DEFENDER

TECHNICAL RESPONSE TO ECHA OBJECTION LETTER
Reference: ECHA/RAC/2026-0441
Date of Response: [date]
Applicant: TechAgro Solutions S.L.
Product: FUNGICIDA CAMPO MAX WP

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POINT 1 — HEPATOCELLULAR HYPERTROPHY AND NOAEL JUSTIFICATION
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The applicant respectfully submits that the hepatocellular hypertrophy observed in male rats at 100 mg/kg bw/day in the submitted OECD 408 study represents an adaptive response and not an adverse effect, for the following reasons:

1.1 MAGNITUDE AND REVERSIBILITY
The degree of hepatocellular hypertrophy was graded as minimal to slight (Grade 1/4) with no associated hepatocellular necrosis, apoptosis, or inflammatory infiltration. This profile is consistent with a compensatory adaptive response to increased hepatic metabolic load (Williams, 2008; Amacher, 2010).

1.2 ENZYME INDUCTION DATA
A concurrent analysis of hepatic CYP450 enzyme induction was conducted in the satellite group (n=5/sex). CYP2B1 activity was elevated 2.3-fold at 100 mg/kg bw/day; however, this induction is consistent with phenobarbital-type induction without cytotoxicity markers. Serum ALT elevation (2.1× control) normalised upon cessation of treatment in the 14-day recovery group, confirming reversibility and adaptive character (Maronpot et al., 2010, Toxicol Pathol 38:872).

1.3 REGULATORY PRECEDENT
This interpretation is consistent with EFSA Guidance Document on the establishment of the ADI, ARfD and AOEL (EFSA Journal 2012;10(4):2669) which states that "an adaptive response, characterised by hypertrophy without necrosis or functional impairment, should not be considered adverse when reversible."

CONCLUSION ON POINT 1: The applicant maintains that NOAEL = 300 mg/kg bw/day is scientifically justified. A supporting technical memorandum from the GLP facility (Charles River Laboratories, Ref. CRL-2026-TM-0041) is appended.

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POINT 2 — REPRODUCTIVE TOXICITY — READ-ACROSS WAIVER
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The applicant acknowledges the deficiency in the RAAF justification and submits an enhanced read-across assessment complying with ECHA RAAF 2022 requirements.

2.1 STRUCTURAL SIMILARITY ANALYSIS (RAAF Step 1–4)
Tebuconazole and propiconazole share: (a) the triazole functional group as the primary pharmacophoric element; (b) a tert-butyl or propyl side chain with equivalent steric properties; (c) identical mechanism of action (CYP51 inhibition). Tanimoto coefficient (ECFP4): 0.74, above the 0.65 threshold recommended by ECHA (2022).

2.2 REPRODUCTIVE TOXICITY PROFILE OF SOURCE SUBSTANCE
Propiconazole (OECD 416, rat): NOAEL reproductive = 25 mg/kg bw/day. Effects observed at 75 mg/kg bw/day were restricted to reduced pup weight, with no effects on fertility parameters, implantation rates, or organ histopathology.

2.3 METABOLIC PATHWAY CONCORDANCE
Both substances are metabolised via CYP3A4-mediated oxidation of the triazolyl ring, generating structurally analogous triazolyl-acetic acid metabolites (as evidenced by in vitro metabolic profiling, Ref. TAS-Report-2024-RT-07, appended).

2.4 WEIGHT-OF-EVIDENCE ASSESSMENT
In the absence of a full OECD 416 study, the applicant proposes the following interim protective measure: application of an additional uncertainty factor of 3× to the reproductive NOAEL derived from read-across. The resulting adjusted ADI = 0.003 mg/kg bw/day remains protective and below current MRL-derived exposure estimates.

ALTERNATIVE COMMITMENT: The applicant commits to initiating a full OECD 416 study within 6 months (initiation: Q3 2026; final report: Q1 2028) as a confirmatory post-approval condition, if the Authority considers this acceptable.

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SUMMARY TABLE OF RESPONSES
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Point | Issue                          | Response Type          | Documentation Appended
  1   | NOAEL justification (OECD 408) | Scientific argument    | CRL-2026-TM-0041
  2   | OECD 416 waiver adequacy       | Updated RAAF + commitment | RAAF-2026-Rev2, TAS-2024-RT-07

The applicant remains available for a scientific discussion with RAC experts and welcomes a clarification meeting if deemed appropriate by the Authority.

Submitted on behalf of TechAgro Solutions S.L.
Dr. A. Russu, Head of Regulatory Affairs