The threshold of toxicological concern for prenatal developmental toxicity

Area of Science:

• Toxicology
• Risk Assessment
• Developmental Biology

Background:

• The Threshold Toxicological Concern (TTC) principle assumes safety at low exposure levels.
• TTC evaluations have expanded beyond carcinogenicity to other toxicological endpoints.
• Regulatory frameworks like REACH utilize TTC for risk assessment.

Purpose of the Study:

• To evaluate the TTC for oral developmental toxicity in rats.
• To establish a TTC value for maternal and developmental toxicity based on NOAEL data.
• To provide guidance for regulatory decision-making within the REACH framework.

Main Methods:

• Analysis of 92 and 93 NOAEL values from oral developmental toxicity studies (OECD 414) in rats.
• Calculation of the 5th percentile for maternal and developmental toxicity NOAEL distributions.
• Incorporation of additional developmental toxicity data for a joint evaluation.
• Application of a safety factor of 500 to derive TTC values.

Main Results:

• The 5th percentile NOAEL was 4 mg/kg bw/d for maternal toxicity and 5 mg/kg bw/d for developmental toxicity.
• A joint evaluation of 111 NOAEL values yielded a 5th percentile of 4 mg/kg bw/d.
• A TTC value of 8 μg/kg bw/d was calculated for both maternal and developmental toxicity.

Conclusions:

• The derived TTC value of 8 μg/kg bw/d can guide decisions on animal testing requirements.
• This TTC value offers a benchmark for assessing safety at low exposure levels for developmental toxicity.
• The findings support the application of TTC in regulatory risk assessments under REACH.