5-amino-o-cresol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

According to the results of the key study (OECD method 415, GLP compliant, Klimisch 1), the registered substance induced adverse effect at the dose level of 1000 mg/kg bw/day as mortality, clinical signs, and on reproductive parameters too as mean duration of gestation, decreased number of pups at birth, increased post-natal loss. Hence, the No Observe Adverse Effect Level was defined at 200 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Additional information

The key study (Klimisch 1, OECD guideline 415 method, GLP compliant) was performed in order to investigate a potential effect of the registered substance on male and female reproductive performance. A total of 192 (96/sex) Wistar rats, age 5-6 weeks (F0 males); 13-14 weeks (F0 females) were used and treated by oral route (gavage) at differents dose levels :

- Group 1: 0 mg/kg b.w./day (vehicle control)

- Group 2: 40 mg/kg b.w./day (low dose group)

- Group 3: 200 mg/kg b.w./day (mid dose group)

- Group 4: 1000 mg/kg b.w./day (high dose group)

Males were treated 10 weeks prior to mating up to sacrifice and females 2 weeks prior to mating up to sacrifice. Females were paired on a one-to-one-basis with males from the same treatment group. 

The day on which mating was designated Day 0 of gestation (= day 0 post-coitum).

Animals were observed once daily for clinical signs and twice daily for mortality during the entire treatment period. Body weights were recorded on the first day of exposure and weekly thereafter until necropsy. Food consumption was measured at weekly intervals until delivery (except during mating). During lactation, food consumption was recorded on days 1, 4, 7, 14 and 21 post partum.

Females without litters or which lost their litters were killed and necropsied. The sex ratio of pups was recorded at Day 0, 4, and Day 21 of lactation. Pup weights were noted on days 1, 4, 7, 14 and 21 of lactation. Pups were also observed daily for survival as well as for physical and behavioural abnormalities. The number of pups was reduced to 4 males and 4 females per litter on day 4 post partum. The remaining pups, from all litters with more than 4 pups per sex, were examined macroscopically. On Day 21 post partum, all pups were examined internally and externally for abnormalities and, if indicated, skeletal development was examined after staining.At necropsy of the parent animals, a macroscopical examination with special focus on the organs of the reproductive system was performed and several organs were weighed.Kidneys and livers from all animals of all groups were processed and examined by the pathologist. All abnormalities were recorded.

No treatment-related findings were noted at 40 mg/kg bw/day. In the 1000 mg/kg bw/day and 200 mg/kg bw/day groups, all males and females showed brown discolouration of the urine during treatment.

At 1000 mg/kg bw/day, an increased incidence in mortality (2/24 males (about 8 %) and 5/24 females (about 21%)) was noted. Treatment-related clinical signs in dosed animals consisted of tonic spasms, lateral recumbency, rales, gasping, emaciation, hypothermia, lethargy, labored respiration, pale appearance, chromodacryorrhoea and ptosis. In males, increased absolute and relative liver weights as well as increased relative weights of kidneys and testes were noted. During the histopathological examination, minor grades of hepatocellular vacuolation were found in females. Males showed increased incidence and severity (primarily slight or moderate) of midzonal/centrilobular liver hypertrophy and increased severity of renal corticomedullary tubular atrophy and hyaline casts.

 

Reproduction parameters like slightly increased mean duration of gestation, delivery difficulties, and a decreased number of pups at birth were observed. In the high dose group, developmental toxicity consisted of an increased post-natal loss resulting in a decreased viability index, as well as an increased incidence of clinical signs and decreased body weights in the offspring. As effects on reproduction, breeding, and development were observed at the same dose levels as general toxicity, a direct effect of the test substance on reproduction cannot be excluded nor established.

Hence, the definitive parental, reproductive, breeding and developmental No Observed Adverse Effect Level (NOAEL) was established as being 200 mg/kg body weight/day. (Beekhuijzen, 2003).

Effects on developmental toxicity

Description of key information

In the rat teratogenicity study (Orsterburg, 1984), no treatment-related changes were noted in any of the dose groups of 20, 40 and 180 mg /kg bw/day administered from day 6 to day 15 post coitum. Consequently, a NOAEL of 180 mg/kg bw for maternal and embryo-foetal effects is determined for 4-amino-2-hydroxytoluene

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

180 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

A key study was available for assessment (Orsterburg, Klimisch 2, 1984, similar to OECD 414 guideline). Mature male and female Sprague-Dawley rats were housed together, and day 0 of pregnancy was defined as the day on which vaginal sperm were detected. Females were then housed separately and dosed by gavage during the embryonic period GD 6 -15. Treated rats were observed daily and weighed on GD 0, 6, 15 and 20. On GD 20, dams were euthanized with CO2, the uterine horns were removed and numbers and conditions of foetuses recorded Half the foetuses were fixed in Bouin’s solution for examination of soft tissue, and the other half were fixed in ethanol and stained with Alizarin Red S for examination of skeletal effects. In this rat teratogenicity study, no treatment-related changes were noted in any of the dose groups of 20, 40 and 180 mg /kg bw/day administered from day 6 to day 15 post coitum. Consequently, a NOAEL of 180 mg/kg bw for maternal and embryo-foetal effects is determined for 4-amino-2-hydroxytoluene.

No rationale was given for dose selections. The dose could be considered as too low. Furthermore, the absence of any findings up to the top dose in this teratogenicity study is consistent with the results of a state-of-the-art one-generation study using dose levels of  40, 200, and 1000 mg/kg bw ( Beekhuijzen, MEW, 2003) and teratogenicity study using doses of 0, 0.3 %, 1 % and 3 % in the diet. These two studies did not reveal treatment related findings ip to the dose level of 200 mg/kg bw/day or 0.3% (nominal) in diet (corresponding to 205.88 mg/kg bw/day). Thus, even at maternal toxic doses, no indications were noted that 4-AMINO-2-HYDROXYTOLUENE may impair reproduction or can cause teratogenic effects in rats.

Justification for classification or non-classification

According to the results of the key study, the registered substance did not induce adverse effect in a teratogenicity study on rats, exposed orally.

In the rat teratogenicity study (Orsterburg, 1984), the NOAEL of 180 mg/kg bw for maternal and embryo-foetal effects was determined for 4-amino-2-hydroxytoluene.