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Key value for chemical safety assessment

Effects on fertility

Description of key information

Data regarding effects of tetrahydronaphthalene on fertility are not available.

An extended one generation reproductive toxicity study (EOGRTS) according to OECD TG 443 is proposed.

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Study period:
after 06-2018
Justification for type of information:
Considerations that the general adaptation possibilities of Annex XI of the REACH Regulation are not adequate to generate the necessary information
• available GLP studies
No GLP studies on the test substance are available for the endpoint ‘reproductive toxicity’.

• available non-GLP studies
No non-GLP studies are available for the endpoint ‘reproductive toxicity’.

• historical human data
No human data suggesting reproductive toxicity are available for this substance.

• (Q)SAR
No validated (Q)SAR’s exist for this endpoint.

• in vitro methods
In accordance with ECHA’s guidance on the information requirements and chemical safety assessment, chapter R7a., the regulatory acceptance of in vitro studies for reproductive toxicity and approaches to replace the animal testing for reproductive toxicity has not been achieved as they do not provide equivalent information and thus, cannot be used alone for classification and labelling and/or risk assessment.

• weight of evidence
Insufficient reliable data are available to complete the IUCLID requirements as a weight of evidence approach.

• grouping and read-across
There are no other substances that are suitable for read-across or grouping. Structurally related substances such as naphthalene or decahydronaphthalene have to some extent similar properties but show on the other hand significant differences (e.g. water solubility, flammability, lipophilicity, acute toxicity, etc.)


• substance-tailored exposure driven testing [if applicable]
Based on hazard properties THN has to be handeled under controlled conditions, but exposure during (industrial) use of substance cannot strictly excluded.

Considerations that the specific adaptation possibilities of Annexes VI to X (and column 2 thereof) were not applicable:
Adaptation options as defined in Annexes VI to X were not applicable for this substance and this endpoint.

Until now there is no decision from ECHA available regarding the implementation of the extended one generation reproductive toxicity study (EOGRTS, OECD 443) with tetrahydronaphthalene.
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Version / remarks:
basic test design (Cohorts 1A, and 1B without extension)
Principles of method if other than guideline:
It is proposed to conduct the study with rats by using oral exposure.
Justification: In mice, uterus atrophy and atrophy of the ovary were found in a 13 weeks inhalation study. No such effects were found in a corresponding 13 weeks inhalation study with rats. In the 2-years inhalation study with mice no uterus atrophy and no ovary atrophy was observed at the same doses that are used in the 13 week inhalation study. Therefore, it can be concluded that these may be mice specific and transient effects.
However a 2 year inhalation study with rats showed effects on the uterus (incidences of stromal polyp and endometrium hyperplasia in the high dose group 660 mg/m³ were significantly greater than those in the chamber controls; see Chapter 7.7 "Carcinogenicity" of IUCLID and Chapter 5.8 of this CSR). Therefore, an effect of the substance on reproduction (fertility) cannot be excluded.

Furthermore it is proposed to conduct the study by using oral exposure because according to the toxicokinetic results the substance will be readiliy resorbed into the body and hence it is systemic available after oral gavage. Other exposure routes like nose-only inhalation exposure is technically not feasible especiallybecause very young and hence very small animals have to be used in this study.
Limit test:
no
Justification for study design:
Until now there is no decision from ECHA available regarding the implementation/study design of the extended one generation reproductive toxicity study (EOGRTS, OECD 443) with tetrahydronaphthalene.

Proposal for basic study design (Cohorts 1A, and 1B without extension):
10 weeks premating exposure duration for parental (P0) generation
- Dose level setting shall aim to induce some toxicity at the highest dose level
- Cohort 1A (Reproductive toxicity)
- Cohort 1B (Reproductive toxicity) without extension to mate the Cohort 1B animals to produce the F2 generation

- Route of administration: oral

- There is no trigger for Cohorts 2A/2B or Cohort 3.
Reproductive effects observed:
not specified
Additional information

Studies in Animals Effects on Fertility

Partly cited from SIAR to SIAM 19 (Berlin, 19-22 October 2004):

In a subchronic inhalation study, 25 male and 20 female Fischer 344 rats per dose level were exposed (whole body) to nominal 1,2,3,4-tetrahydronaphthalene concentrations of 7.5; 15; 30; 60; 120 ppm = 41.2; 82.4; 165; 330; 660 mg/m3 = exposure levels 1; 2; 3; 4; 5 for 13 weeks on 6 h/day, 5 days/week. Rats were subdivided into groups of 5 male renal toxicity rats + 10 male and 10 female core study rats + 10 male and 10 female clinical pathology rats. General test conditions and observations are reported above in chapter 3.1.5 of SIAR (annotation: and chapter 7.5.3 of IUCLID 5). In order to determine whether 1,2,3,4-tetrahydronaphthalene may be a reproductive toxicant, vaginal cytology was evaluated for 12 days during the last 2 weeks of the study in all females in the 0-, 30-, 60-, and 120-ppm groups. Epididymal sperm concentration, spermatid heads/testis, and left caudal, epididymal and testicular weights were evaluated in all males from the same groups. No indications of reproductive toxicity were reported (NTP, 1997). A similar subchronic inhalation study was performed by NTP (1997) in B6C3F1 mice, which were exposed whole-body in groups of 10 per dose and sex to nominal 1,2,3,4- tetrahydronaphthalene concentrations of 7.5; 15; 30; 60; 120 ppm = 41.2; 82.4; 165; 330; 660 mg/m3 = levels 1; 2; 3; 4; 5 for 13 weeks on 6 h/day, 5 days/week. General test conditions and observations are reported above in chapter 3.1.5 of SIAR (annotation: and chapter 7.5.3 of IUCLID 5). In order to determine whether 1,2,3,4-tetrahydronaphthalene may be a reproductive toxicant, vaginal cytology was evaluated for 12 days during the last 2 weeks of the study on all females in the 0-, 30-, 60-, and 120-ppm groups. Epididymal sperm concentration, spermatid heads/testis, and left caudal, epididymal & testicular weights were evaluated in all males from the same groups.

In histopathology, ovary and uterus atrophy was observed in high dose females. Incidences of ovary

atrophy at minimal doses of observation and above were 4/10 (330 mg/m3), and 8/10 (660 mg/m3).

Incidences of uterus atrophy at minimal doses of observation and above were 2/10 (82.4 mg/m3),

2/10 (165 mg/m3), 6/10 (330 mg/m3), and 8/10 (660 mg/m3). Information on severity is not

reported. No other indications of reproductive toxicity were reported.

Uterus atrophy and atrophy of the ovary were found in the absence of systemic toxicity in mice

but no such effect was evident in equal studies on rats. Furthermore in the 2-years inhalation study with mice no uterus atrophy and no ovary atrophy was observed at the same doses that are used in the 13 week inhalation study. Therefore, it can be concluded that these may be mice specific and transient effects. However a 2 year inhalation study with rats showed effects on the uterus (incidences of stromal polyp and endometrium hyperplasia in the high dose group 660 mg/m³ were significantly greater than those in the chamber controls; see Chapter 7.7 "Carcinogenicity" of IUCLID and Chapter 5.8 of this CSR). Therefore an effect of the substance on reproduction (fertility) cannot be excluded.


Short description of key information:
An extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension acc OECD TG 443 is proposed.
No specific studies have been performed on the toxicity of 1,2,3,4-tetrahydronaphthalene to fertility. There were no indications of an adverse effect on vaginal cytology, sperm and on reproductive organs from the 13-week inhalation study on rats. In mice, no effects on vaginal cytology and sperm were noted in the 13-week inhalation study, but uterus atrophy and atrophy of the ovary were found in the absence of systemic toxicity (cf. repeated dose section). In the 2-years inhalation study with mice no uterus atrophy and no ovary atrophy was observed at the same doses that are used in the 13 week inhalation study. Therefore, it can be concluded that these may be mice specific and transient effects. However a 2 year inhalation study with rats showed effects on the uterus (incidences of stromal polyp and endometrium hyperplasia in the high dose group 660 mg/m³ were significantly greater than those in the chamber controls; see Chapter 7.7 "Carcinogenicity" of IUCLID and Chapter 5.8 of this CSR). Therefore an effect of the substance on reproduction (fertility) cannot be excluded.

Effects on developmental toxicity

Description of key information
No adverse effects on development were observed in a teratogenicity study according to OECD TG 414 in rats at dose levels up to 135 mg/kg bw/d
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
135 mg/kg bw/day
Additional information

Partly cited from SIAR to SIAM 19 (Berlin, 19-22 October 2004:

Based on the results of the 28-day study in rats (Hüls AG, 1995 a), four groups of 24 mated female Sprague-Dawley rats received 1,2,3,4-tetrahydronaphthalene by daily oral administration (gavage) at 0 (sesame oil = control), 15, 45 and 135 mg/kg bw/day from day 6 to day 19 post-coitum inclusive. On day 20 post-coitum, the dams were sacrificed and subjected to macroscopic examination. The study was designed according to OECD TG 414 (2001) (Ehling, 2004).There was no treatment-related death in any of the dams. Clinical signs were not observed. Mean absolute and relative food consumption was distinctly to slightly decreased in high dose animals as compared to the controls, attaining statistical significance on study days 6 - 18 (absolute 6 - 9: 33 %: 9 - 13: -12 %; 13 - 16: -10 %; 16 - 18: -12 %; relative 6 - 9: -32 %; 9 - 13: - 10 %; 13 - 16: -7 %; 16 - 18: -9 %). In mid dose females, mean absolute and relative food consumption was slightly to marginally lower (statistically significant) during study days 6 - 9 (absolute: -15 %; relative: -16 %) and 13 - 16 (absolute and relative: -6 %) only. The terminal body weight (gestation day 20) was decreased in a statistically significant way (-5 %) for high dose females as compared to controls. A significantly lower body weight gain was recorded for the whole treatment period (0 - 20: -15 %).

Abortions, premature delivery or total resorptions were not observed in any of the test groups, nor were there any macroscopic findings that were ascribed to treatment with the test item. No treatment related effects were observed on pre- or post-implantation loss, fetal weight or sex-ratio. There was no statistically significant difference in the mean crown-rump length for either male or female fetuses in any group. However, evaluation of both genders together revealed a slight but statistically significant decrease of the mean crown-rump length for all high dose fetuses against the control. In addition, the mean placenta weight was slightly but statistically significant decreased in the high dose group. These findings were marginal and considered to be within the physiological range for this rat strain and age. However, a treatment-related influence on these endpoints could not be excluded. With respect to the fetuses, no test item related external or soft tissue malformations or variations were detected. Evaluation of skeletal defects revealed isolated findings of statistical significance for high-dose fetuses at the thoracic vertebra centra and in the rib (here also for low-dose fetuses): There was one tail aplasia in a fetus of a high dose female (1 fetus out of 152 examined, i.e. 0.7 %). This fetus also showed a large variety of other skeletal minor defects on the vertebra and skeletal retardations which were all associated with spina bifida occulta as the major defect diagnosis for this fetus. This complex finding was associated with insufficient oxygen supply of this fetus, which is known to occur incidentally during embryonal development within relatively large litters (14 fetuses in total in this litter). In the absence of correlating findings either in other fetuses or other litters of this group, these findings were considered to be incidental.

Minor skeletal defects of statistical significance included aplasia/fused/fragmented thoracic vertrebra centra in 0 % (control), 0.6 % (low dose), 0 % (mid dose), and 2.0 % (high dose) animals.

As the incidences were only slightly above inhouse control data (0 - 1.5 %) and did not follow a dose response relationship, they were considered to be incidental. Another minor defect of statistical significance was uni- or bilateral knoddy ribs in 0 % (control), 3.2 % (low dose), 0 % (mid dose), and 7.9 % (high dose) animals. As historical control data were not yet available for this

endpoint and the occurrence of this effect did not follow a dose response relationship, it was considered to be incidental.

The NOAEL for maternotoxicity was 45 mg/kg bw/day and 135 mg/kg bw/day for embryonic development (Ehling, 2004).

Tetrahydronaphthalene did not show any developmental effects in a gavage study with rats

performed in accordance with OECD TG 414 (2001) up to and including the highest tested dose

level of 135 mg/kg bw/day. The NOAEL for maternal toxicity was 45 mg/kg bw/day, effects at

135 mg/kg bw/day were reduced food consumption and reduced body weight gain. The NOAEL for

developmental toxicity is 135 mg/kg bw/day. (Partly cited from SIAR to SIAM 19 (Berlin, 19-22 October 2004)

Studies in Humans

There were no studies available.

Justification for classification or non-classification

No specific studies have been performed on the toxicity of 1,2,3,4-tetrahydronaphthalene to

fertility. There were no indications of an adverse effect on vaginal cytology, sperm and on

reproductive organs from the 13-week inhalation study on rats. In mice, no effects on vaginal

cytology and sperm were noted in the 13-week inhalation study, but uterus atrophy and atrophy of

the ovary were found in the absence of systemic toxicity (cf. repeated dose section). In the 2-years inhalation study with mice no uterus atrophy and no ovary atrophy was observed at the same doses that are used in the 13 week inhalation study. Therefore, it can be concluded that these may be mice specific and transient effects. However a 2 year inhalation study with rats showed effects on the uterus (incidences of stromal polyp and endometrium hyperplasia in the high dose group 660 mg/m³ were significantly greater than those in the chamber controls; see Chapter 7.7 "Carcinogenicity" of IUCLID and Chapter 5.8 of this CSR). Therefore an effect of the substance on reproduction (fertility) cannot be excluded.

1,2,3,4-tetrahydronaphthalene did not show any developmental effects in a gavage study with rats

performed in accordance with OECD TG 414 (2001) up to and including the highest tested dose

level of 135 mg/kg bw/day. The NOAEL for maternal toxicity was 45 mg/kg bw/day, effects at

135 mg/kg bw/day were reduced food consumption and reduced body weight gain. The NOAEL for

developmental toxicity is 135 mg/kg bw/day.

Study results indicate that tetrahydronaphthalene has no adverse effects on development.Therefore no classification regarding development is required.

Data on fertility are lacking. An extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension) in rats according to OECD TG 443 is proposed.