4-isopropyl-m-cresol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information as a whole meets the tonnage driven data requirements of REACH. Moreover, reliability and consistency are observed across the different studies.

Additional information

Justification for selection of Effect on fertility via oral route:
Key study conducted according to OECD 422 guideline without any deviations and in compliance with GLP.

Effects on developmental toxicity

Description of key information

NOAEL for parental systemic toxicity, reproduction and developmental toxicity = 15000 ppm (1038 mg/kg bw/day for the males, 1048-1888 mg/kg bw/day for the main reprotoxicity phase females and 1010 mg/kg bw/day for the toxicity phase females) (OECD 422, GLP, rel.1).

Additional information

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted according to OECD Guideline 422 and in compliance with GLP, Parathymol P16029 was administered to groups of Crl:CD(SD) rats (10/sex/dose) at dietary concentrations of 1500, 4500 or 15000 ppm. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 7 of lactation. The F1 generation received no direct administration of the test substance; any exposure wasin uteroor via the milk. A similarly constituted Control group received the vehicle, untreated diet of the same batch. During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology (peripheral blood), blood chemistry, pre-coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology investigations were undertaken. Histopathology investigations were undertaken for the first five males and first five females from the Control and high dose groups. The clinical condition, litter size and survival, sex ratio, body weight and macropathology for all offspring were also assessed.

Overall achieved dose levels of Parathymol P16029 for males were 98, 289 and 1038 mg/kg bw/day at 1500, 4500 and 15000 ppm respectively. Achieved dose levels for females were 110, 320 and 1010 mg/kg bw/day before pairing, 104, 323 and 1048 mg/kg bw/day during gestation and 206, 608 and 1888 mg/kg bw/day during lactation.

 

There were no premature deaths; there were no effects on clinical signs, sensory reactivity, grip strength or motor activity.

 

Males receiving 15000 ppm had low mean body weight change during the first four weeks of treatment. Food consumption for these animals was low only for the first three days of study. Male body weight and food performance at 4500 or 1500 ppm was essentially similar to Controls and not adversely affected by treatment.

Females receiving 15000 ppm during week 1 of study had body weight loss coinciding with a period of low food consumption and during weeks 1-2 before pairing body weight gain was low. At this dose level, low body weight gain was observed throughout gestation and until Day 4 of lactation. Food consumption was also low during this time often attaining statistical significance. At 4500 ppm females had low body weight gain during the period prior to pairing and during Days 0-6 of gestation, for these animals food consumption was also low for Days 1-4 of lactation. Females receiving 1500 ppm did not have any periods of statistically low food or body weight performance.

 

Visual water consumption was notably high in animals receiving 15000 or 4500 ppm. 

 

Minor changes in haematology and biochemistry parameters did not demonstrate an adverse effect of treatment at the degree observed.

 

Organ weights adjusted for terminal body weight indicated high kidney and liver weights for males receiving 15000 ppm, and slightly low heart and ovary weights for females at 15000 ppm, these differences did not correlate with any histopathological changes.

 

The macroscopic examination performed on the males after 6 weeks of treatment and on the females on Day 7 of lactation revealed no test substance related lesions. Histopathology investigations identified a treatment related change in the thymus of an increased incidence and severity for involution/atrophy seen in all females receiving 15000 ppm. This change was not observed at lower dose levels.

 

The screen for reproductive performance indicated there was no effect of Parathymol P16029 on pre-coital interval, fertility or gestation length. Clinical signs of offspring did not indicate any reaction to maternal exposure at dose levels up to 15000 ppm.

 

The mean number of implantations and subsequent mean litter size was lower than Controls for females receiving 15000 ppm. Despite this there was no subsequent effect of treatment upon post-partum offspring survival or sex ratio to Day 7 of age at 15000 ppm. Mean numbers of implantations, litter size and sex ratio at 4500 or 1500 ppm were similar to Controls.

 

At 15000 ppm mean body weight of male and female offspring on Day 1 of age were lower than Control, and subsequent body weight gain to Day 7 of age, was also lower than Controls. Offspring body weight on Day 1 of age, and subsequent body weight gain to Day 7 of age, at 4500 or 1500 ppm was similar to Controls, and unaffected by treatment. According the authors, it is likely that the low body weight gain in offspring was associated with poor maternal body weight performance, low food consumption and the resultant maternal stress. 

 

Changes detected at necropsy on offspring killed or dying at or before scheduled termination were part of the normal spectrum expected in this strain of animal, at these ages and at this laboratory.

Under the test conditions, the NOAEL of Parathymol P16029 to male and females adult rats for at least 5 weeks was 15000 ppm (equivalent to 1000 mg/kg bw/d). Low implantation site counts impacting subsequent litter size was observed at 15000 ppm. However, the significantly reduced food consumption and reduced bodyweight gain in the females receiving 15000 ppm is considered to be an important factor for the reduced implantations/litter size as described in the literature (Terry et al., 2005) and this interpretation is strengthened by the observation that females receiving 15000 ppm showed involution/atrophy of the thymus which was considered to be indicative of a stress response secondary to the reduced food intake. This was an isolated finding as there was no effect of treatment on mating performance or fertility, the survival of the offspring and no treatment related macroscopic or microscopic changes were detected in the male and female reproductive systems. Therefore, the low implantation counts and litter size at 15000 ppm were considered to be associated with the reduced food consumption and not to reflect an intrinsic, specific property of Parathymol” (UN GHS for labelling of chemicals).

Justification for classification or non-classification

Harmonized classification:

Parathymol has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP8.

Self-classification:

Based on the available data, no additional classification is proposed.