Thymol

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Key, rat, OECD 422, NOAEL (fertility) > 200 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

22 MAR 1996

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Crj:CD, SPF

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) 8 wks
- Weight at study initiation: (P) Males: 333-371 g; Females: 193-221 g
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 25
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 3% gum arabic solution

Details on mating procedure:

no data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

males: 43 days
females: from 14 days before mating to day 3 of lactation

Frequency of treatment:

daily

Details on study schedule:

terminal kill:
males: 44 days
females: day 4 of lactation

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

8 mg/kg bw/day (actual dose received)

Dose / conc.:

40 mg/kg bw/day (actual dose received)

Dose / conc.:

200 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 males + 10 females/group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Doses were selected based on the results of a pre-test performed at doses of 30, 100 and 300 mg/kg bw/d.

Positive control:

none

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: every week and at termination of study

Oestrous cyclicity (parental animals):

estrous cycle in days was monitored

Sperm parameters (parental animals):

Parameters examined in P male parental generations: testis weight, epididymis weight

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals 42 d after commencement of treatment
- Maternal animals: All surviving animals at PND 4

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 3 were prepared for microscopic examination and weighed, respectively.

Statistics:

Bartlett, Kruskal-Wallis, Dunnett, Scheffé

Reproductive indices:

Mating index (%) = (Number of pairs with successful mating/number of pairs examined) x 100
Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating) x 100
Gestation index (%) = (Number of females with live pups/number of pregnant females) x 100
Implantation index (%) = (Number of implantation sites/number of corpora lutea) x 100

Offspring viability indices:

Delivery index (%) = (Number of pups delivered/number of implantation sites) x 100
Live birth index (%) = (Number of live pups on day 0/number of pups delivered) x 100
Viability index (%) = (Number of live pups on day 4/number of live pups on day 0) x 100

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Decreased locomotor activity and an ataxic gait in females were observed in the 200 mg/kg group.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

One male rat died in the 200 mg/kg group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A tendency for suppression of body weight gain in males was observed in the 200 mg/kg group.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

gavage administration

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

gavage administration

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Endocrine findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Decreased locomotor activity and an ataxic gait in females were observed in the 200 mg/kg group.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological examination revealed mucosal hyperplasia, inflammatory cell infiltration and edema in the forestomach of both sexes, involution of the thymus of females and an increase of fatty droplets in the fascicular zone of the adrenals of females in the 200 mg/kg group. In the 40 mg/kg group, similar histopathological changes were observed in the forestomach of both sexes and in the thymus of females (table 3).

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Description (incidence and severity):

The duration of the oestrous cycle was unchanged by treatment (table 4).

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

The compound exerted no effects on reproductive parameters such as the estrous cycle, mating index, fertility index, gestation length, number of corpora lutea or implatations, the implantation index, gestation index, delivery index, parturition or maternal behaviour. Birth weight and body weight gain tended to be low in the 200 mg/kg group neonates. This is considered to be caused by the higher litter size. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates (please refer to table 4 and 5).

Key result

Dose descriptor:

NOEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Remarks on result:

not measured/tested

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The slightly reduced viability index in the 200 mg/kg bw dose group on PND 4 (table 5) is considered to be caused by the higher litter size.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The slightly reduced body weight of the pups on PND 0 and PND 4 in the 200 mg/kg bw dose group (table 5) is considered to be caused by the higher litter size.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not examined

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOEL

Generation:

F1

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Marginally reduced birth weight at 200 mg/kg bw is considered to be related to higher litter size.

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Remarks on result:

not measured/tested

Critical effects observed:

not specified

Reproductive effects observed:

no

Table 1: Absolute and relative organ weights in rats treated orally with thymol m the combined repeat dose and reproductive/developmental toxicity screening test
Dose (mg/kg/day)	0	8	40	200
Male
Number of animals	10	9	10	9
Body weight (g)	528 ± 23.5	510±24.7	519 ± 46.4	506±27.7
Absolute organ weight
Pituitary (mg)	14.3 ± 1.36	14.4±1.30	14.2±0.99	14.7 ± 1.45
Thymus (mg)	356 ± 54.4	353 ± 82.8	361±108.4	391±67.6
Liver (g)	14.48 ± 1.277	13.37 ± 0.817	14.55 ± 2.130	14.12 ± 1.455
Kidney (g)	3.14±0.186	3.07 ± 0.330	3.34±0.437	3.20 ± 0.211
Adrenal (mg)	70.2 ± 9.05	63.5 ± 11.04	64.9 ± 8.16	65.7±10.00
Testis (g)	3.54 ± 0.210	3.45 ± 0.229	3.48 ± 0.398	3.55 ± 0.175
Prostate (g)	0.71 ±0.209	0.63 ± 0.132	0.65±0.109	0.73±0.251
Epididymis (g)	1.28 ± 0.069	1.28 ± 0.091	1.29 ± 0.129	1.27 ± 0.058
Relative organ weight
Pituitary (mg%)	2.7 ± 0.28	2.8 ± 0.23	2.8 ± 0.19	2.9 ± 0.26
Thymus (mg%)	67±9.9	69 ± 16.2	69 ± 17.0	78 ± 16.3
Liver (g%)	2.74 ± 0.185	2.62±0.174	2.79 ± 0.203	2.79 ± 0.186
Kidney (g%)	0.59±0.032	0.60 ± 0.061	0.64 ± 0.058	0.64 ± 0,060
Adrenal (mg%)	13.3±2.07	12.4 ± 1.88	12.6 ± 2.12	13.0±1.S4
Testis (g%)	0.67±0.052	0.68 ±0.070	0.67 ± 0.095	0.70 ± 0.037
Prostate (g%)	0.13 ± 0.039	0.12 ± 0.028	0.13±0.031	0.14 ± 0.047
Epididymis (g%)	0.24 ± 0.018	0.25 ± 0.022	0.25±0.030	0.25 ± 0.009
Female
Number of animals	10	10	10	8
Body weight (g)	313 ± 12.2	320±13.8	324 ± 11.5.	314±23.3
Absolute organ weight.
Pituitary (mg)	21.3±2.95	21.3±2.90	21.9±1.29	20.3±3.26
Thymus (mg.)	212 ± 56.5	232 ± 39.5	216±67.9	210 ± 79.7
Liver (g)	13.78±0.612	13.50 ± 1.493	15.09 ± 1.021	14.91 ± 1.189
Kidney (g)	1.98 ± 0.163	1.98 ± 0.134	2.02 ± 0.157	2.05 ± 0.180
Adrenal (mg)	71.7±11.83	71.9±9.19	77.7 ± 9.04	70.1 ± 9.05
Relative organ weight
Pituitary (mg%)	6.8 ± 0.94	6.7±0.80	6.8 ± 0.31	6.5±0.75
Thymus (mg%)	68 ± 18.3	73±12.4	67 ±22.6	65±22.8
Liver (g%)	4.41±0.172	4.22 ± 0.422	4.66 ± 0.259	4.75 ± 0.240
Kidney (g%)	0.63 ± 0.034	0.62±0.039	0.63 ± 0.038	0.65±0.073
Adrenal (mg%)	22.9 ± 3.33	22.5 ± 2.93	24.0 ± 2.60	22.3 ± 2.14
Values are expressed as Mean±S.D.

Table 2: Summary of necropsy findings in rats treated orally with thymol in the combined repeat dose and reproductive/developmental toxicity screening test
	Sex	Male					Female
Organ Findings	Fate	Scheduled sacrifice				Dead	Scheduled sacrifice
	Dose (mg/kg/day)	0	8	40	200	200	0	8	40	200
Number of animals		10	9	10	9	1#	10	10	10	9
Thymus
Small		0	0	0	0	0	0	0	1	1
Stomach
Thickening of wall in forestomach		0	0	0	9	1	0	0	0	1
Heart
Dilatation of atrium		0	0	0	0	1	0	0	0	0
Lung
Congestion		0	0	0	0	1	0	0	0	0
Liver
Congestion		0	0	0	0	1	0	0	0	0
Adrenal
Whitish		0	0	0	0	0	0	0	0	2
Brain
Dilatation of cerebral ventricle		0	0	0	1	0	0	0	0	0
#, One animal died at43days after commencement of treatment.

Table 3: Summary of histopathological findings in rats treated orally with thymol in the combined repeat dose and reproductive/developmental toxicity screening test
	Sex		Male					Female
Organ Findings	Fate		Scheduled sacrifice				Dead	Scheduled sacrifice
	Dose (mg/kg/day)		0	8	40	200	200	0	8	40	200
Number of animals			10	9	10	9	1*	10	10	10	9
Thymus
Involution		+	*	*	*	*	*	0	0	1	1
Stomach
Edema, forestomach		+	0	0	4	5	0	0/2&	0/5&	0/5&	0/5&
Erosion, forestomach		+	0	0	0	0	0	0/2	0/5	1/5	0/5
Hyperplasia, mucosa, forestomach		+	0	0	9	4	1	0/2	0/5	2/5	3/5
		++	0	0	0	5	0	0/2	0/5	0/5	1/5
Inflammatory cell infiltration, forestomach		+	0	0	6	9	0	0/2	0/5	0/5	2/5
Heart
Inflammatory cell infiltration, focal		+	6	*	*	1	0	0	*	*	1
Spleen
Extramedullar hematopoiesis		+	0	*	*	0	0	0	*	*	1
Lung
Congestive edema		++	*	*	*	*	1	*	*	*	*
Inflammatory cell infiltration		+	*	*	*	*	1	*	*	*	*
Liver
Congestion		+	0	*	*	0	1	0	*	*	0
Extramedullar hematopoiesis		+	0	*	*	0	0	0	*	*	1
Hemorrhage, focal		+	2	*	*	0	0	0	*	*	0
Microgranuloma		+	9	*	*	6	0	1	*	*	0
Kidney
Basophilic change, tubular epithelium		+	1	*	*	0	0	3	*	*	2
Calcification, corticomedullar junction		+	2	*	*	1	0	1	*	*	1
Cyst		+	1	*	*	0	0	1	*	*	0
Fibrosis, focal		+	0	*	*	0	0	1	*	*	1
Hyaline droplet, tubular elithelium		+	2	*	*	1	0	0	*	*	0
Testis
Atrophy, seminiferous tubule		+	1	*	*	0	0
Epididymis
Inflammatory cell infiltration		+	1	*	*	1	0
Prostate
Inflammatory cell infiltration		+	10	*	*	4	0
Pituitary
Cyst		+	0	*	*	0	0	0	*	*	1
Hyperplasia, rathke's pouch		+	1	*	*	0	0	0	*	*	0
Adrenal
Increase of fatty droplet, fascicular zone		+	0	*	*	0	0	0	0	0	1
Brain
Dilatation of cerebral ventricle		+	0	*	*	1	0	0	*	*	0
+, Slight; ++, Moderate; *, Not examined.
&, Number of animals showing lesion / number of animals examined.
#, One animal died at 43 days after commencement of treatment.

Table 4: Fertility and pregnancy data in rats treated orally with thymol in the combined repeat dose and reproductive/developmental toxicity screening test
Dose (mg/kg/day)	0	8	40	200
Estrous cycle (days)	4.3±0.41^c)	4.3 ± 0.35	4.6 ± 0.60	4.3 ± 0.42
Number of pairs examined	10	10	10	10
Number of pairs with successful mating	10	10	10	10
Mating index (%)^a)	100.0	100.0	100.0	100.0
Number of pregnant females	10	10	10	10
Fertility index (%)^b)	100.0	100.0	100.0	100.0
Pairing days until mating	2.3 ± 1.06	2.7 ± 1.16	3.0 ± 0.94	3.6 ± 3.89
Number of estrous stages without mating	0.0 ± 0.00	0.0 ± 0.00	0.0 ± 0.00	0.0 ± 0.00
a)  Mating index (%) = (Number of pairs with successful mating/number of pairs examined) x 100 b)  Fertility index (%) = (Number of pregnant animals/number of pairs with successful mating) x 100 c)  Values are expressed as Mean±S.D.

Table 5: Delivery and litter data in rats treated orally with thymol in the combined repeat dose and reproductive/developmental toxicity screening test
Dose (mg/kg/day)	0	8	40	200
Number of females examined	10	10	10	9
Number of females with live pups	10	10	10	8
Gestation index (%)^a)	100.0	100.0	100.0	88.9
Gestation length (days)	22.3 ± 0.48^f)	22.5 ± 0.53	22.4 ± 0.52	22.4 ± 0.52
Number of corpora lutea	17.2 ± 1.81	17.5±1.72	18.3 ± 2.26	17.9 ± 1.97
Number of implantation sites	15.9 ± 1.37	16.5 ± 1.95	17.2 ± 2.57	15.6 ± 4.58
Implantation index (%)^b)	92.9	94.4	93.9	86.9
Delivery index (%)^c)	96.7	90.7	93.5	84.9
Number of pups delivered	15.4 ± 1.78	15.0 ± 2.16	16.0 + 2.05	16.4 ± 1.77
Number of live pups on day 0	15.3 ± 1.70	14.8 ± 2.10	15.8 ± 1.81	16.1 ±1.73
Live birth index (%)^d)	99.4	98.7	99.0	98.5
Sex ratio (male/female)	0.83 (70/84)	0.74 (64/86)	1.05 (82/78)	0.87 (61/70)
Number of live pups on day 4	15.3 ± 1.70	14.6 ± 2.46	15.6 ± 1.90	15.3±1.98
Viability index on day 4 (%)^e)	100.0	98.3	98.7	94.9
Body weight of pups (g)
on day 0 male	6.8 ± 0.66	6.7 ± 0.53	6.5 ± 0.85	6.1 ± 0.56
female	6.4 ± 0.62	6.3 ± 0.52	6.1 ± 0.78	5.8 ± 0.46
on day 4 male	10.8 ±1.06	10.7 ± 1.07	10.5 ±1.09	9.7±1.29
female	10.2 ± 1.06	10.2 ±1.06	10.2 ± 1.11	9.3 ± 1.16
Body weight gain of pups (g)
day 0 to 4 male	4.1 ± 0.61	4.0 ± 0.59	4.0 ± 0.48	3.5 ± 0.79
female	3.8 ± 0.63	3.9 ± 0.57	4.1 ± 0.53	3.4 ± 0.78
a)   Gestation index (%) = (Number of females with live pups/number of pregnant females) x 100 b)   Implantation index (%) = (Number of implantation sites/number of corpora lutea) x 100 c)   Delivery index (%) = (Number of pups delivered/number of implantation sites) x 100 d)   Live birth index (%) = (Number of live pups on day0/number of pups delivered) x 100 e)   Viability index (%) = (Number of live pups on day4/number of live pups on day0) x 100 f)    Values are expressed as Mean + S.D.

Conclusions:

The NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day for parental males and females, and 200 mg/kg/day for offspring. The marginally reduced birth weight at 200 mg/kg bw was related to higher litter size.

Executive summary:

Thymol was studied for oral toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test according to OECD TG 422 at doses of 0 (vehicle), 8, 40, 200 mg/kg day.

The compound exerted no effects on reproductive parameters such as the estrous cycle, mating index, fertility index, gestation length, number of corpora lutea or implantations, the implantation index, gestation index, delivery index, parturition or maternal behaviour. Birth weight and body weight gain tended to be low in the 200 mg/kg group neonates. This is considered to be related to the higher litter size. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates.

The NOELs for reproductive and developmental toxicity are considered to be 200 mg/kg/day for parental males and females, and 200 mg/kg/day for offspring (marginaly reduced birth weight at 200 mg/kg bw was related to higher litter size).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a repeated dose study (Hagan 1967, see section 7.5.1), 5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks. After termination of the study gross and histopathological examination revealed no adverse effects on the reproductive organs (testis).

In an OECD combined repeated dose and reproductive/developmental toxicity test in rats with oral doses of 0 (vehicle), 8, 40, 200 mg/kg day, the highest applied dose of 200 mg/kg bw/d had no significant adverse effects on the reproductive organs (testis, epididymis, prostatate). Additional, thymol exerted no effects on reproductive parameters such as the estrous cycle, mating index, fertility index, gestation lenght, number of corpora lutea or implantations, the implantation index, gestation index, delivery index, parturition or maternal behaviour. Birth weight and body weight gain tended to be low in the 200 mg/kg group neonates. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study planned

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out:
Thymol (CAS 89-83-8)

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Based on a recent literature search only the mentioned studies were available. No further information is available.

- Available GLP studies:
No GLP studies are available for the endpoint ‘developmental toxicity’. A repeated-dose and reproductive screening test according to OECD TG 422 is available. In this study no signs of teratogenicity were observed. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates up to the highest dose of 200 mg/kg bw/d. This study design, however, is not sufficient to cover the endpoint ‘developmental toxicity’.

- Available non-GLP studies:
The toxicity and teratogenicity of thymol was investigated by administration to developing chicken embryos (Verrett et al. 1980). Four test conditions were used: injection via air cell and via the yolk; and two times, preincubation 0 h and 96 h. For each condition, at least 100 embryos per dose level were treated at a minimum of five dose levels. Appropriate groups of vehicle controls and untreated controls were included in all experiments. All embryos and hatched chicks were examined grossly for any abnormalities in development, both functional and structural.
Injection into the fertile egg via the air cell and a preincubation time of 0 hours induced significant teratogenic effects. Up to 36% abnormal embryos (of 617) were found.
Injection into the fertile egg via the air cell and a preincubation time of 96 hours induced significant teratogenic effects. Up to 14% abnormal embryos (of 735) were found.
Injection into the fertile egg via the yolk sac and a preincubation time of 0 hours induced no significant teratogenic effects. Up to 16% abnormal embryos (of 575) were found.
Injection into the fertile egg via the yolk sac and a preincubation time of 96 hours induced no significant teratogenic effects. Up to 6% abnormal embryos (of 550) were found.

- Historical human/control data:
None available

- (Q)SAR:
No QSAR models allowing a profound prediction for the endpoint ‘developmental toxicity’ are available so far. Thus, no QSAR calculation can be used as stand-alone method to address this endpoint. However, existing rule-based models can give an indication for developmental toxicity potential. The ‘DART scheme’ implemented in the OECD QSAR Toolbox v 4.4 identifies the structure of thymol as an alert for ‘reproductive and developmental toxic potential’. However, this is just an indication based on similarity to known reproductive and developmental toxic chemicals identified by the model.

- In vitro methods:
No in vitro methods allowing a profound hazard assessment for the endpoint ‘developmental toxicity’ are available so far.

- Weight of evidence:
There are not sufficient data available for the endpoint ‘developmental toxicity’, which could be included in a weight-of-evidence approach.

- Grouping and read-across:
Potential read-across candidates were searched for using the OECD QSAR Toolbox v4.4. No adequate substances with robust data for the endpoint ‘developmental toxicity’ could be identified.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- According to Regulation EC No 1907/2006 (REACH) Annex IX point 8.7.2 the ‘Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414)’ is a standard requirement. No specific adaptation to omit this study is indicated in column 2.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- A study according to OECD TG 414 in rat (oral administration) is proposed.

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Thymol was studied for oral toxicity in rats in an OECD combined repeated dose and reproductive/developmental toxicity screening test at doses of 0 (vehicle), 8, 40, 200 mg/kg bw/day. Birth weight and body weight gain tended to be low in the 200 mg/kg bw/d group neonates - but the marginally reduced birth weight at 200 mg/kg bw was related to higher litter size. There were no significant differences in numbers of offspring or live offspring at birth, the sex ratio, live birth index or viability index. No abnormal findings ascribable to the compound were found on external examination, or in terms of clinical signs or necropsy finding for the neonates.

Justification for classification or non-classification

Based on the available studies, it is concluded that the substance does not need to be classified for reproductive toxicity according to Regulation (EC) No 1272/2008.