013.05.482

P18-07Comparison of methods for calculation ofcarry-over limits and their values withoccupational exposure limits

Ester Lovsin Barle ∗, Margaret Amelia Cudd, Rudolf Bechter,Winkler Gian Christian

Novartis Pharma AG, Basel, Switzerland

There are several methods in use for calculating carry-over lim-its in the manufacture of pharmaceuticals. The point of departurefor calculation (toxicity and pharmacology) is the same as thatused for calculating occupational exposure limits (OEL). In orderto compare and evaluate carry-over limits calculated with threedifferent approaches and compare them to their respective OELs,we have selected several drug substances with different mecha-nisms of action. Calculating carry-over limits from LD50 resultedconsistently in much higher values than other methods of calcu-lation. This indicates that the LD50 is not an appropriate valueleading to a safe carry-over limit. Comparison of the OELs and per-missible daily exposures (PDEs) has revealed no constant relationbetween the values, because there is a difference in the thresholdused for calculation (i.e. human minimally effective dose versus notoxicological/pharmacological effect level), as well as in the tar-get populations (e.g. patients, children, employees). Whenever thelowest therapeutic dose is taken as a basis for an OEL calculation,there is a relation between the OEL and the carry-over limit calcu-lated from the carry-over value (COV), because both calculationsare based on the human minimally effective dose; the differencesare related to the use of safety factors. Extrapolating PDE or COVinto an OEL value would not be appropriate without a detailed eval-uation of the end points in animal studies and doses at which effectsare seen in humans.

http://dx.doi.org/10.1016/j.toxlet.2013.05.483

P18-08Derivation of a guidance limit for cadmium inchildren’s jewellery: Health Canada’sperspective

John Field 1,∗, Pierre Chantal 2, Sandra Wright 3, Paul Chowhan 4,Patricia Pelletier 1, Helen Ryan 1,2, Gordon Barrett 1

1 Toxicology and Flammability Risk Assessment Unit, ConsumerProduct Safety Directorate, Health Canada, Canada, 2 Product SafetyLaboratory, Consumer Product Safety Directorate, Health Canada,Canada, 3 Compliance and Enforcement Division, Consumer ProductSafety Directorate, Health Canada, Canada, 4 Risk ManagementStrategies Division, Consumer Product Safety Directorate, HealthCanada, Canada

It has been demonstrated that swallowed jewellery items maybecome lodged in the stomach, and morbidity and mortality havebeen associated with jewellery containing lead. Due to its inher-ent toxicity, the use of cadmium to make costume jewellery maypose an analogous threat. In the absence of reliable human toxi-city data, the results from animal studies were used to derive anoral acute provisional minimal risk level (pMRL) of 0.0732 mg/kgbw for cadmium. Health Canada analyzed approximately 200 chil-dren’s jewellery samples that were judged small enough to fit intoa child’s mouth for cadmium content. A subset of these sampleswere also subjected to migration testing, which revealed no con-sistency between the total amount of cadmium in a sample, andthe amount that might be released in the simulated physiologicalenvironment of the stomach over an extended period (such as in thecase of a piece of jewellery lodged in the stomach over several days).Since standardized migration testing cannot accurately predict theamount of cadmium that might leach out of a sample under suchcircumstances, the use of total cadmium content to derive a guide-line is considered the most health-protective approach. Limitingtotal cadmium content to 130 ppm removes variables that interferewith migratable cadmium quantification (such as the thickness andcomposition of the surface plating, and elemental composition of