Toxicology of Industrial Compounds

appropriate and cost effective health protection within our industrialized
world.
Threshold effects
Classification
H.-P.GELBKE 365
The classification system of the EU resides in the designation of
appropriate R-phrases. In most cases they are rather meant for hazard
identification (e.g. irritation, sensitization, carcinogenicity) and not so
much for risk characterization. Sometimes, risk aspects are also involved
when specific dose levels are decisive for a specific R-phrase (e.g. acute
toxicity). Thereby not only the effect per se is taken into account but also
the strength of the effect.
This latter principle also applies to the R 48-phrase (‘danger of serious
damage to health by prolonged exposure'), if severe (irreversible) toxic
effects are observed at dose levels of ≤50 mg kg −1 body weight per day in a
90-day test after oral administration. For other routes and durations of
exposure similar provisions exist. The strategy to use dose limits is
certainly appropriate for threshold effects.
Although for reproductive and developmental effects thresholds are also
accepted in most cases, no such dose limits are given apart from 1000 mg
kg −1 body weight per day. This dose limit is not equivalent to that for the R
48-phrase, because it only stems from the limit dose levels of the test
guideline and is higher by more than one magnitude. Thus, for
reproductive/ developmental toxicity classification, exposure and risk
considerations are not influential in contrast to the R 48. Such a simplified
‘yes or no’ approach for a threshold effect is not justifiable neither from a
scientific point of view nor for an appropriate health protection. This is
even more so, if the proposal for the ‘Restrictions on Marketing and Use
Directive’ (13th Amendment to Directive 76/769/EEC) is implemented
calling for a general prohibition of category 1 and 2 reproductive/
developmental toxicants in consumer products in concentrations of ≥0.5%
—if no specific concentration limit has been accepted according to the
preparation guideline (Commission Directive 93/18/EEC; Council Directive
88/379/EEC).
The inconsistency of the approaches for ‘classical’ organ toxicity and
developmental/reproductive toxicity can easily be demonstrated by the
following theoretical example:
For neurotoxicity a LOEL of 40 mg kg −1 day −1 in a 90-day oral test will
result in a R 48-phrase, but a LOEL of 80 mg kg −1 day −1 would not
lead to classification. On the other hand, slight foetal weight